Clinical Review

Until recently, thyroid dysfunction was thought to have little influence on pregnancy as long as it was treated, and management was straightforward. That was before case-control studies in prominent journals suggested an association between even subclinical hypothyroidism and impaired neonatal neurodevelopment.^1-4

The risk associated with hyperthyroidism in pregnancy is less clear. Currently, it is believed to cause no adverse effects; the low thyroid-stimulating hormone (TSH) resolves in most women within 4 to 12 weeks.

As for the nonpregnant state, there is no agreement between the American College of Physicians and its British counterpart as to whether isolated, subclinical hyperthyroidism leads to morbidity or mortality, although some investigators have found an excess risk of atrial fibrillation and possibly increased bone loss in postmenopausal women. Treatment of hyperthyroidism in non-pregnant women is recommended only if low TSH persists after 4 to 12 weeks and the level is less than 0.1 mIU/L.⁵

This article discusses the detection and management of thyroid disease in pregnancy, concentrating on 2 representative cases. (See TABLE 1, for a list of the full spectrum of thyroid disorders.)

TABLE 1

The spectrum of thyroid disorders is wide

Hypothyroidism
Hashimoto’s or subacute thyroiditis
Subclinical hypothyroidism
Subclinical hypothyroxemia
Postpartum thyroiditis
Secondary hypothyroidism
Hypothalamic dysfunction Radioactive iodine therapy Thyroidectomy Iodine deficiency TSH receptor resistance/mutation
Hyperthyroidism
Grave’s disease
Subclinical hyperthyroidism
Thyroid storm
Secondary hyperthyroidism
TSH-producing pituitary adenoma Toxic multinodular goiter Toxic adenoma Subacute thyroiditis Metastatic follicular thyroid cancer Iodine excess Factitious/iatrogenic Thyroid hormone resistance syndrome Struma ovarii Gestational trophoblastic neoplasia Hyperemesis gravidarum

CASE 1: History of Graves’ disease

S.H., 32, is 6 weeks’ pregnant with her first child. She has a history of Graves’ disease, and underwent radioactive iodine treatment 10 years ago. She then became hypothyroid and has been on levothyroxine replacement for the past 9 years. She visits her endocrinologist annually and reports good control on 125 μg daily of oral levothyroxine sodium.

How should her pregnancy be managed?

When the mother has a history of Graves’ disease, regardless of her current thyroid state, 1% to 5% of newborns develop hyperthyroidism due to transplacental passage of thyroid-stimulating immunoglobulins (TSI). Fetal or neonatal hyperthyroidism is associated with fetal tachycardia (heart rate >160 bpm), poor growth, goiter, craniosynostosis, and advanced bone age. Therefore, fetal growth and heart rate should be monitored throughout pregnancy in these women. Investigators have published monograms on fetal thyroid measurement,⁶ and even argued that Doppler ultrasonography can differentiate between fetal hypo- and hyperthyroidism caused by drugs or disease processes.⁷ However, measurement of TSI levels (poor predictive value) and ultrasonography for fetal goiter (low yield) are controversial.

Another important consideration: The requirement for thyroxine hormone increases by approximately 30% in women on thyroid supplementation during pregnancy.⁸ This has been demonstrated in more than 9 studies, with athyrotic women experiencing greater increases than women with autoimmune hypothyroidism.⁹ The need for thyroxine increases as early as 5 weeks’ gestation and plateaus by 16 weeks.

Because hypothyroxemia or hypothyroidism (clinical or subclinical) may be associated with adverse neurodevelopment in the newborn, I recommend increasing the dosage of levothyroxine at the first encounter with this patient to 150 μg/day (<25% dosage increase). I also suggest measuring the baseline TSH level, if no reading is available from the past 3 months. If baseline TSH is less than 2.5 mIU/L, the dosage increase is probably adequate. If the TSH exceeds 2.5 mIU/L, however, I would ask the patient to take 1 extra pill (125 μg) on 2 days of the week (>30% dosage increase) and measure TSH again 4 to 6 weeks later (thyroxine takes 5 weeks to equilibrate after a change in dosage). Once the dosage has been adequately adjusted, I would monitor TSH every 6 to 8 weeks until delivery. At that time, the dosage should be reduced to the prepregnancy level, with TSH measured again in 4 to 6 weeks to confirm that the dosage is adequate.

Levothyroxine absorption is hampered by ferrous sulfate, aluminum hydroxide antacids, proton-pump inhibitors, and cholestyramine. Levothyroxine should be ingested at least 4 hours before or after the prenatal vitamin. The metabolism of levothyroxine is altered by phenytoin, carbamazepine, and rifampin.

Subclinical hypothyroidism can progress to overt disease

The majority of women with hypothyroidism are asymptomatic, with only 20% to 30% having any complaints, usually nonspecific (TABLE 2). Women with 1 or 2 symptoms are no more likely to have abnormal thyroid function tests than are asymptomatic women.

 

Overt hypothyroidism is primarily diagnosed with laboratory tests—specifically, low free thyroxine (FT₄) or free triiodothyronine (FT₃), or both, resulting in elevated TSH levels.

If untreated, overt hypothyroidism is associated with significant morbidity in both the nonpregnant and pregnant states (TABLE 3). Levothyroxine is easily administered and well tolerated, with no to few adverse effects with appropriate follow-up.¹⁰

In women with subclinical hypothyroidism, only 1 of the thyroid function tests is elevated—either elevated TSH with normal free thyroid hormone levels (mild thyroid failure) or normal TSH with low FT₄ levels (hypothyroxemia). Most cases of mild thyroid failure are thought to be related to thyroid dysfunction, whereas hypothyroxemia is usually associated with a deficiency of iodine.

Subclinical hypothyroidism can occur in women with a history of thyroid disease, after surgery or radioactive iodine therapy for toxic goiter, or as the result of an inadequate dosage of thyroid medication. It can also occur in women with no history of thyroid dysfunction, detected in routine testing in women with no symptoms or with nonspecific complaints that could be related to thyroid disease. Experts agree that women with secondary subclinical disease should be treated to achieve a euthyroid state because approximately 5% per year will develop overt disease. Considerable controversy clouds management of women with primary subclinical hypothyroidism.

Subclinical hypothyroidism is more common among white women (~67%) than among black women.

TABLE 2

Know these signs and symptoms of thyroid dysfunction

HYPOTHYROIDISM	HYPERTHYROIDISM
Fatigue	Resting tremors
Constipation	Hyperdefecation
Somnolence	Insomnia
Cold intolerance	Heat intolerance
Hair loss	Diaphoresis
Depression	Nervousness
Decreased libido	Palpitations
Menstrual irregularities
Weight gain despite poor appetite	Weight loss
Dry skin	Warm, moist skin
Deafness	Ophthalmopathy
Hoarseness	Sinus tachycardia
Paresthesia
Carpal tunnel syndrome
Periorbital puffiness
Slow cerebration or movement
Slowing ankle jerk	Hyperreflexia
Goiter	Thyromegaly

TABLE 3

Consequences of untreated thyroid dysfunction are significant

HYPOTHYROIDISM	HYPERTHYROIDISM
Nonpregnant state
Hyperlipidemia	Atrial fibrillation
Atherosclerosis	Congestive heart failure
Osteoporosis
Neuropsychiatric disorders	Neuropsychiatric disorders with or without dementia/Alzheimer’s disease
Reduced functional status and quality of life	Reduced functional status and quality of life
Pregnancy
Spontaneous abortion	Spontaneous abortion
Preterm delivery <32 weeks	Preterm labor
Low birth weight	Low birth weight
Perinatal morbidity and mortality	Stillbirth
Preeclampsia/gestational hypertension	Preeclampsia
Anovulation
Cesarean delivery
Postpartum hemorrhage
Placental abruption
Nonreassuring fetal heart rate tracing
Impaired neurodevelopment
Subclinical disease
Risk factor for overt disease	Risk factor for overt disease

Subclinical hyperthyroidism is more elusive

Overt hyperthyroidism can be detected through symptom-based screening (TABLE 2).

Subclinical hyperthyroidism is defined as low TSH with normal thyroid hormone levels. The pituitary appears to be more sensitive to the presence of thyroid hormones than to their absence. Subclinical hyperthyroidism is most common in black women and smokers. Approximately 50% of women with subclinical disease will have normal TSH levels several weeks to 1 year later.

Because subclinical hyperthyroidism can occur in up to 20% of women on thyroid replacement therapy, the dosage should be adjusted to achieve a euthyroid state.

CASE 2 Diabetes, with a family history of hypothyroidism

M.H., 30, is 12 weeks’ pregnant with her second child and reports a 12-year history of diabetes. Before she became pregnant, she was taking insulin, with HbA_1C=8.5%. Her history includes a mother with hypothyroidism.

How should she be managed?

Besides the obvious need for good diabetes control, this case merits screening for thyroid dysfunction, as the patient has 2 risk factors (TABLE 4).

One prominent controversy of the 21st century is whether all pregnant women should undergo routine screening for hypothyroidism. The controversy extends to screening all women of childbearing age.

TABLE 4

Risk factors for hypothyroidism include other autoimmune disorders

Family history of thyroid disease
More than 3 symptoms
History of postpartum thyroid disease
Type 1 diabetes mellitus
Recurrent spontaneous abortions
Unexplained intrauterine fetal demise
Other autoimmune disorders
Vitiligo Addison’s disease Pernicious anemia Multiple sclerosis Rheumatoid arthritis Sjögren’s disease

$64,000 question: Should all women be screened?

Screening would involve testing thyroid function in women with no history and few or no signs and symptoms of thyroid dysfunction. Such screening could be population-based (using special methods to recruit, contact, and follow patients) or case-finding (performed on patients who present for unrelated reasons). The decision to screen a woman who is pregnant or planning to conceive should be based on many factors, most notably whether treatment prevents impaired neonatal neurodevelopment and preterm delivery.

A mother’s elevated TSH level can have lasting effects in the child

Haddow and colleagues¹ measured the IQ of 47 children, ages 7 to 9 years, whose mothers had had an elevated serum TSH concentration in the second trimester, 15 children whose mothers had high serum TSH values in combination with low thyroxine levels in the second trimester, and 124 children whose mothers had normal TSH values. None of these children had hypothyroidism at birth. The children of the women with an elevated TSH concentration had lower IQs. Interestingly, the group with hypothyroxemia was not evaluated at the time, and the mean FT₄ level was low in the entire group, suggesting overt hypothyroidism rather than subclinical disease.

 

In a study from the Netherlands, Pop and associates² found impaired psychomotor function in 22 infants (age 10 months) whose mothers had had FT₄ below the 10th percentile at 12 weeks of gestation, compared with 194 infants whose mothers had normal readings. When these children were reevaluated at 2 years, no neurodevelopmental delay was found in the infants whose mothers had a spontaneously increased free thyroxine level after the first trimester.

There is much speculation about precisely when thyroid hormone is critical for fetal brain development. The study by Pop and associates² would suggest it is important after the first trimester. That study also recommends exogenous thyroxine for FT₄ values below 0.96 ng/mL (12 pmol/L).

In Italy, Vermiglio and coworkers¹¹ conducted behavioral and neuropsychological testing in 27 children at ages 18 to 36 months and again at 8 to 10 years. Mothers of 16 of these children were from a moderately iodine-deficient area (group A), and the mothers of 11 children were from a marginally iodine-sufficient area and were monitored with thyroid function tests in the first trimester (group B). Attention-deficit and hyperactivity disorders were more prevalent in group A.

Two studies published in 2006 also suggest that maternal free thyroxine levels in the first trimester of pregnancy correlate with impaired neonatal behavior at 3 months, and impaired mental development at ages 6, 9, and 12 months.^3,4

No consensus on whom to test or what test is best

There is no clear agreement about which population should be targeted for screening or what test to use. Most medical societies do not recommend routine screening, including the American College of Obstetricians and Gynecologists, which recommends TSH testing only in women with a history of thyroid disease and in women with “symptoms” (but does not specify which symptoms or how many symptoms warrant testing). A majority of organizations agree that all high-risk women should be tested when pregnancy is planned or as soon as pregnancy is confirmed.

TABLE 5

Comparison of screening recommendations highlights lack of consensus (and, in pregnancy, the absence of guidance)

YEAR	ORGANIZATION	NONPREGNANT STATE	PREGNANCY
1994	American Association of Clinical Endocrinologists (AACE), American Academy of Family Physicians	Periodic assessment via thyroid function tests in older women	No recommendation
1998	American College of Physicians	Office screening of women >50 years of age	No recommendation
2000	American Thyroid Association (ATA)	Measure TSH every 5 years in women age 35 and older (probably men also)	No recommendation
2002	American College of Obstetricians and Gynecologists	Measure TSH every 5 years in women age 65 and older	No screening recommended
2003	Institute of Medicine	Screening is not cost-effective in Medicare population	No recommendation
2004	United States Preventive Services Task Force	Routine screening of children and adults is not recommended	No recommendation
2004	AACE, ATA, the Endocrine Society Consensus Group	No population-based screening, but “aggressive case finding” in women at high risk and those over age 60	Do not support routine testing; recommend “aggressive case finding” and screening pregnant women at high risk

Proponents of routine screening argue that it may limit health risks to children and save money in the long run, and they point out that thyroid disease is easy to treat with pills. Opponents note that no cost-benefit analysis has been performed, the benefits of treating mild disease are unclear, and screening a large population could be a significant expense ($40–100 per person) and would necessitate a lifelong commitment to daily medication in asymptomatic patients.

As a diagnostic test, the TSH immunoassay has 98% sensitivity and 92% specificity, and the current third-generation test lacks biases between methods and does not require method-specific reference ranges. However, it has low predictive value as a screening test (7–25%), possibly because of multiple confounding variables. Despite being the “gold standard,” it can lead to falsely positive results.

TABLE 6

What makes a TSH measurement falsely high or low?

ELEVATED TSH	LOW TSH
Recovery from nonthyroidal illness	Euthyroid sick syndrome
Late evening TSH surge	Recovery from normal pregnancy
Assay variability
Adrenal insufficiency
Drugs: metoclopramide, amiodarone, cholecystographic dye (sodium ipodate)	Drugs: glucocorticoids, dopamine

As for the value of FT₄ alone as a screening test, we lack sufficient data on its utility. Another problem is that equilibrium dialysis, the most accurate and reliable laboratory method to measure FT₄, is too technically complex and expensive for routine use. The most widely used 2-step radioimmunoassay is automated, but different methods are used by different commercial laboratories, cutoffs vary for every laboratory, and the results are sensitive to abnormal binding-protein states such as pregnancy in a method-specific manner. Tandem mass spectrometry is as reliable as equilibrium dialysis, but is not yet readily available.¹²

 

Another consideration: The physiologic changes in pregnancy render the cutoffs for the nongravid state inapplicable. TSH is lower in pregnancy, whereas the FT₄ level is probably slightly increased or unchanged (TT₄ is 1.5 times the prepregnancy value).

The normal reference values in each trimester of pregnancy from iodine-sufficient, autoimmune thyroid antibody-negative women are becoming available for TSH,¹² as are nomograms that adjust for fetal number and gestational age.¹² The measurement of FT₄ still needs to be standardized across laboratories (method-specific, trimester-specific, and, possibly, population-specific reference ranges) for pregnancy.

How to manage subclinical thyroid disorders

In the nonpregnant state, subclinical hyperthyroidism should be treated in the following groups if the abnormal thyroid levels persist beyond 4 to 12 weeks and the TSH level is less than 0.1 mIU/L:

• High-risk women: postmenopausal or over age 60
• Low-risk women with cardiac disease, low bone density, or nodular thyroid disease.

If the TSH level is between 0.1 and 0.5 mIU/L, treatment is recommended for high-risk women with cardiac disease, low bone density, or nodular thyroid disease.

Subclinical hypothyroidism with a TSH level of 4.5 to 10 mIU/L need not be treated even in an elderly woman or a patient with a high antibody titer. Treatment of any woman is beneficial when the TSH level exceeds 10 mIU/L because it can ease symptoms, reduce low-density lipoprotein cholesterol, and prevent progression to overt disease. However, treatment may not lower morbidity and mortality and carries a roughly 20% risk of causing subclinical hyperthyroidism. It also involves a lifelong commitment to daily medication.

How to treat subclinical hypothyroidism in pregnancy

It is clear that overt hypothyroidism warrants treatment in both the pregnant and nonpregnant states, but the management of subclinical disease remains controversial. No trials have assessed the benefits of thyroid hormone replacement on the neuropsychological development of the newborn. Expert opinion suggests that women be treated if they are planning a pregnancy, are already pregnant, or have high TSH or low FT₄.

Until we have more data, pregnant women and those planning a pregnancy should be treated with levothyroxine (starting at 2 μg/kg/day) if they are found to have elevated TSH or low FT₄.

Two studies will answer questions about effects in pregnancy

The Controlled Antenatal Thyroid Screening (CATS) study will be completed in 2009, and the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (NICHD-MFMU) study will conclude in 2014. The CATS study screened 22,000 pregnant women in the United Kingdom before 16 weeks’ gestation. Half these women were treated with levothyroxine in pregnancy if they had a TSH measurement above the 97.5th percentile or FT₄ below the 2.5th percentile, and half had their blood samples stored and tested only after delivery.¹⁴ Cutoff values were derived from previously obtained antenatal sera from well-dated pregnancies, and were adjusted after every 2,000 to 3,000 samples.

The CATS study was conducted in an iodine-sufficient area with a median urinary iodine excretion of 100 μg/L (range: 11–240 μg/L). Each group contained 400 women with subclinical hypothyroidism (52% had low FT₄, 45% had high TSH, and 3% had both). Antithyroid peroxidase antibodies were present in 50% of women with elevated TSH but in only 10% of women with low FT₄. Neuropsychological development in their children is being tested at 3 years of age.

The NICHD-MFMU study plans to screen 110,000 women at 14 centers over 2 years, and will randomize roughly 1,000 women to thyroxine treatment or placebo. They plan to assess intellectual development of the infants yearly for 5 years, and test the mothers for postpartum thyroid dysfunction and follow them at 1 and 5 years to detect the rate of progression to overt hypothyroidism.

Postpartum dysfunction can be transient or permanent

Postpartum thyroid dysfunction (PPTD) is an autoimmune disorder that occurs at 13 to 19 weeks postpartum, affects 1 in 12 women worldwide, and is usually associated with psychiatric symptomatology.¹⁵

PPTD also is strongly associated with antithyroid peroxidase antibodies (TPOAbs).¹⁶ Premawardhana and colleagues found that 10% of women are TPOAbs-positive in the first trimester; of these, 50% develop PPTD. Of the women with PPTD, 20% to 30% develop permanent hypothyroidism, and an additional 30% to 40% develop it by 7 years. In contrast, only 5% of women without PPTD progress to overt disease by 7 years. These findings have generated considerable controversy about routine screening for PPTD. Proponents argue that PPTD is highly prevalent, linked to considerable morbidity, is easily diagnosed with relatively inexpensive tests, and is easy to treat effectively. Critics note the lack of consensus on the best screening test (thyroid function test versus TPOAbs), optimal timing of screening (early pregnancy or postpartum), and lack of high-quality, prospective cost-benefit analyses. The NICHD-MFMU hopes to resolve these controversies.

 

The author reports no financial relationships relevant to this article.

Until recently, thyroid dysfunction was thought to have little influence on pregnancy as long as it was treated, and management was straightforward. That was before case-control studies in prominent journals suggested an association between even subclinical hypothyroidism and impaired neonatal neurodevelopment.^1-4

The risk associated with hyperthyroidism in pregnancy is less clear. Currently, it is believed to cause no adverse effects; the low thyroid-stimulating hormone (TSH) resolves in most women within 4 to 12 weeks.

As for the nonpregnant state, there is no agreement between the American College of Physicians and its British counterpart as to whether isolated, subclinical hyperthyroidism leads to morbidity or mortality, although some investigators have found an excess risk of atrial fibrillation and possibly increased bone loss in postmenopausal women. Treatment of hyperthyroidism in non-pregnant women is recommended only if low TSH persists after 4 to 12 weeks and the level is less than 0.1 mIU/L.⁵

This article discusses the detection and management of thyroid disease in pregnancy, concentrating on 2 representative cases. (See TABLE 1, for a list of the full spectrum of thyroid disorders.)

TABLE 1

The spectrum of thyroid disorders is wide

Hypothyroidism
Hashimoto’s or subacute thyroiditis
Subclinical hypothyroidism
Subclinical hypothyroxemia
Postpartum thyroiditis
Secondary hypothyroidism
Hypothalamic dysfunction Radioactive iodine therapy Thyroidectomy Iodine deficiency TSH receptor resistance/mutation
Hyperthyroidism
Grave’s disease
Subclinical hyperthyroidism
Thyroid storm
Secondary hyperthyroidism
TSH-producing pituitary adenoma Toxic multinodular goiter Toxic adenoma Subacute thyroiditis Metastatic follicular thyroid cancer Iodine excess Factitious/iatrogenic Thyroid hormone resistance syndrome Struma ovarii Gestational trophoblastic neoplasia Hyperemesis gravidarum

CASE 1: History of Graves’ disease

S.H., 32, is 6 weeks’ pregnant with her first child. She has a history of Graves’ disease, and underwent radioactive iodine treatment 10 years ago. She then became hypothyroid and has been on levothyroxine replacement for the past 9 years. She visits her endocrinologist annually and reports good control on 125 μg daily of oral levothyroxine sodium.

How should her pregnancy be managed?

When the mother has a history of Graves’ disease, regardless of her current thyroid state, 1% to 5% of newborns develop hyperthyroidism due to transplacental passage of thyroid-stimulating immunoglobulins (TSI). Fetal or neonatal hyperthyroidism is associated with fetal tachycardia (heart rate >160 bpm), poor growth, goiter, craniosynostosis, and advanced bone age. Therefore, fetal growth and heart rate should be monitored throughout pregnancy in these women. Investigators have published monograms on fetal thyroid measurement,⁶ and even argued that Doppler ultrasonography can differentiate between fetal hypo- and hyperthyroidism caused by drugs or disease processes.⁷ However, measurement of TSI levels (poor predictive value) and ultrasonography for fetal goiter (low yield) are controversial.

Another important consideration: The requirement for thyroxine hormone increases by approximately 30% in women on thyroid supplementation during pregnancy.⁸ This has been demonstrated in more than 9 studies, with athyrotic women experiencing greater increases than women with autoimmune hypothyroidism.⁹ The need for thyroxine increases as early as 5 weeks’ gestation and plateaus by 16 weeks.

Because hypothyroxemia or hypothyroidism (clinical or subclinical) may be associated with adverse neurodevelopment in the newborn, I recommend increasing the dosage of levothyroxine at the first encounter with this patient to 150 μg/day (<25% dosage increase). I also suggest measuring the baseline TSH level, if no reading is available from the past 3 months. If baseline TSH is less than 2.5 mIU/L, the dosage increase is probably adequate. If the TSH exceeds 2.5 mIU/L, however, I would ask the patient to take 1 extra pill (125 μg) on 2 days of the week (>30% dosage increase) and measure TSH again 4 to 6 weeks later (thyroxine takes 5 weeks to equilibrate after a change in dosage). Once the dosage has been adequately adjusted, I would monitor TSH every 6 to 8 weeks until delivery. At that time, the dosage should be reduced to the prepregnancy level, with TSH measured again in 4 to 6 weeks to confirm that the dosage is adequate.

Levothyroxine absorption is hampered by ferrous sulfate, aluminum hydroxide antacids, proton-pump inhibitors, and cholestyramine. Levothyroxine should be ingested at least 4 hours before or after the prenatal vitamin. The metabolism of levothyroxine is altered by phenytoin, carbamazepine, and rifampin.

Subclinical hypothyroidism can progress to overt disease

The majority of women with hypothyroidism are asymptomatic, with only 20% to 30% having any complaints, usually nonspecific (TABLE 2). Women with 1 or 2 symptoms are no more likely to have abnormal thyroid function tests than are asymptomatic women.

 

Overt hypothyroidism is primarily diagnosed with laboratory tests—specifically, low free thyroxine (FT₄) or free triiodothyronine (FT₃), or both, resulting in elevated TSH levels.

If untreated, overt hypothyroidism is associated with significant morbidity in both the nonpregnant and pregnant states (TABLE 3). Levothyroxine is easily administered and well tolerated, with no to few adverse effects with appropriate follow-up.¹⁰

In women with subclinical hypothyroidism, only 1 of the thyroid function tests is elevated—either elevated TSH with normal free thyroid hormone levels (mild thyroid failure) or normal TSH with low FT₄ levels (hypothyroxemia). Most cases of mild thyroid failure are thought to be related to thyroid dysfunction, whereas hypothyroxemia is usually associated with a deficiency of iodine.

Subclinical hypothyroidism can occur in women with a history of thyroid disease, after surgery or radioactive iodine therapy for toxic goiter, or as the result of an inadequate dosage of thyroid medication. It can also occur in women with no history of thyroid dysfunction, detected in routine testing in women with no symptoms or with nonspecific complaints that could be related to thyroid disease. Experts agree that women with secondary subclinical disease should be treated to achieve a euthyroid state because approximately 5% per year will develop overt disease. Considerable controversy clouds management of women with primary subclinical hypothyroidism.

Subclinical hypothyroidism is more common among white women (~67%) than among black women.

TABLE 2

Know these signs and symptoms of thyroid dysfunction

HYPOTHYROIDISM	HYPERTHYROIDISM
Fatigue	Resting tremors
Constipation	Hyperdefecation
Somnolence	Insomnia
Cold intolerance	Heat intolerance
Hair loss	Diaphoresis
Depression	Nervousness
Decreased libido	Palpitations
Menstrual irregularities
Weight gain despite poor appetite	Weight loss
Dry skin	Warm, moist skin
Deafness	Ophthalmopathy
Hoarseness	Sinus tachycardia
Paresthesia
Carpal tunnel syndrome
Periorbital puffiness
Slow cerebration or movement
Slowing ankle jerk	Hyperreflexia
Goiter	Thyromegaly

TABLE 3

Consequences of untreated thyroid dysfunction are significant

HYPOTHYROIDISM	HYPERTHYROIDISM
Nonpregnant state
Hyperlipidemia	Atrial fibrillation
Atherosclerosis	Congestive heart failure
Osteoporosis
Neuropsychiatric disorders	Neuropsychiatric disorders with or without dementia/Alzheimer’s disease
Reduced functional status and quality of life	Reduced functional status and quality of life
Pregnancy
Spontaneous abortion	Spontaneous abortion
Preterm delivery <32 weeks	Preterm labor
Low birth weight	Low birth weight
Perinatal morbidity and mortality	Stillbirth
Preeclampsia/gestational hypertension	Preeclampsia
Anovulation
Cesarean delivery
Postpartum hemorrhage
Placental abruption
Nonreassuring fetal heart rate tracing
Impaired neurodevelopment
Subclinical disease
Risk factor for overt disease	Risk factor for overt disease

Subclinical hyperthyroidism is more elusive

Overt hyperthyroidism can be detected through symptom-based screening (TABLE 2).

Subclinical hyperthyroidism is defined as low TSH with normal thyroid hormone levels. The pituitary appears to be more sensitive to the presence of thyroid hormones than to their absence. Subclinical hyperthyroidism is most common in black women and smokers. Approximately 50% of women with subclinical disease will have normal TSH levels several weeks to 1 year later.

Because subclinical hyperthyroidism can occur in up to 20% of women on thyroid replacement therapy, the dosage should be adjusted to achieve a euthyroid state.

CASE 2 Diabetes, with a family history of hypothyroidism

M.H., 30, is 12 weeks’ pregnant with her second child and reports a 12-year history of diabetes. Before she became pregnant, she was taking insulin, with HbA_1C=8.5%. Her history includes a mother with hypothyroidism.

How should she be managed?

Besides the obvious need for good diabetes control, this case merits screening for thyroid dysfunction, as the patient has 2 risk factors (TABLE 4).

One prominent controversy of the 21st century is whether all pregnant women should undergo routine screening for hypothyroidism. The controversy extends to screening all women of childbearing age.

TABLE 4

Risk factors for hypothyroidism include other autoimmune disorders

Family history of thyroid disease
More than 3 symptoms
History of postpartum thyroid disease
Type 1 diabetes mellitus
Recurrent spontaneous abortions
Unexplained intrauterine fetal demise
Other autoimmune disorders
Vitiligo Addison’s disease Pernicious anemia Multiple sclerosis Rheumatoid arthritis Sjögren’s disease

$64,000 question: Should all women be screened?

Screening would involve testing thyroid function in women with no history and few or no signs and symptoms of thyroid dysfunction. Such screening could be population-based (using special methods to recruit, contact, and follow patients) or case-finding (performed on patients who present for unrelated reasons). The decision to screen a woman who is pregnant or planning to conceive should be based on many factors, most notably whether treatment prevents impaired neonatal neurodevelopment and preterm delivery.

A mother’s elevated TSH level can have lasting effects in the child

Haddow and colleagues¹ measured the IQ of 47 children, ages 7 to 9 years, whose mothers had had an elevated serum TSH concentration in the second trimester, 15 children whose mothers had high serum TSH values in combination with low thyroxine levels in the second trimester, and 124 children whose mothers had normal TSH values. None of these children had hypothyroidism at birth. The children of the women with an elevated TSH concentration had lower IQs. Interestingly, the group with hypothyroxemia was not evaluated at the time, and the mean FT₄ level was low in the entire group, suggesting overt hypothyroidism rather than subclinical disease.

 

In a study from the Netherlands, Pop and associates² found impaired psychomotor function in 22 infants (age 10 months) whose mothers had had FT₄ below the 10th percentile at 12 weeks of gestation, compared with 194 infants whose mothers had normal readings. When these children were reevaluated at 2 years, no neurodevelopmental delay was found in the infants whose mothers had a spontaneously increased free thyroxine level after the first trimester.

There is much speculation about precisely when thyroid hormone is critical for fetal brain development. The study by Pop and associates² would suggest it is important after the first trimester. That study also recommends exogenous thyroxine for FT₄ values below 0.96 ng/mL (12 pmol/L).

In Italy, Vermiglio and coworkers¹¹ conducted behavioral and neuropsychological testing in 27 children at ages 18 to 36 months and again at 8 to 10 years. Mothers of 16 of these children were from a moderately iodine-deficient area (group A), and the mothers of 11 children were from a marginally iodine-sufficient area and were monitored with thyroid function tests in the first trimester (group B). Attention-deficit and hyperactivity disorders were more prevalent in group A.

Two studies published in 2006 also suggest that maternal free thyroxine levels in the first trimester of pregnancy correlate with impaired neonatal behavior at 3 months, and impaired mental development at ages 6, 9, and 12 months.^3,4

No consensus on whom to test or what test is best

There is no clear agreement about which population should be targeted for screening or what test to use. Most medical societies do not recommend routine screening, including the American College of Obstetricians and Gynecologists, which recommends TSH testing only in women with a history of thyroid disease and in women with “symptoms” (but does not specify which symptoms or how many symptoms warrant testing). A majority of organizations agree that all high-risk women should be tested when pregnancy is planned or as soon as pregnancy is confirmed.

TABLE 5

Comparison of screening recommendations highlights lack of consensus (and, in pregnancy, the absence of guidance)

YEAR	ORGANIZATION	NONPREGNANT STATE	PREGNANCY
1994	American Association of Clinical Endocrinologists (AACE), American Academy of Family Physicians	Periodic assessment via thyroid function tests in older women	No recommendation
1998	American College of Physicians	Office screening of women >50 years of age	No recommendation
2000	American Thyroid Association (ATA)	Measure TSH every 5 years in women age 35 and older (probably men also)	No recommendation
2002	American College of Obstetricians and Gynecologists	Measure TSH every 5 years in women age 65 and older	No screening recommended
2003	Institute of Medicine	Screening is not cost-effective in Medicare population	No recommendation
2004	United States Preventive Services Task Force	Routine screening of children and adults is not recommended	No recommendation
2004	AACE, ATA, the Endocrine Society Consensus Group	No population-based screening, but “aggressive case finding” in women at high risk and those over age 60	Do not support routine testing; recommend “aggressive case finding” and screening pregnant women at high risk

Proponents of routine screening argue that it may limit health risks to children and save money in the long run, and they point out that thyroid disease is easy to treat with pills. Opponents note that no cost-benefit analysis has been performed, the benefits of treating mild disease are unclear, and screening a large population could be a significant expense ($40–100 per person) and would necessitate a lifelong commitment to daily medication in asymptomatic patients.

As a diagnostic test, the TSH immunoassay has 98% sensitivity and 92% specificity, and the current third-generation test lacks biases between methods and does not require method-specific reference ranges. However, it has low predictive value as a screening test (7–25%), possibly because of multiple confounding variables. Despite being the “gold standard,” it can lead to falsely positive results.

TABLE 6

What makes a TSH measurement falsely high or low?

ELEVATED TSH	LOW TSH
Recovery from nonthyroidal illness	Euthyroid sick syndrome
Late evening TSH surge	Recovery from normal pregnancy
Assay variability
Adrenal insufficiency
Drugs: metoclopramide, amiodarone, cholecystographic dye (sodium ipodate)	Drugs: glucocorticoids, dopamine

As for the value of FT₄ alone as a screening test, we lack sufficient data on its utility. Another problem is that equilibrium dialysis, the most accurate and reliable laboratory method to measure FT₄, is too technically complex and expensive for routine use. The most widely used 2-step radioimmunoassay is automated, but different methods are used by different commercial laboratories, cutoffs vary for every laboratory, and the results are sensitive to abnormal binding-protein states such as pregnancy in a method-specific manner. Tandem mass spectrometry is as reliable as equilibrium dialysis, but is not yet readily available.¹²

 

Another consideration: The physiologic changes in pregnancy render the cutoffs for the nongravid state inapplicable. TSH is lower in pregnancy, whereas the FT₄ level is probably slightly increased or unchanged (TT₄ is 1.5 times the prepregnancy value).

The normal reference values in each trimester of pregnancy from iodine-sufficient, autoimmune thyroid antibody-negative women are becoming available for TSH,¹² as are nomograms that adjust for fetal number and gestational age.¹² The measurement of FT₄ still needs to be standardized across laboratories (method-specific, trimester-specific, and, possibly, population-specific reference ranges) for pregnancy.

How to manage subclinical thyroid disorders

In the nonpregnant state, subclinical hyperthyroidism should be treated in the following groups if the abnormal thyroid levels persist beyond 4 to 12 weeks and the TSH level is less than 0.1 mIU/L:

• High-risk women: postmenopausal or over age 60
• Low-risk women with cardiac disease, low bone density, or nodular thyroid disease.

If the TSH level is between 0.1 and 0.5 mIU/L, treatment is recommended for high-risk women with cardiac disease, low bone density, or nodular thyroid disease.

Subclinical hypothyroidism with a TSH level of 4.5 to 10 mIU/L need not be treated even in an elderly woman or a patient with a high antibody titer. Treatment of any woman is beneficial when the TSH level exceeds 10 mIU/L because it can ease symptoms, reduce low-density lipoprotein cholesterol, and prevent progression to overt disease. However, treatment may not lower morbidity and mortality and carries a roughly 20% risk of causing subclinical hyperthyroidism. It also involves a lifelong commitment to daily medication.

How to treat subclinical hypothyroidism in pregnancy

It is clear that overt hypothyroidism warrants treatment in both the pregnant and nonpregnant states, but the management of subclinical disease remains controversial. No trials have assessed the benefits of thyroid hormone replacement on the neuropsychological development of the newborn. Expert opinion suggests that women be treated if they are planning a pregnancy, are already pregnant, or have high TSH or low FT₄.

Until we have more data, pregnant women and those planning a pregnancy should be treated with levothyroxine (starting at 2 μg/kg/day) if they are found to have elevated TSH or low FT₄.

Two studies will answer questions about effects in pregnancy

The Controlled Antenatal Thyroid Screening (CATS) study will be completed in 2009, and the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (NICHD-MFMU) study will conclude in 2014. The CATS study screened 22,000 pregnant women in the United Kingdom before 16 weeks’ gestation. Half these women were treated with levothyroxine in pregnancy if they had a TSH measurement above the 97.5th percentile or FT₄ below the 2.5th percentile, and half had their blood samples stored and tested only after delivery.¹⁴ Cutoff values were derived from previously obtained antenatal sera from well-dated pregnancies, and were adjusted after every 2,000 to 3,000 samples.

The CATS study was conducted in an iodine-sufficient area with a median urinary iodine excretion of 100 μg/L (range: 11–240 μg/L). Each group contained 400 women with subclinical hypothyroidism (52% had low FT₄, 45% had high TSH, and 3% had both). Antithyroid peroxidase antibodies were present in 50% of women with elevated TSH but in only 10% of women with low FT₄. Neuropsychological development in their children is being tested at 3 years of age.

The NICHD-MFMU study plans to screen 110,000 women at 14 centers over 2 years, and will randomize roughly 1,000 women to thyroxine treatment or placebo. They plan to assess intellectual development of the infants yearly for 5 years, and test the mothers for postpartum thyroid dysfunction and follow them at 1 and 5 years to detect the rate of progression to overt hypothyroidism.

Postpartum dysfunction can be transient or permanent

Postpartum thyroid dysfunction (PPTD) is an autoimmune disorder that occurs at 13 to 19 weeks postpartum, affects 1 in 12 women worldwide, and is usually associated with psychiatric symptomatology.¹⁵

PPTD also is strongly associated with antithyroid peroxidase antibodies (TPOAbs).¹⁶ Premawardhana and colleagues found that 10% of women are TPOAbs-positive in the first trimester; of these, 50% develop PPTD. Of the women with PPTD, 20% to 30% develop permanent hypothyroidism, and an additional 30% to 40% develop it by 7 years. In contrast, only 5% of women without PPTD progress to overt disease by 7 years. These findings have generated considerable controversy about routine screening for PPTD. Proponents argue that PPTD is highly prevalent, linked to considerable morbidity, is easily diagnosed with relatively inexpensive tests, and is easy to treat effectively. Critics note the lack of consensus on the best screening test (thyroid function test versus TPOAbs), optimal timing of screening (early pregnancy or postpartum), and lack of high-quality, prospective cost-benefit analyses. The NICHD-MFMU hopes to resolve these controversies.

 

The author reports no financial relationships relevant to this article.

Until recently, thyroid dysfunction was thought to have little influence on pregnancy as long as it was treated, and management was straightforward. That was before case-control studies in prominent journals suggested an association between even subclinical hypothyroidism and impaired neonatal neurodevelopment.^1-4

The risk associated with hyperthyroidism in pregnancy is less clear. Currently, it is believed to cause no adverse effects; the low thyroid-stimulating hormone (TSH) resolves in most women within 4 to 12 weeks.

As for the nonpregnant state, there is no agreement between the American College of Physicians and its British counterpart as to whether isolated, subclinical hyperthyroidism leads to morbidity or mortality, although some investigators have found an excess risk of atrial fibrillation and possibly increased bone loss in postmenopausal women. Treatment of hyperthyroidism in non-pregnant women is recommended only if low TSH persists after 4 to 12 weeks and the level is less than 0.1 mIU/L.⁵

This article discusses the detection and management of thyroid disease in pregnancy, concentrating on 2 representative cases. (See TABLE 1, for a list of the full spectrum of thyroid disorders.)

TABLE 1

The spectrum of thyroid disorders is wide

Hypothyroidism
Hashimoto’s or subacute thyroiditis
Subclinical hypothyroidism
Subclinical hypothyroxemia
Postpartum thyroiditis
Secondary hypothyroidism
Hypothalamic dysfunction Radioactive iodine therapy Thyroidectomy Iodine deficiency TSH receptor resistance/mutation
Hyperthyroidism
Grave’s disease
Subclinical hyperthyroidism
Thyroid storm
Secondary hyperthyroidism
TSH-producing pituitary adenoma Toxic multinodular goiter Toxic adenoma Subacute thyroiditis Metastatic follicular thyroid cancer Iodine excess Factitious/iatrogenic Thyroid hormone resistance syndrome Struma ovarii Gestational trophoblastic neoplasia Hyperemesis gravidarum

CASE 1: History of Graves’ disease

S.H., 32, is 6 weeks’ pregnant with her first child. She has a history of Graves’ disease, and underwent radioactive iodine treatment 10 years ago. She then became hypothyroid and has been on levothyroxine replacement for the past 9 years. She visits her endocrinologist annually and reports good control on 125 μg daily of oral levothyroxine sodium.

How should her pregnancy be managed?

When the mother has a history of Graves’ disease, regardless of her current thyroid state, 1% to 5% of newborns develop hyperthyroidism due to transplacental passage of thyroid-stimulating immunoglobulins (TSI). Fetal or neonatal hyperthyroidism is associated with fetal tachycardia (heart rate >160 bpm), poor growth, goiter, craniosynostosis, and advanced bone age. Therefore, fetal growth and heart rate should be monitored throughout pregnancy in these women. Investigators have published monograms on fetal thyroid measurement,⁶ and even argued that Doppler ultrasonography can differentiate between fetal hypo- and hyperthyroidism caused by drugs or disease processes.⁷ However, measurement of TSI levels (poor predictive value) and ultrasonography for fetal goiter (low yield) are controversial.

Another important consideration: The requirement for thyroxine hormone increases by approximately 30% in women on thyroid supplementation during pregnancy.⁸ This has been demonstrated in more than 9 studies, with athyrotic women experiencing greater increases than women with autoimmune hypothyroidism.⁹ The need for thyroxine increases as early as 5 weeks’ gestation and plateaus by 16 weeks.

Because hypothyroxemia or hypothyroidism (clinical or subclinical) may be associated with adverse neurodevelopment in the newborn, I recommend increasing the dosage of levothyroxine at the first encounter with this patient to 150 μg/day (<25% dosage increase). I also suggest measuring the baseline TSH level, if no reading is available from the past 3 months. If baseline TSH is less than 2.5 mIU/L, the dosage increase is probably adequate. If the TSH exceeds 2.5 mIU/L, however, I would ask the patient to take 1 extra pill (125 μg) on 2 days of the week (>30% dosage increase) and measure TSH again 4 to 6 weeks later (thyroxine takes 5 weeks to equilibrate after a change in dosage). Once the dosage has been adequately adjusted, I would monitor TSH every 6 to 8 weeks until delivery. At that time, the dosage should be reduced to the prepregnancy level, with TSH measured again in 4 to 6 weeks to confirm that the dosage is adequate.

Levothyroxine absorption is hampered by ferrous sulfate, aluminum hydroxide antacids, proton-pump inhibitors, and cholestyramine. Levothyroxine should be ingested at least 4 hours before or after the prenatal vitamin. The metabolism of levothyroxine is altered by phenytoin, carbamazepine, and rifampin.

Subclinical hypothyroidism can progress to overt disease

The majority of women with hypothyroidism are asymptomatic, with only 20% to 30% having any complaints, usually nonspecific (TABLE 2). Women with 1 or 2 symptoms are no more likely to have abnormal thyroid function tests than are asymptomatic women.

 

Overt hypothyroidism is primarily diagnosed with laboratory tests—specifically, low free thyroxine (FT₄) or free triiodothyronine (FT₃), or both, resulting in elevated TSH levels.

If untreated, overt hypothyroidism is associated with significant morbidity in both the nonpregnant and pregnant states (TABLE 3). Levothyroxine is easily administered and well tolerated, with no to few adverse effects with appropriate follow-up.¹⁰

In women with subclinical hypothyroidism, only 1 of the thyroid function tests is elevated—either elevated TSH with normal free thyroid hormone levels (mild thyroid failure) or normal TSH with low FT₄ levels (hypothyroxemia). Most cases of mild thyroid failure are thought to be related to thyroid dysfunction, whereas hypothyroxemia is usually associated with a deficiency of iodine.

Subclinical hypothyroidism can occur in women with a history of thyroid disease, after surgery or radioactive iodine therapy for toxic goiter, or as the result of an inadequate dosage of thyroid medication. It can also occur in women with no history of thyroid dysfunction, detected in routine testing in women with no symptoms or with nonspecific complaints that could be related to thyroid disease. Experts agree that women with secondary subclinical disease should be treated to achieve a euthyroid state because approximately 5% per year will develop overt disease. Considerable controversy clouds management of women with primary subclinical hypothyroidism.

Subclinical hypothyroidism is more common among white women (~67%) than among black women.

TABLE 2

Know these signs and symptoms of thyroid dysfunction

HYPOTHYROIDISM	HYPERTHYROIDISM
Fatigue	Resting tremors
Constipation	Hyperdefecation
Somnolence	Insomnia
Cold intolerance	Heat intolerance
Hair loss	Diaphoresis
Depression	Nervousness
Decreased libido	Palpitations
Menstrual irregularities
Weight gain despite poor appetite	Weight loss
Dry skin	Warm, moist skin
Deafness	Ophthalmopathy
Hoarseness	Sinus tachycardia
Paresthesia
Carpal tunnel syndrome
Periorbital puffiness
Slow cerebration or movement
Slowing ankle jerk	Hyperreflexia
Goiter	Thyromegaly

TABLE 3

Consequences of untreated thyroid dysfunction are significant

HYPOTHYROIDISM	HYPERTHYROIDISM
Nonpregnant state
Hyperlipidemia	Atrial fibrillation
Atherosclerosis	Congestive heart failure
Osteoporosis
Neuropsychiatric disorders	Neuropsychiatric disorders with or without dementia/Alzheimer’s disease
Reduced functional status and quality of life	Reduced functional status and quality of life
Pregnancy
Spontaneous abortion	Spontaneous abortion
Preterm delivery <32 weeks	Preterm labor
Low birth weight	Low birth weight
Perinatal morbidity and mortality	Stillbirth
Preeclampsia/gestational hypertension	Preeclampsia
Anovulation
Cesarean delivery
Postpartum hemorrhage
Placental abruption
Nonreassuring fetal heart rate tracing
Impaired neurodevelopment
Subclinical disease
Risk factor for overt disease	Risk factor for overt disease

Subclinical hyperthyroidism is more elusive

Overt hyperthyroidism can be detected through symptom-based screening (TABLE 2).

Subclinical hyperthyroidism is defined as low TSH with normal thyroid hormone levels. The pituitary appears to be more sensitive to the presence of thyroid hormones than to their absence. Subclinical hyperthyroidism is most common in black women and smokers. Approximately 50% of women with subclinical disease will have normal TSH levels several weeks to 1 year later.

Because subclinical hyperthyroidism can occur in up to 20% of women on thyroid replacement therapy, the dosage should be adjusted to achieve a euthyroid state.

CASE 2 Diabetes, with a family history of hypothyroidism

M.H., 30, is 12 weeks’ pregnant with her second child and reports a 12-year history of diabetes. Before she became pregnant, she was taking insulin, with HbA_1C=8.5%. Her history includes a mother with hypothyroidism.

How should she be managed?

Besides the obvious need for good diabetes control, this case merits screening for thyroid dysfunction, as the patient has 2 risk factors (TABLE 4).

One prominent controversy of the 21st century is whether all pregnant women should undergo routine screening for hypothyroidism. The controversy extends to screening all women of childbearing age.

TABLE 4

Risk factors for hypothyroidism include other autoimmune disorders

Family history of thyroid disease
More than 3 symptoms
History of postpartum thyroid disease
Type 1 diabetes mellitus
Recurrent spontaneous abortions
Unexplained intrauterine fetal demise
Other autoimmune disorders
Vitiligo Addison’s disease Pernicious anemia Multiple sclerosis Rheumatoid arthritis Sjögren’s disease

$64,000 question: Should all women be screened?

Screening would involve testing thyroid function in women with no history and few or no signs and symptoms of thyroid dysfunction. Such screening could be population-based (using special methods to recruit, contact, and follow patients) or case-finding (performed on patients who present for unrelated reasons). The decision to screen a woman who is pregnant or planning to conceive should be based on many factors, most notably whether treatment prevents impaired neonatal neurodevelopment and preterm delivery.

A mother’s elevated TSH level can have lasting effects in the child

Haddow and colleagues¹ measured the IQ of 47 children, ages 7 to 9 years, whose mothers had had an elevated serum TSH concentration in the second trimester, 15 children whose mothers had high serum TSH values in combination with low thyroxine levels in the second trimester, and 124 children whose mothers had normal TSH values. None of these children had hypothyroidism at birth. The children of the women with an elevated TSH concentration had lower IQs. Interestingly, the group with hypothyroxemia was not evaluated at the time, and the mean FT₄ level was low in the entire group, suggesting overt hypothyroidism rather than subclinical disease.

 

In a study from the Netherlands, Pop and associates² found impaired psychomotor function in 22 infants (age 10 months) whose mothers had had FT₄ below the 10th percentile at 12 weeks of gestation, compared with 194 infants whose mothers had normal readings. When these children were reevaluated at 2 years, no neurodevelopmental delay was found in the infants whose mothers had a spontaneously increased free thyroxine level after the first trimester.

There is much speculation about precisely when thyroid hormone is critical for fetal brain development. The study by Pop and associates² would suggest it is important after the first trimester. That study also recommends exogenous thyroxine for FT₄ values below 0.96 ng/mL (12 pmol/L).

In Italy, Vermiglio and coworkers¹¹ conducted behavioral and neuropsychological testing in 27 children at ages 18 to 36 months and again at 8 to 10 years. Mothers of 16 of these children were from a moderately iodine-deficient area (group A), and the mothers of 11 children were from a marginally iodine-sufficient area and were monitored with thyroid function tests in the first trimester (group B). Attention-deficit and hyperactivity disorders were more prevalent in group A.

Two studies published in 2006 also suggest that maternal free thyroxine levels in the first trimester of pregnancy correlate with impaired neonatal behavior at 3 months, and impaired mental development at ages 6, 9, and 12 months.^3,4

No consensus on whom to test or what test is best

There is no clear agreement about which population should be targeted for screening or what test to use. Most medical societies do not recommend routine screening, including the American College of Obstetricians and Gynecologists, which recommends TSH testing only in women with a history of thyroid disease and in women with “symptoms” (but does not specify which symptoms or how many symptoms warrant testing). A majority of organizations agree that all high-risk women should be tested when pregnancy is planned or as soon as pregnancy is confirmed.

TABLE 5

Comparison of screening recommendations highlights lack of consensus (and, in pregnancy, the absence of guidance)

YEAR	ORGANIZATION	NONPREGNANT STATE	PREGNANCY
1994	American Association of Clinical Endocrinologists (AACE), American Academy of Family Physicians	Periodic assessment via thyroid function tests in older women	No recommendation
1998	American College of Physicians	Office screening of women >50 years of age	No recommendation
2000	American Thyroid Association (ATA)	Measure TSH every 5 years in women age 35 and older (probably men also)	No recommendation
2002	American College of Obstetricians and Gynecologists	Measure TSH every 5 years in women age 65 and older	No screening recommended
2003	Institute of Medicine	Screening is not cost-effective in Medicare population	No recommendation
2004	United States Preventive Services Task Force	Routine screening of children and adults is not recommended	No recommendation
2004	AACE, ATA, the Endocrine Society Consensus Group	No population-based screening, but “aggressive case finding” in women at high risk and those over age 60	Do not support routine testing; recommend “aggressive case finding” and screening pregnant women at high risk

Proponents of routine screening argue that it may limit health risks to children and save money in the long run, and they point out that thyroid disease is easy to treat with pills. Opponents note that no cost-benefit analysis has been performed, the benefits of treating mild disease are unclear, and screening a large population could be a significant expense ($40–100 per person) and would necessitate a lifelong commitment to daily medication in asymptomatic patients.

As a diagnostic test, the TSH immunoassay has 98% sensitivity and 92% specificity, and the current third-generation test lacks biases between methods and does not require method-specific reference ranges. However, it has low predictive value as a screening test (7–25%), possibly because of multiple confounding variables. Despite being the “gold standard,” it can lead to falsely positive results.

TABLE 6

What makes a TSH measurement falsely high or low?

ELEVATED TSH	LOW TSH
Recovery from nonthyroidal illness	Euthyroid sick syndrome
Late evening TSH surge	Recovery from normal pregnancy
Assay variability
Adrenal insufficiency
Drugs: metoclopramide, amiodarone, cholecystographic dye (sodium ipodate)	Drugs: glucocorticoids, dopamine

As for the value of FT₄ alone as a screening test, we lack sufficient data on its utility. Another problem is that equilibrium dialysis, the most accurate and reliable laboratory method to measure FT₄, is too technically complex and expensive for routine use. The most widely used 2-step radioimmunoassay is automated, but different methods are used by different commercial laboratories, cutoffs vary for every laboratory, and the results are sensitive to abnormal binding-protein states such as pregnancy in a method-specific manner. Tandem mass spectrometry is as reliable as equilibrium dialysis, but is not yet readily available.¹²

 

Another consideration: The physiologic changes in pregnancy render the cutoffs for the nongravid state inapplicable. TSH is lower in pregnancy, whereas the FT₄ level is probably slightly increased or unchanged (TT₄ is 1.5 times the prepregnancy value).

The normal reference values in each trimester of pregnancy from iodine-sufficient, autoimmune thyroid antibody-negative women are becoming available for TSH,¹² as are nomograms that adjust for fetal number and gestational age.¹² The measurement of FT₄ still needs to be standardized across laboratories (method-specific, trimester-specific, and, possibly, population-specific reference ranges) for pregnancy.

How to manage subclinical thyroid disorders

In the nonpregnant state, subclinical hyperthyroidism should be treated in the following groups if the abnormal thyroid levels persist beyond 4 to 12 weeks and the TSH level is less than 0.1 mIU/L:

• High-risk women: postmenopausal or over age 60
• Low-risk women with cardiac disease, low bone density, or nodular thyroid disease.

If the TSH level is between 0.1 and 0.5 mIU/L, treatment is recommended for high-risk women with cardiac disease, low bone density, or nodular thyroid disease.

Subclinical hypothyroidism with a TSH level of 4.5 to 10 mIU/L need not be treated even in an elderly woman or a patient with a high antibody titer. Treatment of any woman is beneficial when the TSH level exceeds 10 mIU/L because it can ease symptoms, reduce low-density lipoprotein cholesterol, and prevent progression to overt disease. However, treatment may not lower morbidity and mortality and carries a roughly 20% risk of causing subclinical hyperthyroidism. It also involves a lifelong commitment to daily medication.

How to treat subclinical hypothyroidism in pregnancy

It is clear that overt hypothyroidism warrants treatment in both the pregnant and nonpregnant states, but the management of subclinical disease remains controversial. No trials have assessed the benefits of thyroid hormone replacement on the neuropsychological development of the newborn. Expert opinion suggests that women be treated if they are planning a pregnancy, are already pregnant, or have high TSH or low FT₄.

Until we have more data, pregnant women and those planning a pregnancy should be treated with levothyroxine (starting at 2 μg/kg/day) if they are found to have elevated TSH or low FT₄.

Two studies will answer questions about effects in pregnancy

The Controlled Antenatal Thyroid Screening (CATS) study will be completed in 2009, and the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (NICHD-MFMU) study will conclude in 2014. The CATS study screened 22,000 pregnant women in the United Kingdom before 16 weeks’ gestation. Half these women were treated with levothyroxine in pregnancy if they had a TSH measurement above the 97.5th percentile or FT₄ below the 2.5th percentile, and half had their blood samples stored and tested only after delivery.¹⁴ Cutoff values were derived from previously obtained antenatal sera from well-dated pregnancies, and were adjusted after every 2,000 to 3,000 samples.

The CATS study was conducted in an iodine-sufficient area with a median urinary iodine excretion of 100 μg/L (range: 11–240 μg/L). Each group contained 400 women with subclinical hypothyroidism (52% had low FT₄, 45% had high TSH, and 3% had both). Antithyroid peroxidase antibodies were present in 50% of women with elevated TSH but in only 10% of women with low FT₄. Neuropsychological development in their children is being tested at 3 years of age.

The NICHD-MFMU study plans to screen 110,000 women at 14 centers over 2 years, and will randomize roughly 1,000 women to thyroxine treatment or placebo. They plan to assess intellectual development of the infants yearly for 5 years, and test the mothers for postpartum thyroid dysfunction and follow them at 1 and 5 years to detect the rate of progression to overt hypothyroidism.

Postpartum dysfunction can be transient or permanent

Postpartum thyroid dysfunction (PPTD) is an autoimmune disorder that occurs at 13 to 19 weeks postpartum, affects 1 in 12 women worldwide, and is usually associated with psychiatric symptomatology.¹⁵

PPTD also is strongly associated with antithyroid peroxidase antibodies (TPOAbs).¹⁶ Premawardhana and colleagues found that 10% of women are TPOAbs-positive in the first trimester; of these, 50% develop PPTD. Of the women with PPTD, 20% to 30% develop permanent hypothyroidism, and an additional 30% to 40% develop it by 7 years. In contrast, only 5% of women without PPTD progress to overt disease by 7 years. These findings have generated considerable controversy about routine screening for PPTD. Proponents argue that PPTD is highly prevalent, linked to considerable morbidity, is easily diagnosed with relatively inexpensive tests, and is easy to treat effectively. Critics note the lack of consensus on the best screening test (thyroid function test versus TPOAbs), optimal timing of screening (early pregnancy or postpartum), and lack of high-quality, prospective cost-benefit analyses. The NICHD-MFMU hopes to resolve these controversies.

 

The author reports no financial relationships relevant to this article.

CASE Could bowel obstruction have been prevented?

B.H., 34, undergoes laparotomy for removal of an 8-cm myoma and a left ovarian cyst, which is found to be an endometrioma. Now she has come to the emergency department complaining of abdominal distension, pain, vomiting, and an inability to defecate. Small-bowel obstruction is diagnosed. Another laparotomy reveals that the obstructed bowel is adhered to the prior surgical incision.

Could this scenario have been avoided?

Adhesions need no introduction. Every surgeon is familiar with them; they are so ubiquitous they sometimes seem to be a given. Nevertheless, there are steps you can take to reduce the incidence of postoperative adhesions. In this article we describe surgical techniques, barriers, and peritoneal instillates that can help.

Why worry?

Intra-abdominal adhesions can cause pain, infertility, and bowel obstruction, and complicate future surgeries.^1-3 Most studies suggest that more than 50% of women with adhesion-related small bowel obstruction have a history of gynecologic or obstetric operations. Within 1 year of laparotomy, adhesions cause intestinal obstruction in 1% of patients. After even a single previous abdominal operation, 93% of patients develop adhesions, compared with only 10.4% of patients who have never undergone laparotomy (FIGURE 1).^1-3

We recently found an incidence of adhesion-related intestinal obstruction after operation for a benign gynecologic indication of 8 cases per 1,000 operations.⁴ Total abdominal hysterectomy (TAH) was the most common cause of small bowel obstruction (13.6 cases per 1,000 surgeries).

FIGURE 1 Adhesions through the laparoscope

Severe adhesions between the intestines and omentum to the uterus.

Omental adhesions to the anterior abdominal wall.

Adhesion between the intestine (lower left hand corner) and the anterior abdominal wall.

Surgical technique

Basic strategies

Tissue desiccation, necrosis, and the use of reactive suture material can predispose the patient to adhesion formation. Many studies in animal models have demonstrated an association between adhesions and these parameters. The following practices can help:

• Continuously irrigate the operative field during laparotomy
• Use nonreactive suture material such as polyglycolic acid (Dexon), polyglactin (Vicryl), or polydioxanone (PDS). Using reactive material, such as catgut, is discouraged
• Use powder-free gloves and prevent foreign-body infiltration (eg, powder, gauze, lint) of the wound.

No single parameter is as important as good surgical technique, attention to microsurgical principles, and precise hemostasis (TABLE 1).

TABLE 1

Surgical principles to reduce adhesion formation

Take a laparoscopic approach when feasible
Minimize tissue necrosis
Provide meticulous hemostasis
Liberally irrigate the abdominal cavity
Use nonreactive suture materials
When performing laparotomy Avoid contamination with glove powder, lint, or other foreign bodies Do not suture the peritoneum

Peritoneal closure is unnecessary

Several randomized trials have demonstrated that closure of the parietal or visceral peritoneum is unnecessary. This practice is associated with slightly longer operating times and greater postoperative pain and may cause more adhesions.⁵ In 1 study, the rate of adhesion formation after laparotomy with peritoneal closure was 22.2%, compared with 16% without closure.⁶

Ellis⁷ noted an increasing number of medicolegal claims arising from adhesion-related complications, and recommended that “peritoneal defects and the pelvic floor should be left open, since they rapidly reperitonealized.”

Laparoscopy is more protective than open surgery

Abdominal surgeries injure tissues more severely than laparoscopy, and are associated with a greater degree of adhesion formation in up to 94% of patients, although laparoscopy can also cause adhesions.² Laparoscopy is more protective because it involves minimal handling of tissue and little manipulation of the internal organs. Surgery is performed in a closed environment, tissue moistness is maintained, and contamination with glove powders or lint does not occur. In addition, the tamponade effect of carbon dioxide pneumoperitoneum facilitates hemostasis. Laparoscopy is also associated with a lower incidence of infection.

Adhesion-reducing substances

Many adhesion-reducing products have been evaluated in human and animal models. A basic assumption behind these substances is that surgically injured tissues heal without forming adhesions if the traumatized surfaces in apposition are separated to allow each to heal independently.

The ideal substance is resorbable, adherent to the traumatized surface, applicable through the laparoscope, and inexpensive, with high biocompatibility. So far, no substance or material has proved to be unequivocally effective.

Adhesion barriers are widely studied

The following products are among the most widely investigated substances (TABLE 2).

Expanded polytetrafluoroethylene, or ePTFE. Gore-Tex surgical membrane, constructed of ePTFE (Preclude, WL Gore), is nonabsorbable and produced in thin sheets (0.1 mm), with an average pore size of less than 1 μm. It is sutured to the tissue so that it overlaps the incision by at least 1 cm. It prevents adhesion formation—and reformation—independent of the type of injury. It is also effective in the presence of blood.

 

In a randomized trial, ePTFE decreased postmyomectomy and pelvic sidewall adhesions.^8,9 In our experience, this is the most effective adhesion-reducing substance available. It is not widely used, however, because it is nonabsorbable and has to be fixed to the tissue.

Combined hyaluronic acid (HA) and carboxymethylcellulose (CMC). Known most widely by its trade name, Seprafilm (Genzyme Corp), this bioresorbable product is composed of sodium HA and CMC, a combination that produces a transparent and absorbable membrane that lasts for 7 days after application.^10,11

In a study of 259 patients undergoing laparotomy for bowel resection or enterolysis, the incidence of repeat bowel obstruction was similar in the group treated with Seprafilm and the historical control group.¹¹ However, 9 of 12 bowel obstructions in the treated group resolved without surgery, compared with 5 of 12 in the control group. The enterolysis rate in the treated group was 1.5%, compared with 3.9% in the control group.

Because of its stickiness, Seprafilm is not ideal for laparoscopy. However, it can be rolled and passed through the trocar, with the film separated from its paper backing inside the abdominal cavity.

Oxidized regenerated cellulose. Known under the brand name Interceed (TC7), this absorbable adhesion barrier (Johnson & Johnson) is the most widely studied product available today. Several randomized trials have shown that it reduces postoperative formation of adhesions on the pelvic sidewalls and near the adnexa.^12-14

The efficacy of Interceed is reduced in the presence of blood. It is the easiest adhesion barrier to use at laparoscopy.

Newer agents in development include CMC and polyethylene oxide (PEO) composite gel (Oxiplex/AP, FrizoMed) and polylactide (PLa): copolymer of 70:30 Poly (L-lactide-co-D,L-lactide) film (SurgiWrap, Mast Biosurgery).

TABLE 2

The array of selected adhesion barriers and peritoneal instillates, and how they work

PRODUCT	SPECIAL FEATURES
Barriers
Expanded polytetrafluoroethylene (Preclude [Gore-Tex surgical membrane])	Very effective Nonreactive Nondegradable Requires fixation to the tissue Difficult to apply by laparoscopy Unpopular
Hyaluronic acid and carboxymethylcellulose (Seprafilm)	Blood-insensitive Brittle and sticky Difficult to use by laparoscopy
Oxidized regenerated cellulose (Interceed [TC7])	The most widely studied material Easy to handle Blood-sensitive
Instillates
4% icodextrin (Adept)	Requires high volume (1 L) Decreases adhesion formation and reformation after laparoscopic gynecologic surgery
Hyaluronic acid and ferric ion (InterGel)	Effective Withdrawn from market
HAL-C bioresorbable membrane (Sepracoat)	Absorbed within 7 days Reduces tissue desiccation
Hydrogel (SprayGel) to form membrane	Two polymers must be combined Sprayable Easy to use at laparoscopy Pivotal study stopped prior to completion
Hydrogel (Adhibit)	Not available in the US
Fibrin sealant (Tissucol)	Scarce data

Peritoneal instillates

The newest peritoneal instillate is 4% icodextrin solution (Adept, Baxter BioSurgery). It is FDA-approved for the reduction of adhesion reformation after laparoscopic adhesiolysis. In a randomized study, the authors found that instillation of 4% icodextrin solution decreased adhesion formation and reformation after laparoscopic gynecologic surgery.¹⁵

Hyaluronic acid. Intergel (Lifecore, Johnson & Johnson Gynecare) is a cross-linked HA with ferric ion. It effectively reduces the number, severity, and extent of adhesions after abdominal operation.¹⁶ However, the product was withdrawn from the market after several reports of late-onset postoperative pain requiring surgery.

Sepracoat. This product (HAL-C Bioresorbable Membrane, Genzyme Corp) is a modification of Seprafilm. It coats serosal surfaces and is absorbed from the peritoneal cavity within 7 days. Its mechanism of action includes the reduction of tissue desiccation. Preliminary data show it to be effective in reducing postoperative adhesions.¹⁷ However, it did not receive FDA approval for clinical use, and was withdrawn from the market in 1997.

Hydrogel. A novel technique of substance delivery into the abdominal cavity is by combining 2 streams of liquid polymers, delivered via catheter to target tissue. When combined, the 2 streams produce a solid polymer within minutes. Sprayable hydrogel (SprayGel, Confluent Surgical) can be easily applied at laparoscopy. The solid polymer acts as an adhesion barrier and can potentially serve as a vehicle for localized delivery of drugs.

In a randomized study, Mettler et al¹⁸ evaluated 66 women who underwent myomectomy with or without SprayGel application. Second-look laparoscopy was performed in 40 women. Seven of 22 patients (31.8%) in the SprayGel group and 2 of 18 patients (11.1%) in the control group remained free of adhesions. However, the power of this study is small, and the authors did not break the women into subgroups based on whether they underwent surgery via laparoscopy or laparotomy. In the United States, the pivotal study of SprayGel was stopped prior to completion.

A similar product is a sprayable selfpolymerizing gel called Adhibit (Angiotech). An unpublished study from Europe showed it to be promising.

Fibrin sealant. Fibrin glue (Tissucol, Baxter) has been used as an adhesion-reducing substance, although clinical data on this application are scarce. This product is not approved by the FDA.

Which operations are the biggest culprits?

 

Myomectomy

Myomectomy performed through a laparotomy incision usually causes adhesions, so women who undergo this operation are good candidates for adhesion-reducing substances. The rate of adhesion formation after abdominal myomectomy is more than 90%—and it is 70% by laparoscopy.

Two helpful preventive strategies:

• Use a laparoscopic approach when feasible, and
• apply a barrier, such as the Gore-Tex ePTFE membrane, Seprafilm, or, if the myomectomy incision is not oozing, Interceed. Instillation of 1 L of 4% icodextrin may also be useful.

Hysterectomy

Most small-bowel obstruction follows abdominal hysterectomy, although a considerable period of time may pass before the problem occurs. When it does, a general surgeon usually manages the patient, and the treating gynecologist is unaware of this serious complication.

We recently found an incidence of adhesion-related small-bowel obstruction of 14 cases per 1,000 total abdominal hysterectomies and 1 case per 1,000 vaginal hysterectomies (P<.001).⁴ We did not encounter any small-bowel obstruction among 303 cases of laparoscopic supracervical hysterectomy.

Application of an adhesion-reducing substance to the vaginal vault or cervical stump may prevent small-bowel obstruction. Most adhesions implicated in small-bowel obstruction involve the vaginal vault. Appropriate products include Interceed, Preclude, Seprafilm, or perhaps Adept.

Fertility-promoting surgery

No adhesion-reducing substance has proved to be effective in increasing the pregnancy rate after a fertility-promoting procedure such as reconstructive tubal surgery or surgery for endometriosis.

CASE Recommendations

B.H., the patient described at the beginning of this article, should have had her initial surgery performed by an experienced laparoscopist, with minimal coagulation, meticulous hemostasis, “layered” repair of the myomectomy incision using nonreactive sutures, and liberal irrigation of the abdominal cavity. At the conclusion of the operation, the incision could have been covered with Gore-Tex surgical membrane or Seprafilm (or Interceed if there was no oozing) at least 1 cm beyond the incision. Instillation of Adept might have been useful as well.

The second operation also should have involved a laparoscopic route, which is associated with a lower rate of adhesions and could have reduced her risk of further bowel obstruction.

The authors report no financial relationships relevant to this article.

CASE Could bowel obstruction have been prevented?

B.H., 34, undergoes laparotomy for removal of an 8-cm myoma and a left ovarian cyst, which is found to be an endometrioma. Now she has come to the emergency department complaining of abdominal distension, pain, vomiting, and an inability to defecate. Small-bowel obstruction is diagnosed. Another laparotomy reveals that the obstructed bowel is adhered to the prior surgical incision.

Could this scenario have been avoided?

Adhesions need no introduction. Every surgeon is familiar with them; they are so ubiquitous they sometimes seem to be a given. Nevertheless, there are steps you can take to reduce the incidence of postoperative adhesions. In this article we describe surgical techniques, barriers, and peritoneal instillates that can help.

Why worry?

Intra-abdominal adhesions can cause pain, infertility, and bowel obstruction, and complicate future surgeries.^1-3 Most studies suggest that more than 50% of women with adhesion-related small bowel obstruction have a history of gynecologic or obstetric operations. Within 1 year of laparotomy, adhesions cause intestinal obstruction in 1% of patients. After even a single previous abdominal operation, 93% of patients develop adhesions, compared with only 10.4% of patients who have never undergone laparotomy (FIGURE 1).^1-3

We recently found an incidence of adhesion-related intestinal obstruction after operation for a benign gynecologic indication of 8 cases per 1,000 operations.⁴ Total abdominal hysterectomy (TAH) was the most common cause of small bowel obstruction (13.6 cases per 1,000 surgeries).

FIGURE 1 Adhesions through the laparoscope

Severe adhesions between the intestines and omentum to the uterus.

Omental adhesions to the anterior abdominal wall.

Adhesion between the intestine (lower left hand corner) and the anterior abdominal wall.

Surgical technique

Basic strategies

Tissue desiccation, necrosis, and the use of reactive suture material can predispose the patient to adhesion formation. Many studies in animal models have demonstrated an association between adhesions and these parameters. The following practices can help:

• Continuously irrigate the operative field during laparotomy
• Use nonreactive suture material such as polyglycolic acid (Dexon), polyglactin (Vicryl), or polydioxanone (PDS). Using reactive material, such as catgut, is discouraged
• Use powder-free gloves and prevent foreign-body infiltration (eg, powder, gauze, lint) of the wound.

No single parameter is as important as good surgical technique, attention to microsurgical principles, and precise hemostasis (TABLE 1).

TABLE 1

Surgical principles to reduce adhesion formation

Take a laparoscopic approach when feasible
Minimize tissue necrosis
Provide meticulous hemostasis
Liberally irrigate the abdominal cavity
Use nonreactive suture materials
When performing laparotomy Avoid contamination with glove powder, lint, or other foreign bodies Do not suture the peritoneum

Peritoneal closure is unnecessary

Several randomized trials have demonstrated that closure of the parietal or visceral peritoneum is unnecessary. This practice is associated with slightly longer operating times and greater postoperative pain and may cause more adhesions.⁵ In 1 study, the rate of adhesion formation after laparotomy with peritoneal closure was 22.2%, compared with 16% without closure.⁶

Ellis⁷ noted an increasing number of medicolegal claims arising from adhesion-related complications, and recommended that “peritoneal defects and the pelvic floor should be left open, since they rapidly reperitonealized.”

Laparoscopy is more protective than open surgery

Abdominal surgeries injure tissues more severely than laparoscopy, and are associated with a greater degree of adhesion formation in up to 94% of patients, although laparoscopy can also cause adhesions.² Laparoscopy is more protective because it involves minimal handling of tissue and little manipulation of the internal organs. Surgery is performed in a closed environment, tissue moistness is maintained, and contamination with glove powders or lint does not occur. In addition, the tamponade effect of carbon dioxide pneumoperitoneum facilitates hemostasis. Laparoscopy is also associated with a lower incidence of infection.

Adhesion-reducing substances

Many adhesion-reducing products have been evaluated in human and animal models. A basic assumption behind these substances is that surgically injured tissues heal without forming adhesions if the traumatized surfaces in apposition are separated to allow each to heal independently.

The ideal substance is resorbable, adherent to the traumatized surface, applicable through the laparoscope, and inexpensive, with high biocompatibility. So far, no substance or material has proved to be unequivocally effective.

Adhesion barriers are widely studied

The following products are among the most widely investigated substances (TABLE 2).

Expanded polytetrafluoroethylene, or ePTFE. Gore-Tex surgical membrane, constructed of ePTFE (Preclude, WL Gore), is nonabsorbable and produced in thin sheets (0.1 mm), with an average pore size of less than 1 μm. It is sutured to the tissue so that it overlaps the incision by at least 1 cm. It prevents adhesion formation—and reformation—independent of the type of injury. It is also effective in the presence of blood.

 

In a randomized trial, ePTFE decreased postmyomectomy and pelvic sidewall adhesions.^8,9 In our experience, this is the most effective adhesion-reducing substance available. It is not widely used, however, because it is nonabsorbable and has to be fixed to the tissue.

Combined hyaluronic acid (HA) and carboxymethylcellulose (CMC). Known most widely by its trade name, Seprafilm (Genzyme Corp), this bioresorbable product is composed of sodium HA and CMC, a combination that produces a transparent and absorbable membrane that lasts for 7 days after application.^10,11

In a study of 259 patients undergoing laparotomy for bowel resection or enterolysis, the incidence of repeat bowel obstruction was similar in the group treated with Seprafilm and the historical control group.¹¹ However, 9 of 12 bowel obstructions in the treated group resolved without surgery, compared with 5 of 12 in the control group. The enterolysis rate in the treated group was 1.5%, compared with 3.9% in the control group.

Because of its stickiness, Seprafilm is not ideal for laparoscopy. However, it can be rolled and passed through the trocar, with the film separated from its paper backing inside the abdominal cavity.

Oxidized regenerated cellulose. Known under the brand name Interceed (TC7), this absorbable adhesion barrier (Johnson & Johnson) is the most widely studied product available today. Several randomized trials have shown that it reduces postoperative formation of adhesions on the pelvic sidewalls and near the adnexa.^12-14

The efficacy of Interceed is reduced in the presence of blood. It is the easiest adhesion barrier to use at laparoscopy.

Newer agents in development include CMC and polyethylene oxide (PEO) composite gel (Oxiplex/AP, FrizoMed) and polylactide (PLa): copolymer of 70:30 Poly (L-lactide-co-D,L-lactide) film (SurgiWrap, Mast Biosurgery).

TABLE 2

The array of selected adhesion barriers and peritoneal instillates, and how they work

PRODUCT	SPECIAL FEATURES
Barriers
Expanded polytetrafluoroethylene (Preclude [Gore-Tex surgical membrane])	Very effective Nonreactive Nondegradable Requires fixation to the tissue Difficult to apply by laparoscopy Unpopular
Hyaluronic acid and carboxymethylcellulose (Seprafilm)	Blood-insensitive Brittle and sticky Difficult to use by laparoscopy
Oxidized regenerated cellulose (Interceed [TC7])	The most widely studied material Easy to handle Blood-sensitive
Instillates
4% icodextrin (Adept)	Requires high volume (1 L) Decreases adhesion formation and reformation after laparoscopic gynecologic surgery
Hyaluronic acid and ferric ion (InterGel)	Effective Withdrawn from market
HAL-C bioresorbable membrane (Sepracoat)	Absorbed within 7 days Reduces tissue desiccation
Hydrogel (SprayGel) to form membrane	Two polymers must be combined Sprayable Easy to use at laparoscopy Pivotal study stopped prior to completion
Hydrogel (Adhibit)	Not available in the US
Fibrin sealant (Tissucol)	Scarce data

Peritoneal instillates

The newest peritoneal instillate is 4% icodextrin solution (Adept, Baxter BioSurgery). It is FDA-approved for the reduction of adhesion reformation after laparoscopic adhesiolysis. In a randomized study, the authors found that instillation of 4% icodextrin solution decreased adhesion formation and reformation after laparoscopic gynecologic surgery.¹⁵

Hyaluronic acid. Intergel (Lifecore, Johnson & Johnson Gynecare) is a cross-linked HA with ferric ion. It effectively reduces the number, severity, and extent of adhesions after abdominal operation.¹⁶ However, the product was withdrawn from the market after several reports of late-onset postoperative pain requiring surgery.

Sepracoat. This product (HAL-C Bioresorbable Membrane, Genzyme Corp) is a modification of Seprafilm. It coats serosal surfaces and is absorbed from the peritoneal cavity within 7 days. Its mechanism of action includes the reduction of tissue desiccation. Preliminary data show it to be effective in reducing postoperative adhesions.¹⁷ However, it did not receive FDA approval for clinical use, and was withdrawn from the market in 1997.

Hydrogel. A novel technique of substance delivery into the abdominal cavity is by combining 2 streams of liquid polymers, delivered via catheter to target tissue. When combined, the 2 streams produce a solid polymer within minutes. Sprayable hydrogel (SprayGel, Confluent Surgical) can be easily applied at laparoscopy. The solid polymer acts as an adhesion barrier and can potentially serve as a vehicle for localized delivery of drugs.

In a randomized study, Mettler et al¹⁸ evaluated 66 women who underwent myomectomy with or without SprayGel application. Second-look laparoscopy was performed in 40 women. Seven of 22 patients (31.8%) in the SprayGel group and 2 of 18 patients (11.1%) in the control group remained free of adhesions. However, the power of this study is small, and the authors did not break the women into subgroups based on whether they underwent surgery via laparoscopy or laparotomy. In the United States, the pivotal study of SprayGel was stopped prior to completion.

A similar product is a sprayable selfpolymerizing gel called Adhibit (Angiotech). An unpublished study from Europe showed it to be promising.

Fibrin sealant. Fibrin glue (Tissucol, Baxter) has been used as an adhesion-reducing substance, although clinical data on this application are scarce. This product is not approved by the FDA.

Which operations are the biggest culprits?

 

Myomectomy

Myomectomy performed through a laparotomy incision usually causes adhesions, so women who undergo this operation are good candidates for adhesion-reducing substances. The rate of adhesion formation after abdominal myomectomy is more than 90%—and it is 70% by laparoscopy.

Two helpful preventive strategies:

• Use a laparoscopic approach when feasible, and
• apply a barrier, such as the Gore-Tex ePTFE membrane, Seprafilm, or, if the myomectomy incision is not oozing, Interceed. Instillation of 1 L of 4% icodextrin may also be useful.

Hysterectomy

Most small-bowel obstruction follows abdominal hysterectomy, although a considerable period of time may pass before the problem occurs. When it does, a general surgeon usually manages the patient, and the treating gynecologist is unaware of this serious complication.

We recently found an incidence of adhesion-related small-bowel obstruction of 14 cases per 1,000 total abdominal hysterectomies and 1 case per 1,000 vaginal hysterectomies (P<.001).⁴ We did not encounter any small-bowel obstruction among 303 cases of laparoscopic supracervical hysterectomy.

Application of an adhesion-reducing substance to the vaginal vault or cervical stump may prevent small-bowel obstruction. Most adhesions implicated in small-bowel obstruction involve the vaginal vault. Appropriate products include Interceed, Preclude, Seprafilm, or perhaps Adept.

Fertility-promoting surgery

No adhesion-reducing substance has proved to be effective in increasing the pregnancy rate after a fertility-promoting procedure such as reconstructive tubal surgery or surgery for endometriosis.

CASE Recommendations

B.H., the patient described at the beginning of this article, should have had her initial surgery performed by an experienced laparoscopist, with minimal coagulation, meticulous hemostasis, “layered” repair of the myomectomy incision using nonreactive sutures, and liberal irrigation of the abdominal cavity. At the conclusion of the operation, the incision could have been covered with Gore-Tex surgical membrane or Seprafilm (or Interceed if there was no oozing) at least 1 cm beyond the incision. Instillation of Adept might have been useful as well.

The second operation also should have involved a laparoscopic route, which is associated with a lower rate of adhesions and could have reduced her risk of further bowel obstruction.

The authors report no financial relationships relevant to this article.

CASE Could bowel obstruction have been prevented?

B.H., 34, undergoes laparotomy for removal of an 8-cm myoma and a left ovarian cyst, which is found to be an endometrioma. Now she has come to the emergency department complaining of abdominal distension, pain, vomiting, and an inability to defecate. Small-bowel obstruction is diagnosed. Another laparotomy reveals that the obstructed bowel is adhered to the prior surgical incision.

Could this scenario have been avoided?

Adhesions need no introduction. Every surgeon is familiar with them; they are so ubiquitous they sometimes seem to be a given. Nevertheless, there are steps you can take to reduce the incidence of postoperative adhesions. In this article we describe surgical techniques, barriers, and peritoneal instillates that can help.

Why worry?

Intra-abdominal adhesions can cause pain, infertility, and bowel obstruction, and complicate future surgeries.^1-3 Most studies suggest that more than 50% of women with adhesion-related small bowel obstruction have a history of gynecologic or obstetric operations. Within 1 year of laparotomy, adhesions cause intestinal obstruction in 1% of patients. After even a single previous abdominal operation, 93% of patients develop adhesions, compared with only 10.4% of patients who have never undergone laparotomy (FIGURE 1).^1-3

We recently found an incidence of adhesion-related intestinal obstruction after operation for a benign gynecologic indication of 8 cases per 1,000 operations.⁴ Total abdominal hysterectomy (TAH) was the most common cause of small bowel obstruction (13.6 cases per 1,000 surgeries).

FIGURE 1 Adhesions through the laparoscope

Severe adhesions between the intestines and omentum to the uterus.

Omental adhesions to the anterior abdominal wall.

Adhesion between the intestine (lower left hand corner) and the anterior abdominal wall.

Surgical technique

Basic strategies

Tissue desiccation, necrosis, and the use of reactive suture material can predispose the patient to adhesion formation. Many studies in animal models have demonstrated an association between adhesions and these parameters. The following practices can help:

• Continuously irrigate the operative field during laparotomy
• Use nonreactive suture material such as polyglycolic acid (Dexon), polyglactin (Vicryl), or polydioxanone (PDS). Using reactive material, such as catgut, is discouraged
• Use powder-free gloves and prevent foreign-body infiltration (eg, powder, gauze, lint) of the wound.

No single parameter is as important as good surgical technique, attention to microsurgical principles, and precise hemostasis (TABLE 1).

TABLE 1

Surgical principles to reduce adhesion formation

Take a laparoscopic approach when feasible
Minimize tissue necrosis
Provide meticulous hemostasis
Liberally irrigate the abdominal cavity
Use nonreactive suture materials
When performing laparotomy Avoid contamination with glove powder, lint, or other foreign bodies Do not suture the peritoneum

Peritoneal closure is unnecessary

Several randomized trials have demonstrated that closure of the parietal or visceral peritoneum is unnecessary. This practice is associated with slightly longer operating times and greater postoperative pain and may cause more adhesions.⁵ In 1 study, the rate of adhesion formation after laparotomy with peritoneal closure was 22.2%, compared with 16% without closure.⁶

Ellis⁷ noted an increasing number of medicolegal claims arising from adhesion-related complications, and recommended that “peritoneal defects and the pelvic floor should be left open, since they rapidly reperitonealized.”

Laparoscopy is more protective than open surgery

Abdominal surgeries injure tissues more severely than laparoscopy, and are associated with a greater degree of adhesion formation in up to 94% of patients, although laparoscopy can also cause adhesions.² Laparoscopy is more protective because it involves minimal handling of tissue and little manipulation of the internal organs. Surgery is performed in a closed environment, tissue moistness is maintained, and contamination with glove powders or lint does not occur. In addition, the tamponade effect of carbon dioxide pneumoperitoneum facilitates hemostasis. Laparoscopy is also associated with a lower incidence of infection.

Adhesion-reducing substances

Many adhesion-reducing products have been evaluated in human and animal models. A basic assumption behind these substances is that surgically injured tissues heal without forming adhesions if the traumatized surfaces in apposition are separated to allow each to heal independently.

The ideal substance is resorbable, adherent to the traumatized surface, applicable through the laparoscope, and inexpensive, with high biocompatibility. So far, no substance or material has proved to be unequivocally effective.

Adhesion barriers are widely studied

The following products are among the most widely investigated substances (TABLE 2).

Expanded polytetrafluoroethylene, or ePTFE. Gore-Tex surgical membrane, constructed of ePTFE (Preclude, WL Gore), is nonabsorbable and produced in thin sheets (0.1 mm), with an average pore size of less than 1 μm. It is sutured to the tissue so that it overlaps the incision by at least 1 cm. It prevents adhesion formation—and reformation—independent of the type of injury. It is also effective in the presence of blood.

 

In a randomized trial, ePTFE decreased postmyomectomy and pelvic sidewall adhesions.^8,9 In our experience, this is the most effective adhesion-reducing substance available. It is not widely used, however, because it is nonabsorbable and has to be fixed to the tissue.

Combined hyaluronic acid (HA) and carboxymethylcellulose (CMC). Known most widely by its trade name, Seprafilm (Genzyme Corp), this bioresorbable product is composed of sodium HA and CMC, a combination that produces a transparent and absorbable membrane that lasts for 7 days after application.^10,11

In a study of 259 patients undergoing laparotomy for bowel resection or enterolysis, the incidence of repeat bowel obstruction was similar in the group treated with Seprafilm and the historical control group.¹¹ However, 9 of 12 bowel obstructions in the treated group resolved without surgery, compared with 5 of 12 in the control group. The enterolysis rate in the treated group was 1.5%, compared with 3.9% in the control group.

Because of its stickiness, Seprafilm is not ideal for laparoscopy. However, it can be rolled and passed through the trocar, with the film separated from its paper backing inside the abdominal cavity.

Oxidized regenerated cellulose. Known under the brand name Interceed (TC7), this absorbable adhesion barrier (Johnson & Johnson) is the most widely studied product available today. Several randomized trials have shown that it reduces postoperative formation of adhesions on the pelvic sidewalls and near the adnexa.^12-14

The efficacy of Interceed is reduced in the presence of blood. It is the easiest adhesion barrier to use at laparoscopy.

Newer agents in development include CMC and polyethylene oxide (PEO) composite gel (Oxiplex/AP, FrizoMed) and polylactide (PLa): copolymer of 70:30 Poly (L-lactide-co-D,L-lactide) film (SurgiWrap, Mast Biosurgery).

TABLE 2

The array of selected adhesion barriers and peritoneal instillates, and how they work

PRODUCT	SPECIAL FEATURES
Barriers
Expanded polytetrafluoroethylene (Preclude [Gore-Tex surgical membrane])	Very effective Nonreactive Nondegradable Requires fixation to the tissue Difficult to apply by laparoscopy Unpopular
Hyaluronic acid and carboxymethylcellulose (Seprafilm)	Blood-insensitive Brittle and sticky Difficult to use by laparoscopy
Oxidized regenerated cellulose (Interceed [TC7])	The most widely studied material Easy to handle Blood-sensitive
Instillates
4% icodextrin (Adept)	Requires high volume (1 L) Decreases adhesion formation and reformation after laparoscopic gynecologic surgery
Hyaluronic acid and ferric ion (InterGel)	Effective Withdrawn from market
HAL-C bioresorbable membrane (Sepracoat)	Absorbed within 7 days Reduces tissue desiccation
Hydrogel (SprayGel) to form membrane	Two polymers must be combined Sprayable Easy to use at laparoscopy Pivotal study stopped prior to completion
Hydrogel (Adhibit)	Not available in the US
Fibrin sealant (Tissucol)	Scarce data

Peritoneal instillates

The newest peritoneal instillate is 4% icodextrin solution (Adept, Baxter BioSurgery). It is FDA-approved for the reduction of adhesion reformation after laparoscopic adhesiolysis. In a randomized study, the authors found that instillation of 4% icodextrin solution decreased adhesion formation and reformation after laparoscopic gynecologic surgery.¹⁵

Hyaluronic acid. Intergel (Lifecore, Johnson & Johnson Gynecare) is a cross-linked HA with ferric ion. It effectively reduces the number, severity, and extent of adhesions after abdominal operation.¹⁶ However, the product was withdrawn from the market after several reports of late-onset postoperative pain requiring surgery.

Sepracoat. This product (HAL-C Bioresorbable Membrane, Genzyme Corp) is a modification of Seprafilm. It coats serosal surfaces and is absorbed from the peritoneal cavity within 7 days. Its mechanism of action includes the reduction of tissue desiccation. Preliminary data show it to be effective in reducing postoperative adhesions.¹⁷ However, it did not receive FDA approval for clinical use, and was withdrawn from the market in 1997.

Hydrogel. A novel technique of substance delivery into the abdominal cavity is by combining 2 streams of liquid polymers, delivered via catheter to target tissue. When combined, the 2 streams produce a solid polymer within minutes. Sprayable hydrogel (SprayGel, Confluent Surgical) can be easily applied at laparoscopy. The solid polymer acts as an adhesion barrier and can potentially serve as a vehicle for localized delivery of drugs.

In a randomized study, Mettler et al¹⁸ evaluated 66 women who underwent myomectomy with or without SprayGel application. Second-look laparoscopy was performed in 40 women. Seven of 22 patients (31.8%) in the SprayGel group and 2 of 18 patients (11.1%) in the control group remained free of adhesions. However, the power of this study is small, and the authors did not break the women into subgroups based on whether they underwent surgery via laparoscopy or laparotomy. In the United States, the pivotal study of SprayGel was stopped prior to completion.

A similar product is a sprayable selfpolymerizing gel called Adhibit (Angiotech). An unpublished study from Europe showed it to be promising.

Fibrin sealant. Fibrin glue (Tissucol, Baxter) has been used as an adhesion-reducing substance, although clinical data on this application are scarce. This product is not approved by the FDA.

Which operations are the biggest culprits?

 

Myomectomy

Myomectomy performed through a laparotomy incision usually causes adhesions, so women who undergo this operation are good candidates for adhesion-reducing substances. The rate of adhesion formation after abdominal myomectomy is more than 90%—and it is 70% by laparoscopy.

Two helpful preventive strategies:

• Use a laparoscopic approach when feasible, and
• apply a barrier, such as the Gore-Tex ePTFE membrane, Seprafilm, or, if the myomectomy incision is not oozing, Interceed. Instillation of 1 L of 4% icodextrin may also be useful.

Hysterectomy

Most small-bowel obstruction follows abdominal hysterectomy, although a considerable period of time may pass before the problem occurs. When it does, a general surgeon usually manages the patient, and the treating gynecologist is unaware of this serious complication.

We recently found an incidence of adhesion-related small-bowel obstruction of 14 cases per 1,000 total abdominal hysterectomies and 1 case per 1,000 vaginal hysterectomies (P<.001).⁴ We did not encounter any small-bowel obstruction among 303 cases of laparoscopic supracervical hysterectomy.

Application of an adhesion-reducing substance to the vaginal vault or cervical stump may prevent small-bowel obstruction. Most adhesions implicated in small-bowel obstruction involve the vaginal vault. Appropriate products include Interceed, Preclude, Seprafilm, or perhaps Adept.

Fertility-promoting surgery

No adhesion-reducing substance has proved to be effective in increasing the pregnancy rate after a fertility-promoting procedure such as reconstructive tubal surgery or surgery for endometriosis.

CASE Recommendations

B.H., the patient described at the beginning of this article, should have had her initial surgery performed by an experienced laparoscopist, with minimal coagulation, meticulous hemostasis, “layered” repair of the myomectomy incision using nonreactive sutures, and liberal irrigation of the abdominal cavity. At the conclusion of the operation, the incision could have been covered with Gore-Tex surgical membrane or Seprafilm (or Interceed if there was no oozing) at least 1 cm beyond the incision. Instillation of Adept might have been useful as well.

The second operation also should have involved a laparoscopic route, which is associated with a lower rate of adhesions and could have reduced her risk of further bowel obstruction.

The authors report no financial relationships relevant to this article.

In 1982, more than 20% of women surveyed in a nationally representative sample had discontinued oral contraceptives (OCs) on their own or at the recommendation of their physician due to bleeding or spotting.¹ Sadly, the percentage today has not decreased much.

Understandable concern, embarrassment, and annoyance lead these women to abandon OCs.^1,2 What they often don’t know, though, is that breakthrough bleeding generally is greatest in the first 3 to 4 months after starting OCs,³ and it steadily declines and stabilizes by the end of the fourth cycle.⁴ Timely counsel could enable many of these women to cope with the bleeding and stick with an effective contraceptive method. Additional incentives are noncontraceptive benefits of OCs: improved menstrual regularity and decreased menstrual blood loss, dysmenorrhea, and risk of ovarian and endometrial cancer.

Women who discontinue OCs on their own switch to less effective methods of birth control or use no method.^1,2 Consequences may be unexpected pregnancies and an increased abortion rate.⁵ With patients who are using an OC, it would be appropriate to ask periodically whether they are satisfied with OC use.

In this review, we discuss the mechanisms and management of breakthrough bleeding in women taking OCs, and provide tips for counseling that may help decrease the risk of discontinuation due to menstrual abnormalities in the initial months of use.

Breakthrough bleeding in this review refers to either unplanned spotting or bleeding, regardless of requirement for protection—unless defined otherwise by a specific study under discussion.

Four causes of bleeding

Breakthrough bleeding may be due to any the following variables:

1. physiologic effects of OCs on the endometrium,
   
2. OC-related parameters, including dose, formulation, and regimen,
   
3. patient behavior (including compliance, using concomitant medications, and smoking),
   
4. benign or malignant pathology.
   

OCs and the endometrium: Estrogen-progestin balance significant

Progestin and estrogen in combination OCs have profound effects on the endometrium that, although not contributing to contraception, do lead to a predictable pattern of bleeding or such problems as breakthrough bleeding or lack of withdrawal bleed.

Normally, estrogen causes the endometrium to proliferate. Progesterone stabilizes the growing uterine lining. Since the introduction of OCs in 1960, the trend in formulation has been to use the least amount of hormone necessary to inhibit ovulation. Given that the progestin is primarily responsible for the contraceptive efficacy of OCs, the risk of pregnancy is not altered with decreases in the estrogen component. However, significantly lowering the estrogen in OCs may account for breakthrough bleeding. Unplanned bleeding, though, is not dependent solely on the estrogen component, as variations in the progestin can contribute to breakthrough bleeding.⁷

 

Most OC users in the US take low-dose formulations, so designated because the estrogen component is 8 Studies that have compared OCs containing 20 μg ethinyl estradiol (EE) with those containing 30 μg or 35 μg EE have not been very useful for judging breakthrough bleeding rates because the products often also vary in the phasing and type of progestin. Some studies show more breakthrough bleeding with 20 μg EE pills,^9-11 but others show equal or improved cycle control with the lower EE dose.

Estrogen-progestin balance is more important than absolute level of estrogen.

Endrikat et al¹² conducted a study to compare two 20 μg EE pills containing different progestins, and to compare 2 levonorgestrel-based formulations with differing EE amounts. An OC of 20 μg EE/100 μg levonorgestrel was compared with a preparation of 20 μg EE/500 μg norethisterone. A 30 μg EE/150 μg levonorgestrel pill was used as a standard reference preparation.

Overall, the 30 μg EE preparation showed a lower cumulative incidence of breakthrough bleeding compared with the 20 μg EE/100 μg levonorgestrel and 20 μg EE/500 μg norethisterone pills over 13 cycles (1.0% vs 4.1% and 11.7%, respectively). However, the 20 μg EE/500 μg norethisterone pills consistently had a higher breakthrough bleeding rate than the 20 μg EE/100 μg levonorgestrel pill. This suggests that, although the higher EE component in the 30 μg pill was important when comparing 2 formulations with the same progestin, the difference in progestins of the two 20 μg EE pills was most likely responsible for the differing rates of breakthrough bleeding.

This study highlights the ability to achieve greater cycle control by titrating the EE component of an OC in a balanced ratio with the same progestin, but suggests that the absolute quantity of EE in a given pill may be less important than maintaining a balance between the 2 hormones or less important than the impact of different progestins on breakthrough bleeding rates.

The delicate balance between estrogen and progesterone supplementation required for contraception may also lead to progestin-induced decidualization and endometrial atrophy, which can result in asynchronous, erratic bleeding.^7,13 This has been primarily studied in long-acting progestin-only contraceptives such as implants. Alterations in angiogenic factors¹⁴ may play a role. Hysteroscopic studies have shown abnormalities in superficial endometrial blood vessels in terms of size, proliferation, and fragility in women using norplant.^13,15,16 Abnormalities in endothelial cells and extracellular matrix proteins,¹⁷ tissue factor,¹⁸ and endometrial lymphoid cells¹⁹ may contribute to breakthrough bleeding in progestin-dominant environments.

OC formulations, doses, regimens

More than 30 formulations of combination OCs are available in the US, with different doses and types of estrogen and progestin (TABLE 1).²⁰ Approved OCs have been studied in clinical trials to assess contraceptive efficacy and cycle control; however, comparisons between studies regarding bleeding phenomena are impaired by inconsistent terminology.³

Whereas some studies describe breakthrough bleeding and spotting according to their recognized definitions, others simply refer to intermenstrual bleeding or use spotting to refer to any unexpected bleeding. In addition, cycle control studies of OC users frequently do not account for the effects of missed pills, use of concomitant medications, or smoking. The percentage of women who experience breakthrough bleeding in a given cycle varies widely even in different trials of the same formulation.

Pay attention to progestin level. Conventional wisdom holds that OCs with the lowest doses of EE (≤20 μg) are associated with more breakthrough bleeding.¹¹ However, even moderately low doses of either EE or progestin can increase the incidence of breakthrough bleeding. For example, when 3 pills with the same estrogen and progestin (50 μg EE/100 μg norethindrone; 35 μg EE/100 μg norethindrone; and 35 μg EE/50 μg norethindrone) were compared in 192 women over 8 cycles, the pill containing the lowest amount of norethindrone (35 μg EE/50 μg norethindrone) caused the highest rates of breakthrough bleeding (decreasing to approximately 50% by cycle 8 as compared with 35% in the 35 μg EE/100 μg norethindrone pill and 25% in the 50 μg EE/100 μg norethindrone pill).²¹

In addition, the number of intermenstrual bleeding days plateaued more slowly as the amount of both hormones in the OC formulations decreased. This underscores the importance of the relative proportion of estrogen and progestin contained in combination OCs and its impact on breakthrough bleeding.

Similarly, a large comprehensive study in 1,991 women compared 7 different formulations of combination OCs containing different dose combinations of EE and norgestimate—20/250, 50/250, 35/125, 20/60, 50/60, 30/90, 25/125.²² Total intermenstrual bleeding was more frequent at lower doses of either estrogen or progestin. However, as long as a similar estrogen-progestin ratio was maintained, bleeding rates were considered acceptable (approximately 10% of days per cycle with bleeding). the authors also noted that in the low-dose range of OCs, small changes in the absolute amount of either EE or norgestimate might result in noticeable changes in bleeding

 

TABLE 1

Available OCs by formulation and regimen

TRADE NAME	GENERIC NAME(S)	ESTROGEN (DOSE)	PROGESTIN (DOSE)
MONOPHASIC
Alesse, Levlite	Aviane, Lessina	Ethinyl estradiol (20 μg)	Levonorgestrel (0.1 mg)
Mircette	Kariva	Ethinyl estradiol (20 μg × 21 days + 10 μg × 5 days during placebo week)	Desogestrel (0.15 mg)
Loestrin FE	Microgestin FE 1/20, June FE 1/20	Ethinyl estradiol (20 μg)	Norethindrone acetate (1 mg)
Yaz		Ethinyl estradiol (20 μg)	Drospirenone (3 mg)
Levlen, Nordette	Levora, Portia	Ethinyl estradiol (30 μg)	Levonorgestrel (0.15 mg)
Lo/Ovral	Low-ogestrel, Cryselle	Ethinyl estradiol (30 μg)	Norgestrel (0.3 mg)
Desogen, Ortho-cept	Apri	Ethinyl estradiol (30 μg)	Desogestrel (0.15 mg)
Loestrin 21 1/5/30	Microgestin, Junel Fe	Ethinyl estradiol (30 μg)	Norethindrone acetate (1.5 mg)
Yasmin		Ethinyl estradiol (30 μg)	Drospirenone (3 mg)
Ovcon 35		Ethinyl estradiol (35 μg)	Norethindrone (0.4 mg)
Ortho-Cyclen	Mononesessa, Sprintec	Ethinyl estradiol (35 μg)	Norgestimate (0.25 mg)
Brevicon, Modicon	Nortrel, Necon 0.5/35	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg)
Demulen 1/35	Zovia 1/35	Ethinyl estradiol (35 μg)	Ethynodiol diacetate (1 mg)
Ortho-Novum 1/35, Norinyl 1+35	Necon 1/35, Nortrel	Ethinyl estradiol (35 μg)	Norethindrone (1 mg)
Ortho-Novum 1/50	Necon 1/50	Ethinyl estradiol (50 μg)	Norethindrone (1 mg)
Ovral	Ogestrel	Ethinyl estradiol (50 μg)	Norgestrel (0.5 mg)
Ovcon 50		Ethinyl estradiol (50 μg)	Norethindrone (1 mg)
Demulen 1/50	Zovia 1/50	Ethinyl estradiol (50 μg)	Ethynodiol diacetate (1 mg)
Norinyl 1/50		Mestranol (50 μg)	Norethindrone (1 mg)
BIPHASIC
Ortho-Novum 10/11, Jenest	Necon 10/11, Nelova 10/11	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 10 days, 1 mg × 11 days)
TRIPHASIC
Ortho Tri-Cyclen Lo		Ethinyl estradiol (25 μg)	Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)
Cyclessa	Velivet	Ethinyl estradiol (25 μg)	Desogestrel (0.1 mg × 7 days, 0.125 mg × 7 days, 0.15 mg × 7 days)
Triphasil, Tri-Levlen	Trivora, Enpresse	Ethinyl estradiol (30 μg × 6 days, 40 μg × 5 days, 30 μg × 10 days)	Levonorgestrel (0.05 mg × 6 days, 0.075 mg × 5 days, 0.125 mg × 10 days)
Tri-Norinyl		Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 7 days, 1 mg × 9 days, 0.5 mg × 5 days)
Ortho Tri-Cyclen	Tri-Sprintec, TriNessa	Ethinyl estradiol (35 μg)	Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)
Ortho-Novum 7/7/7	Nortrel 7/7/7, Necon 7/7/7	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 7 days, 0.75 mg × 7 days, 1 mg × 7 days)
Estrostep FE		Ethinyl estradiol (20 μg × 5 days, 30 μg × 7 days, 35 μg × 9 days)	Norethindrone acetate (1 mg)
EXTENDED CYCLE
Seasonale		Ethinyl estradiol (30 μg × 84 days followed by 7 placebo pills)	Levonorgestrel (0.15 mg)
Seasonique		Ethinyl estradiol (30 μg × 84 days followed by 10 μg × 7 days)	Levonorgestrel (0.15 mg)

Type of progestin may affect breakthrough bleeding.

All combination OCs contain either EE or mestranol. However, a variety of progestins have come into use. The 2 most common contraceptive progestins are derived from 19-nortestosterone, and are classified as gonanes or estranes.²³

Estranes include norethindrone and its derivatives, norethindrone acetate and ethinyodiol diacetate. Gonanes include levonorgestrel, norgestrel, desogestrel, gestodene, and norgestimate.

Each progestin differs in half-life, estrogenic, progestogenic, and androgenic properties, and these variations may explain differing rates of breakthrough bleeding among formulations.⁴ As shown by Endrikat et al,¹² pills with the same quantity of EE but different progestins can have marked differences in breakthrough bleeding rates.

Although gonanes have greater progestational activity, no trial has determined which progestin has the best bleeding profile. A recent Cochrane review comparing different progestins did find that, compared with pills containing levonorgestrel, those containing gestodene may be associated with less intermenstrual bleeding.²⁴

Regardless of the progestin used or the quantity of EE, breakthrough bleeding generally decreases with each successive cycle. One study that compared 2 combination OCs composed of EE/norgestimate and EE/norgestrel demonstrated bleeding rates of 11.3% and 10.6% during the first 6 cycles, which decreased to 5.1% and 6.3% in cycles 13 to 24, respectively.²⁵ Additionally, all women using OCs can experience some cycles without a withdrawal bleed—a menstrual abnormality that may be concerning to those who desire a menstrual period as confirmation that they are not pregnant.

Comparing regimens. OC regimens are available as biphasic, triphasic, extended-cycle, and continuous use. Women using extended-cycle contraceptives may experience more breakthrough bleeding than those using a standard 28-day pill. However, in a 3-month cycle, there are only 7 days of planned bleeding. This is in contrast to 28-day cycles during 3 months in which there are 21 days of planned bleeding.

Though women on extended-cycle regimens may initially experience more breakthrough bleeding than women using 28-day regimens, the total number of planned and unplanned bleeding days may still decrease. Women using a 3-month cycle OC (30 μg EE/150 μg levonorgestrel) experienced more unscheduled bleeding than women using a standard 28-day cycle OC of the same formulation and dose.²⁶ The number of bleeding days decreased with each cycle. Another study examined continuous OC use (20 μg EE/100 μg levonorgestrel) over a period of 1 year, and reported a decreasing number of bleeding days over time.²⁷ In the case of continuous use, all bleeding is unscheduled, and any bleeding is considered breakthrough bleeding.

 

Multiphasic OC regimens were developed with the intention of decreasing breakthrough bleeding by mimicking the rising and falling pattern of estrogen and progesterone in the normal menstrual cycle.²⁸ After the introduction of the biphasic pill, an increase in breakthrough bleeding was noted, which led to the development of the triphasic pill.²⁹ Though the multiphasic hypothesis is physiologically plausible, recent reviews of the literature have found the evidence for its efficacy too limited and methodologically flawed to draw any definitive conclusions about a decrease in breakthrough bleeding.^30,31

Patient behaviors are contributory

Skipping a pill is a common cause of breakthrough bleeding.⁵ Compliance with any OC regimen is crucial to achieving a regular and predictable bleeding pattern. Of 6,676 women surveyed retrospectively, 19% reported missing 1 or more pills per cycle, and 10% reported missing 2 or more pills per cycle.³² Prospective studies have found even higher rates of inconsistent use.

TABLE 2

What to review with patients who are starting a combination OC

Breakthrough bleeding is common in the initial months after starting OCs Breakthrough bleeding, if experienced, usually diminishes over the first 3 months of OC use and abates by the 4th cycle Skipping even 1 pill can result in breakthrough bleeding Avoidance of breakthrough bleeding can be aided by taking your pill at the same time every day; you may find it helpful to make pill-taking part of another daily routine such as tooth brushing Tell me about other medications you are taking, including over-the-counter preparations and herbal supplements If you smoke, the chances of breakthrough bleeding are increased If bleeding continues beyond the 4th cycle, there are diagnostic tests available to explore possible underlying causes If bleeding continues without adequate explanation and despite adherence to the regimen, we can try switching you to a different formulation to see if that helps

When an electronic device was used to monitor pill ingestion, as many as 81% of women were found to miss at least 1 pill per cycle and up to 51% missed 3 or more pills per cycle.³³

Other side effects also undermine adherence. For example, women experiencing nausea may skip pills, which leads to breakthrough bleeding and, ultimately, discontinuation.³⁴ Patients need to understand the impact of skipping pills. Women who report irregular bleeding are 1.6 to 1.7 times more likely than those not reporting this side effect to miss 2 or more pills per cycle.⁵ Even 1 missed pill can increase the risk of bleeding irregularities.³⁵

Failure to take the pill at the same time every day and poor comprehension of pill-taking instructions are other strong predictors of inconsistent use and breakthrough bleeding.³²

Taking some prescription and over-the-counter medications, as well as herbal supplements, may interfere with the activity of OCs to alter bleeding patterns and contraceptive efficacy.³⁶ Medications that induce the cytochrome P-450 system (CYP450) in the liver increase the metabolism of OCs. Anticonvulsants, the antituberculosis agent rifampin, and antifungals such as griseofulvin can increase the clearance of steroid hormones and thus lead to breakthrough bleeding. the herbal supplement St. John’s wort, commonly used for mild or moderate depression, is associated with CYP450 induction. It has been shown to increase the incidence of breakthrough bleeding and probably ovulation in women taking an OC.³⁷

Smoking is associated with such anti-estrogenic effects as early menopause, osteoporosis, and menstrual abnormalities.³⁸ these effects may be related to induction of hepatic estrogen and progesterone metabolism by smoking.^39,40

Before receiving OCs, women are made aware of the relationship between smoking, OCs, and an increased risk of myocardial infarction, stroke, and venous thromboembolism.⁴¹ They should also understand that the anti-estrogenic effect of smoking may lower estrogen levels and lead to breakthrough bleeding, even in women who are reliable pill-takers.^42,43

Smoking appears to have a dose-response relationship with breakthrough bleeding. Increasing levels of smoking have been associated with an increased risk of spotting or bleeding in each cycle.⁴⁴ The difference in cycle control between smokers and nonsmokers appears to be more pronounced with each cycle. Smokers demonstrate a 30% elevation in the risk of bleeding irregularities compared with nonsmokers in the first cycle of use, which rises to an 86% increased risk by the sixth cycle.

Reports conflict regarding the relationship between smoking and contraceptive efficacy, suggesting that confounding factors like compliance may be more important than the antihormonal effect of cigarettes.⁴⁵ Nevertheless, women who smoke should be informed of this potential complicating factor to OC use and as yet another reason to encourage smoking cessation.

Bleeding is sometimes pathologic

When a woman experiences difficult cycle control after the first 3 to 4 months of OC use, consider the possibility of benign and malignant growths, including endometrial polyps, submucous myomas, and cervical or endometrial cancer.⁴⁶ Additionally, contraceptive failure must always be a consideration, and what appears to be breakthrough bleeding may actually represent bleeding in early pregnancy.

 

Cervicitis is an important but largely unrecognized source of unplanned bleeding in women using OCs. Causative organisms include Chlamydia trachomatis Neisseria gonorrhoeae, and Trichomonas vaginalis.²² Intermenstrual bleeding in women previously well controlled on OCs is particularly suggestive of asymptomatic chlamydial cervicitis.

Krettek et al⁴⁷ found that 29.2% of women who had been taking OCs for more than 3 months and presented with intermenstrual spotting had a positive test for C. trachomatis. By comparison, chlamydial cervicitis was found in 10.7% of matched controls taking OCs without spotting who were screened for symptoms of vaginitis or high-risk sexual behavior, and in just 6.1% of women undergoing routine screening before the initiation of contraception.

Three-pronged management

Managing breakthrough bleeding involves effective pretreatment; ongoing counseling and reassurance; and timely and appropriate testing (TABLE 2). In some cases, pill-switching or other forms of medical management may be helpful, but these options are largely unproven.

Counseling reduces anxiety, improves satisfaction, adherence

In a recent survey, 649 Canadian women who were picking up prescriptions for OCs were asked to complete a questionnaire at the pharmacy while they waited.⁴⁸ Over one third (34.5%) reported they had not received counseling from their healthcare provider about breakthrough bleeding. Furthermore, only 28.3% of women who were counseled, and 26.1% of women who were not counseled, gave the optimal response to breakthrough bleeding as defined in this study (“continue taking pill and not call my doctor”).

Lack of counseling can lead to poor method satisfaction and significant cost expenditures because of visits and phone calls by women experiencing unexpected bothersome side effects.⁵ Compared with women who reported the highest satisfaction with the care they received from their provider, those reporting the lowest scores were 1.6 to 2.2 times as likely to be dissatisfied with the pill.

Inform women that breakthrough bleeding is common in the first 3 or 4 cycles of OC use, that bleeding irregularities tend to decline with each successive cycle, and that they should not discontinue pill use without discussing their concerns with you. Remind women to keep sanitary protection with them during the first few months.

The impact of poor counseling was underscored in a study of women enrolled in clinical trials of OCs, contraceptive vaginal rings, and Depo-Provera. Women taking an OC were the least likely to have been warned of menstrual irregularities and thus tended to stop using that method more often than those using a ring or Depo-Provera.⁴⁹ Of women who discontinue OCs, 47% use a less effective method and 19% use no method at all.¹

Give specific instructions for specific regimens. Given the array of OC regimens available, make sure women know how to take them properly. This will help ensure contraceptive efficacy and cycle control. Women who do not understand pill-package instructions are up to 2.8 times more likely to miss pills, which increases the risk of breakthrough bleeding and impacts contraceptive efficacy.⁵ Among women who were counseled about the consequences of missed pills, 76% reported knowing what to do in response (“use another form of birth control that month”). Of women who received no such counseling, only 48% gave the appropriate response (P<.001>48

To improve adherence, advise women to establish a routine for pill-taking: taking the pill at the same time each day or linking pill ingestion with another daily activity, such as tooth brushing. Women without an established routine were 3.6 times more likely to miss 2 or more pills per cycle than women with a routine.⁵

Reassurance regarding efficacy

Reassure users who take their pills routinely that breakthrough bleeding and contraceptive efficacy are not linked.⁵⁰ Breakthrough bleeding is not a sign that OCs are not working.⁴ On the other hand, approximately 1 million unintended pregnancies in the United States each year are associated with misuse or discontinuation of OCs.⁵¹

When to consider diagnostic testing

For OC users who continue to experience breakthrough bleeding beyond 3 to 4 cycles, other potential causes must be ruled out using appropriate diagnostic tests. A pregnancy test, appropriate testing for cervical infection, pelvic ultrasonography, Pap smear, or endometrial biopsy may be warranted, depending on clinical circumstances.

Fall-back options

If breakthrough bleeding continues beyond 3 months, and other reasons, including poor adherence and pathologic processes, are excluded, one option would be to provide the patient with estrogen or switch her to a different pill, though no clinical trials support definitive recommendations.

Aside from changing from a multiphasic to a monophasic formulation, altering the progestin component is often a first step in trying to control breakthrough bleeding.⁴⁶ An OC with a gonane rather than an estrane progestin may be beneficial as this class of progestins may provide more consistent hormonal effects on the endometrium.

 

Choosing an OC with a higher quantity of ee may also help, particularly for women using 20 μg pills. When possible, the same progestin should be used.

You may want to start a trial of conjugated estrogen, 1.25 mg, or estradiol, 2 mg, administered for 7 days when bleeding occurs. This can be repeated if necessary; however, if breakthrough bleeding continues despite this treatment, consideration of a different pill or method should be undertaken.

In 1982, more than 20% of women surveyed in a nationally representative sample had discontinued oral contraceptives (OCs) on their own or at the recommendation of their physician due to bleeding or spotting.¹ Sadly, the percentage today has not decreased much.

Understandable concern, embarrassment, and annoyance lead these women to abandon OCs.^1,2 What they often don’t know, though, is that breakthrough bleeding generally is greatest in the first 3 to 4 months after starting OCs,³ and it steadily declines and stabilizes by the end of the fourth cycle.⁴ Timely counsel could enable many of these women to cope with the bleeding and stick with an effective contraceptive method. Additional incentives are noncontraceptive benefits of OCs: improved menstrual regularity and decreased menstrual blood loss, dysmenorrhea, and risk of ovarian and endometrial cancer.

Women who discontinue OCs on their own switch to less effective methods of birth control or use no method.^1,2 Consequences may be unexpected pregnancies and an increased abortion rate.⁵ With patients who are using an OC, it would be appropriate to ask periodically whether they are satisfied with OC use.

In this review, we discuss the mechanisms and management of breakthrough bleeding in women taking OCs, and provide tips for counseling that may help decrease the risk of discontinuation due to menstrual abnormalities in the initial months of use.

Breakthrough bleeding in this review refers to either unplanned spotting or bleeding, regardless of requirement for protection—unless defined otherwise by a specific study under discussion.

Four causes of bleeding

Breakthrough bleeding may be due to any the following variables:

1. physiologic effects of OCs on the endometrium,
   
2. OC-related parameters, including dose, formulation, and regimen,
   
3. patient behavior (including compliance, using concomitant medications, and smoking),
   
4. benign or malignant pathology.
   

OCs and the endometrium: Estrogen-progestin balance significant

Progestin and estrogen in combination OCs have profound effects on the endometrium that, although not contributing to contraception, do lead to a predictable pattern of bleeding or such problems as breakthrough bleeding or lack of withdrawal bleed.

Normally, estrogen causes the endometrium to proliferate. Progesterone stabilizes the growing uterine lining. Since the introduction of OCs in 1960, the trend in formulation has been to use the least amount of hormone necessary to inhibit ovulation. Given that the progestin is primarily responsible for the contraceptive efficacy of OCs, the risk of pregnancy is not altered with decreases in the estrogen component. However, significantly lowering the estrogen in OCs may account for breakthrough bleeding. Unplanned bleeding, though, is not dependent solely on the estrogen component, as variations in the progestin can contribute to breakthrough bleeding.⁷

 

Most OC users in the US take low-dose formulations, so designated because the estrogen component is 8 Studies that have compared OCs containing 20 μg ethinyl estradiol (EE) with those containing 30 μg or 35 μg EE have not been very useful for judging breakthrough bleeding rates because the products often also vary in the phasing and type of progestin. Some studies show more breakthrough bleeding with 20 μg EE pills,^9-11 but others show equal or improved cycle control with the lower EE dose.

Estrogen-progestin balance is more important than absolute level of estrogen.

Endrikat et al¹² conducted a study to compare two 20 μg EE pills containing different progestins, and to compare 2 levonorgestrel-based formulations with differing EE amounts. An OC of 20 μg EE/100 μg levonorgestrel was compared with a preparation of 20 μg EE/500 μg norethisterone. A 30 μg EE/150 μg levonorgestrel pill was used as a standard reference preparation.

Overall, the 30 μg EE preparation showed a lower cumulative incidence of breakthrough bleeding compared with the 20 μg EE/100 μg levonorgestrel and 20 μg EE/500 μg norethisterone pills over 13 cycles (1.0% vs 4.1% and 11.7%, respectively). However, the 20 μg EE/500 μg norethisterone pills consistently had a higher breakthrough bleeding rate than the 20 μg EE/100 μg levonorgestrel pill. This suggests that, although the higher EE component in the 30 μg pill was important when comparing 2 formulations with the same progestin, the difference in progestins of the two 20 μg EE pills was most likely responsible for the differing rates of breakthrough bleeding.

This study highlights the ability to achieve greater cycle control by titrating the EE component of an OC in a balanced ratio with the same progestin, but suggests that the absolute quantity of EE in a given pill may be less important than maintaining a balance between the 2 hormones or less important than the impact of different progestins on breakthrough bleeding rates.

The delicate balance between estrogen and progesterone supplementation required for contraception may also lead to progestin-induced decidualization and endometrial atrophy, which can result in asynchronous, erratic bleeding.^7,13 This has been primarily studied in long-acting progestin-only contraceptives such as implants. Alterations in angiogenic factors¹⁴ may play a role. Hysteroscopic studies have shown abnormalities in superficial endometrial blood vessels in terms of size, proliferation, and fragility in women using norplant.^13,15,16 Abnormalities in endothelial cells and extracellular matrix proteins,¹⁷ tissue factor,¹⁸ and endometrial lymphoid cells¹⁹ may contribute to breakthrough bleeding in progestin-dominant environments.

OC formulations, doses, regimens

More than 30 formulations of combination OCs are available in the US, with different doses and types of estrogen and progestin (TABLE 1).²⁰ Approved OCs have been studied in clinical trials to assess contraceptive efficacy and cycle control; however, comparisons between studies regarding bleeding phenomena are impaired by inconsistent terminology.³

Whereas some studies describe breakthrough bleeding and spotting according to their recognized definitions, others simply refer to intermenstrual bleeding or use spotting to refer to any unexpected bleeding. In addition, cycle control studies of OC users frequently do not account for the effects of missed pills, use of concomitant medications, or smoking. The percentage of women who experience breakthrough bleeding in a given cycle varies widely even in different trials of the same formulation.

Pay attention to progestin level. Conventional wisdom holds that OCs with the lowest doses of EE (≤20 μg) are associated with more breakthrough bleeding.¹¹ However, even moderately low doses of either EE or progestin can increase the incidence of breakthrough bleeding. For example, when 3 pills with the same estrogen and progestin (50 μg EE/100 μg norethindrone; 35 μg EE/100 μg norethindrone; and 35 μg EE/50 μg norethindrone) were compared in 192 women over 8 cycles, the pill containing the lowest amount of norethindrone (35 μg EE/50 μg norethindrone) caused the highest rates of breakthrough bleeding (decreasing to approximately 50% by cycle 8 as compared with 35% in the 35 μg EE/100 μg norethindrone pill and 25% in the 50 μg EE/100 μg norethindrone pill).²¹

In addition, the number of intermenstrual bleeding days plateaued more slowly as the amount of both hormones in the OC formulations decreased. This underscores the importance of the relative proportion of estrogen and progestin contained in combination OCs and its impact on breakthrough bleeding.

Similarly, a large comprehensive study in 1,991 women compared 7 different formulations of combination OCs containing different dose combinations of EE and norgestimate—20/250, 50/250, 35/125, 20/60, 50/60, 30/90, 25/125.²² Total intermenstrual bleeding was more frequent at lower doses of either estrogen or progestin. However, as long as a similar estrogen-progestin ratio was maintained, bleeding rates were considered acceptable (approximately 10% of days per cycle with bleeding). the authors also noted that in the low-dose range of OCs, small changes in the absolute amount of either EE or norgestimate might result in noticeable changes in bleeding

 

TABLE 1

Available OCs by formulation and regimen

TRADE NAME	GENERIC NAME(S)	ESTROGEN (DOSE)	PROGESTIN (DOSE)
MONOPHASIC
Alesse, Levlite	Aviane, Lessina	Ethinyl estradiol (20 μg)	Levonorgestrel (0.1 mg)
Mircette	Kariva	Ethinyl estradiol (20 μg × 21 days + 10 μg × 5 days during placebo week)	Desogestrel (0.15 mg)
Loestrin FE	Microgestin FE 1/20, June FE 1/20	Ethinyl estradiol (20 μg)	Norethindrone acetate (1 mg)
Yaz		Ethinyl estradiol (20 μg)	Drospirenone (3 mg)
Levlen, Nordette	Levora, Portia	Ethinyl estradiol (30 μg)	Levonorgestrel (0.15 mg)
Lo/Ovral	Low-ogestrel, Cryselle	Ethinyl estradiol (30 μg)	Norgestrel (0.3 mg)
Desogen, Ortho-cept	Apri	Ethinyl estradiol (30 μg)	Desogestrel (0.15 mg)
Loestrin 21 1/5/30	Microgestin, Junel Fe	Ethinyl estradiol (30 μg)	Norethindrone acetate (1.5 mg)
Yasmin		Ethinyl estradiol (30 μg)	Drospirenone (3 mg)
Ovcon 35		Ethinyl estradiol (35 μg)	Norethindrone (0.4 mg)
Ortho-Cyclen	Mononesessa, Sprintec	Ethinyl estradiol (35 μg)	Norgestimate (0.25 mg)
Brevicon, Modicon	Nortrel, Necon 0.5/35	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg)
Demulen 1/35	Zovia 1/35	Ethinyl estradiol (35 μg)	Ethynodiol diacetate (1 mg)
Ortho-Novum 1/35, Norinyl 1+35	Necon 1/35, Nortrel	Ethinyl estradiol (35 μg)	Norethindrone (1 mg)
Ortho-Novum 1/50	Necon 1/50	Ethinyl estradiol (50 μg)	Norethindrone (1 mg)
Ovral	Ogestrel	Ethinyl estradiol (50 μg)	Norgestrel (0.5 mg)
Ovcon 50		Ethinyl estradiol (50 μg)	Norethindrone (1 mg)
Demulen 1/50	Zovia 1/50	Ethinyl estradiol (50 μg)	Ethynodiol diacetate (1 mg)
Norinyl 1/50		Mestranol (50 μg)	Norethindrone (1 mg)
BIPHASIC
Ortho-Novum 10/11, Jenest	Necon 10/11, Nelova 10/11	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 10 days, 1 mg × 11 days)
TRIPHASIC
Ortho Tri-Cyclen Lo		Ethinyl estradiol (25 μg)	Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)
Cyclessa	Velivet	Ethinyl estradiol (25 μg)	Desogestrel (0.1 mg × 7 days, 0.125 mg × 7 days, 0.15 mg × 7 days)
Triphasil, Tri-Levlen	Trivora, Enpresse	Ethinyl estradiol (30 μg × 6 days, 40 μg × 5 days, 30 μg × 10 days)	Levonorgestrel (0.05 mg × 6 days, 0.075 mg × 5 days, 0.125 mg × 10 days)
Tri-Norinyl		Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 7 days, 1 mg × 9 days, 0.5 mg × 5 days)
Ortho Tri-Cyclen	Tri-Sprintec, TriNessa	Ethinyl estradiol (35 μg)	Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)
Ortho-Novum 7/7/7	Nortrel 7/7/7, Necon 7/7/7	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 7 days, 0.75 mg × 7 days, 1 mg × 7 days)
Estrostep FE		Ethinyl estradiol (20 μg × 5 days, 30 μg × 7 days, 35 μg × 9 days)	Norethindrone acetate (1 mg)
EXTENDED CYCLE
Seasonale		Ethinyl estradiol (30 μg × 84 days followed by 7 placebo pills)	Levonorgestrel (0.15 mg)
Seasonique		Ethinyl estradiol (30 μg × 84 days followed by 10 μg × 7 days)	Levonorgestrel (0.15 mg)

Type of progestin may affect breakthrough bleeding.

All combination OCs contain either EE or mestranol. However, a variety of progestins have come into use. The 2 most common contraceptive progestins are derived from 19-nortestosterone, and are classified as gonanes or estranes.²³

Estranes include norethindrone and its derivatives, norethindrone acetate and ethinyodiol diacetate. Gonanes include levonorgestrel, norgestrel, desogestrel, gestodene, and norgestimate.

Each progestin differs in half-life, estrogenic, progestogenic, and androgenic properties, and these variations may explain differing rates of breakthrough bleeding among formulations.⁴ As shown by Endrikat et al,¹² pills with the same quantity of EE but different progestins can have marked differences in breakthrough bleeding rates.

Although gonanes have greater progestational activity, no trial has determined which progestin has the best bleeding profile. A recent Cochrane review comparing different progestins did find that, compared with pills containing levonorgestrel, those containing gestodene may be associated with less intermenstrual bleeding.²⁴

Regardless of the progestin used or the quantity of EE, breakthrough bleeding generally decreases with each successive cycle. One study that compared 2 combination OCs composed of EE/norgestimate and EE/norgestrel demonstrated bleeding rates of 11.3% and 10.6% during the first 6 cycles, which decreased to 5.1% and 6.3% in cycles 13 to 24, respectively.²⁵ Additionally, all women using OCs can experience some cycles without a withdrawal bleed—a menstrual abnormality that may be concerning to those who desire a menstrual period as confirmation that they are not pregnant.

Comparing regimens. OC regimens are available as biphasic, triphasic, extended-cycle, and continuous use. Women using extended-cycle contraceptives may experience more breakthrough bleeding than those using a standard 28-day pill. However, in a 3-month cycle, there are only 7 days of planned bleeding. This is in contrast to 28-day cycles during 3 months in which there are 21 days of planned bleeding.

Though women on extended-cycle regimens may initially experience more breakthrough bleeding than women using 28-day regimens, the total number of planned and unplanned bleeding days may still decrease. Women using a 3-month cycle OC (30 μg EE/150 μg levonorgestrel) experienced more unscheduled bleeding than women using a standard 28-day cycle OC of the same formulation and dose.²⁶ The number of bleeding days decreased with each cycle. Another study examined continuous OC use (20 μg EE/100 μg levonorgestrel) over a period of 1 year, and reported a decreasing number of bleeding days over time.²⁷ In the case of continuous use, all bleeding is unscheduled, and any bleeding is considered breakthrough bleeding.

 

Multiphasic OC regimens were developed with the intention of decreasing breakthrough bleeding by mimicking the rising and falling pattern of estrogen and progesterone in the normal menstrual cycle.²⁸ After the introduction of the biphasic pill, an increase in breakthrough bleeding was noted, which led to the development of the triphasic pill.²⁹ Though the multiphasic hypothesis is physiologically plausible, recent reviews of the literature have found the evidence for its efficacy too limited and methodologically flawed to draw any definitive conclusions about a decrease in breakthrough bleeding.^30,31

Patient behaviors are contributory

Skipping a pill is a common cause of breakthrough bleeding.⁵ Compliance with any OC regimen is crucial to achieving a regular and predictable bleeding pattern. Of 6,676 women surveyed retrospectively, 19% reported missing 1 or more pills per cycle, and 10% reported missing 2 or more pills per cycle.³² Prospective studies have found even higher rates of inconsistent use.

TABLE 2

What to review with patients who are starting a combination OC

Breakthrough bleeding is common in the initial months after starting OCs Breakthrough bleeding, if experienced, usually diminishes over the first 3 months of OC use and abates by the 4th cycle Skipping even 1 pill can result in breakthrough bleeding Avoidance of breakthrough bleeding can be aided by taking your pill at the same time every day; you may find it helpful to make pill-taking part of another daily routine such as tooth brushing Tell me about other medications you are taking, including over-the-counter preparations and herbal supplements If you smoke, the chances of breakthrough bleeding are increased If bleeding continues beyond the 4th cycle, there are diagnostic tests available to explore possible underlying causes If bleeding continues without adequate explanation and despite adherence to the regimen, we can try switching you to a different formulation to see if that helps

When an electronic device was used to monitor pill ingestion, as many as 81% of women were found to miss at least 1 pill per cycle and up to 51% missed 3 or more pills per cycle.³³

Other side effects also undermine adherence. For example, women experiencing nausea may skip pills, which leads to breakthrough bleeding and, ultimately, discontinuation.³⁴ Patients need to understand the impact of skipping pills. Women who report irregular bleeding are 1.6 to 1.7 times more likely than those not reporting this side effect to miss 2 or more pills per cycle.⁵ Even 1 missed pill can increase the risk of bleeding irregularities.³⁵

Failure to take the pill at the same time every day and poor comprehension of pill-taking instructions are other strong predictors of inconsistent use and breakthrough bleeding.³²

Taking some prescription and over-the-counter medications, as well as herbal supplements, may interfere with the activity of OCs to alter bleeding patterns and contraceptive efficacy.³⁶ Medications that induce the cytochrome P-450 system (CYP450) in the liver increase the metabolism of OCs. Anticonvulsants, the antituberculosis agent rifampin, and antifungals such as griseofulvin can increase the clearance of steroid hormones and thus lead to breakthrough bleeding. the herbal supplement St. John’s wort, commonly used for mild or moderate depression, is associated with CYP450 induction. It has been shown to increase the incidence of breakthrough bleeding and probably ovulation in women taking an OC.³⁷

Smoking is associated with such anti-estrogenic effects as early menopause, osteoporosis, and menstrual abnormalities.³⁸ these effects may be related to induction of hepatic estrogen and progesterone metabolism by smoking.^39,40

Before receiving OCs, women are made aware of the relationship between smoking, OCs, and an increased risk of myocardial infarction, stroke, and venous thromboembolism.⁴¹ They should also understand that the anti-estrogenic effect of smoking may lower estrogen levels and lead to breakthrough bleeding, even in women who are reliable pill-takers.^42,43

Smoking appears to have a dose-response relationship with breakthrough bleeding. Increasing levels of smoking have been associated with an increased risk of spotting or bleeding in each cycle.⁴⁴ The difference in cycle control between smokers and nonsmokers appears to be more pronounced with each cycle. Smokers demonstrate a 30% elevation in the risk of bleeding irregularities compared with nonsmokers in the first cycle of use, which rises to an 86% increased risk by the sixth cycle.

Reports conflict regarding the relationship between smoking and contraceptive efficacy, suggesting that confounding factors like compliance may be more important than the antihormonal effect of cigarettes.⁴⁵ Nevertheless, women who smoke should be informed of this potential complicating factor to OC use and as yet another reason to encourage smoking cessation.

Bleeding is sometimes pathologic

When a woman experiences difficult cycle control after the first 3 to 4 months of OC use, consider the possibility of benign and malignant growths, including endometrial polyps, submucous myomas, and cervical or endometrial cancer.⁴⁶ Additionally, contraceptive failure must always be a consideration, and what appears to be breakthrough bleeding may actually represent bleeding in early pregnancy.

 

Cervicitis is an important but largely unrecognized source of unplanned bleeding in women using OCs. Causative organisms include Chlamydia trachomatis Neisseria gonorrhoeae, and Trichomonas vaginalis.²² Intermenstrual bleeding in women previously well controlled on OCs is particularly suggestive of asymptomatic chlamydial cervicitis.

Krettek et al⁴⁷ found that 29.2% of women who had been taking OCs for more than 3 months and presented with intermenstrual spotting had a positive test for C. trachomatis. By comparison, chlamydial cervicitis was found in 10.7% of matched controls taking OCs without spotting who were screened for symptoms of vaginitis or high-risk sexual behavior, and in just 6.1% of women undergoing routine screening before the initiation of contraception.

Three-pronged management

Managing breakthrough bleeding involves effective pretreatment; ongoing counseling and reassurance; and timely and appropriate testing (TABLE 2). In some cases, pill-switching or other forms of medical management may be helpful, but these options are largely unproven.

Counseling reduces anxiety, improves satisfaction, adherence

In a recent survey, 649 Canadian women who were picking up prescriptions for OCs were asked to complete a questionnaire at the pharmacy while they waited.⁴⁸ Over one third (34.5%) reported they had not received counseling from their healthcare provider about breakthrough bleeding. Furthermore, only 28.3% of women who were counseled, and 26.1% of women who were not counseled, gave the optimal response to breakthrough bleeding as defined in this study (“continue taking pill and not call my doctor”).

Lack of counseling can lead to poor method satisfaction and significant cost expenditures because of visits and phone calls by women experiencing unexpected bothersome side effects.⁵ Compared with women who reported the highest satisfaction with the care they received from their provider, those reporting the lowest scores were 1.6 to 2.2 times as likely to be dissatisfied with the pill.

Inform women that breakthrough bleeding is common in the first 3 or 4 cycles of OC use, that bleeding irregularities tend to decline with each successive cycle, and that they should not discontinue pill use without discussing their concerns with you. Remind women to keep sanitary protection with them during the first few months.

The impact of poor counseling was underscored in a study of women enrolled in clinical trials of OCs, contraceptive vaginal rings, and Depo-Provera. Women taking an OC were the least likely to have been warned of menstrual irregularities and thus tended to stop using that method more often than those using a ring or Depo-Provera.⁴⁹ Of women who discontinue OCs, 47% use a less effective method and 19% use no method at all.¹

Give specific instructions for specific regimens. Given the array of OC regimens available, make sure women know how to take them properly. This will help ensure contraceptive efficacy and cycle control. Women who do not understand pill-package instructions are up to 2.8 times more likely to miss pills, which increases the risk of breakthrough bleeding and impacts contraceptive efficacy.⁵ Among women who were counseled about the consequences of missed pills, 76% reported knowing what to do in response (“use another form of birth control that month”). Of women who received no such counseling, only 48% gave the appropriate response (P<.001>48

To improve adherence, advise women to establish a routine for pill-taking: taking the pill at the same time each day or linking pill ingestion with another daily activity, such as tooth brushing. Women without an established routine were 3.6 times more likely to miss 2 or more pills per cycle than women with a routine.⁵

Reassurance regarding efficacy

Reassure users who take their pills routinely that breakthrough bleeding and contraceptive efficacy are not linked.⁵⁰ Breakthrough bleeding is not a sign that OCs are not working.⁴ On the other hand, approximately 1 million unintended pregnancies in the United States each year are associated with misuse or discontinuation of OCs.⁵¹

When to consider diagnostic testing

For OC users who continue to experience breakthrough bleeding beyond 3 to 4 cycles, other potential causes must be ruled out using appropriate diagnostic tests. A pregnancy test, appropriate testing for cervical infection, pelvic ultrasonography, Pap smear, or endometrial biopsy may be warranted, depending on clinical circumstances.

Fall-back options

If breakthrough bleeding continues beyond 3 months, and other reasons, including poor adherence and pathologic processes, are excluded, one option would be to provide the patient with estrogen or switch her to a different pill, though no clinical trials support definitive recommendations.

Aside from changing from a multiphasic to a monophasic formulation, altering the progestin component is often a first step in trying to control breakthrough bleeding.⁴⁶ An OC with a gonane rather than an estrane progestin may be beneficial as this class of progestins may provide more consistent hormonal effects on the endometrium.

 

Choosing an OC with a higher quantity of ee may also help, particularly for women using 20 μg pills. When possible, the same progestin should be used.

You may want to start a trial of conjugated estrogen, 1.25 mg, or estradiol, 2 mg, administered for 7 days when bleeding occurs. This can be repeated if necessary; however, if breakthrough bleeding continues despite this treatment, consideration of a different pill or method should be undertaken.

In 1982, more than 20% of women surveyed in a nationally representative sample had discontinued oral contraceptives (OCs) on their own or at the recommendation of their physician due to bleeding or spotting.¹ Sadly, the percentage today has not decreased much.

Understandable concern, embarrassment, and annoyance lead these women to abandon OCs.^1,2 What they often don’t know, though, is that breakthrough bleeding generally is greatest in the first 3 to 4 months after starting OCs,³ and it steadily declines and stabilizes by the end of the fourth cycle.⁴ Timely counsel could enable many of these women to cope with the bleeding and stick with an effective contraceptive method. Additional incentives are noncontraceptive benefits of OCs: improved menstrual regularity and decreased menstrual blood loss, dysmenorrhea, and risk of ovarian and endometrial cancer.

Women who discontinue OCs on their own switch to less effective methods of birth control or use no method.^1,2 Consequences may be unexpected pregnancies and an increased abortion rate.⁵ With patients who are using an OC, it would be appropriate to ask periodically whether they are satisfied with OC use.

In this review, we discuss the mechanisms and management of breakthrough bleeding in women taking OCs, and provide tips for counseling that may help decrease the risk of discontinuation due to menstrual abnormalities in the initial months of use.

Breakthrough bleeding in this review refers to either unplanned spotting or bleeding, regardless of requirement for protection—unless defined otherwise by a specific study under discussion.

Four causes of bleeding

Breakthrough bleeding may be due to any the following variables:

1. physiologic effects of OCs on the endometrium,
   
2. OC-related parameters, including dose, formulation, and regimen,
   
3. patient behavior (including compliance, using concomitant medications, and smoking),
   
4. benign or malignant pathology.
   

OCs and the endometrium: Estrogen-progestin balance significant

Progestin and estrogen in combination OCs have profound effects on the endometrium that, although not contributing to contraception, do lead to a predictable pattern of bleeding or such problems as breakthrough bleeding or lack of withdrawal bleed.

Normally, estrogen causes the endometrium to proliferate. Progesterone stabilizes the growing uterine lining. Since the introduction of OCs in 1960, the trend in formulation has been to use the least amount of hormone necessary to inhibit ovulation. Given that the progestin is primarily responsible for the contraceptive efficacy of OCs, the risk of pregnancy is not altered with decreases in the estrogen component. However, significantly lowering the estrogen in OCs may account for breakthrough bleeding. Unplanned bleeding, though, is not dependent solely on the estrogen component, as variations in the progestin can contribute to breakthrough bleeding.⁷

 

Most OC users in the US take low-dose formulations, so designated because the estrogen component is 8 Studies that have compared OCs containing 20 μg ethinyl estradiol (EE) with those containing 30 μg or 35 μg EE have not been very useful for judging breakthrough bleeding rates because the products often also vary in the phasing and type of progestin. Some studies show more breakthrough bleeding with 20 μg EE pills,^9-11 but others show equal or improved cycle control with the lower EE dose.

Estrogen-progestin balance is more important than absolute level of estrogen.

Endrikat et al¹² conducted a study to compare two 20 μg EE pills containing different progestins, and to compare 2 levonorgestrel-based formulations with differing EE amounts. An OC of 20 μg EE/100 μg levonorgestrel was compared with a preparation of 20 μg EE/500 μg norethisterone. A 30 μg EE/150 μg levonorgestrel pill was used as a standard reference preparation.

Overall, the 30 μg EE preparation showed a lower cumulative incidence of breakthrough bleeding compared with the 20 μg EE/100 μg levonorgestrel and 20 μg EE/500 μg norethisterone pills over 13 cycles (1.0% vs 4.1% and 11.7%, respectively). However, the 20 μg EE/500 μg norethisterone pills consistently had a higher breakthrough bleeding rate than the 20 μg EE/100 μg levonorgestrel pill. This suggests that, although the higher EE component in the 30 μg pill was important when comparing 2 formulations with the same progestin, the difference in progestins of the two 20 μg EE pills was most likely responsible for the differing rates of breakthrough bleeding.

This study highlights the ability to achieve greater cycle control by titrating the EE component of an OC in a balanced ratio with the same progestin, but suggests that the absolute quantity of EE in a given pill may be less important than maintaining a balance between the 2 hormones or less important than the impact of different progestins on breakthrough bleeding rates.

The delicate balance between estrogen and progesterone supplementation required for contraception may also lead to progestin-induced decidualization and endometrial atrophy, which can result in asynchronous, erratic bleeding.^7,13 This has been primarily studied in long-acting progestin-only contraceptives such as implants. Alterations in angiogenic factors¹⁴ may play a role. Hysteroscopic studies have shown abnormalities in superficial endometrial blood vessels in terms of size, proliferation, and fragility in women using norplant.^13,15,16 Abnormalities in endothelial cells and extracellular matrix proteins,¹⁷ tissue factor,¹⁸ and endometrial lymphoid cells¹⁹ may contribute to breakthrough bleeding in progestin-dominant environments.

OC formulations, doses, regimens

More than 30 formulations of combination OCs are available in the US, with different doses and types of estrogen and progestin (TABLE 1).²⁰ Approved OCs have been studied in clinical trials to assess contraceptive efficacy and cycle control; however, comparisons between studies regarding bleeding phenomena are impaired by inconsistent terminology.³

Whereas some studies describe breakthrough bleeding and spotting according to their recognized definitions, others simply refer to intermenstrual bleeding or use spotting to refer to any unexpected bleeding. In addition, cycle control studies of OC users frequently do not account for the effects of missed pills, use of concomitant medications, or smoking. The percentage of women who experience breakthrough bleeding in a given cycle varies widely even in different trials of the same formulation.

Pay attention to progestin level. Conventional wisdom holds that OCs with the lowest doses of EE (≤20 μg) are associated with more breakthrough bleeding.¹¹ However, even moderately low doses of either EE or progestin can increase the incidence of breakthrough bleeding. For example, when 3 pills with the same estrogen and progestin (50 μg EE/100 μg norethindrone; 35 μg EE/100 μg norethindrone; and 35 μg EE/50 μg norethindrone) were compared in 192 women over 8 cycles, the pill containing the lowest amount of norethindrone (35 μg EE/50 μg norethindrone) caused the highest rates of breakthrough bleeding (decreasing to approximately 50% by cycle 8 as compared with 35% in the 35 μg EE/100 μg norethindrone pill and 25% in the 50 μg EE/100 μg norethindrone pill).²¹

In addition, the number of intermenstrual bleeding days plateaued more slowly as the amount of both hormones in the OC formulations decreased. This underscores the importance of the relative proportion of estrogen and progestin contained in combination OCs and its impact on breakthrough bleeding.

Similarly, a large comprehensive study in 1,991 women compared 7 different formulations of combination OCs containing different dose combinations of EE and norgestimate—20/250, 50/250, 35/125, 20/60, 50/60, 30/90, 25/125.²² Total intermenstrual bleeding was more frequent at lower doses of either estrogen or progestin. However, as long as a similar estrogen-progestin ratio was maintained, bleeding rates were considered acceptable (approximately 10% of days per cycle with bleeding). the authors also noted that in the low-dose range of OCs, small changes in the absolute amount of either EE or norgestimate might result in noticeable changes in bleeding

 

TABLE 1

Available OCs by formulation and regimen

TRADE NAME	GENERIC NAME(S)	ESTROGEN (DOSE)	PROGESTIN (DOSE)
MONOPHASIC
Alesse, Levlite	Aviane, Lessina	Ethinyl estradiol (20 μg)	Levonorgestrel (0.1 mg)
Mircette	Kariva	Ethinyl estradiol (20 μg × 21 days + 10 μg × 5 days during placebo week)	Desogestrel (0.15 mg)
Loestrin FE	Microgestin FE 1/20, June FE 1/20	Ethinyl estradiol (20 μg)	Norethindrone acetate (1 mg)
Yaz		Ethinyl estradiol (20 μg)	Drospirenone (3 mg)
Levlen, Nordette	Levora, Portia	Ethinyl estradiol (30 μg)	Levonorgestrel (0.15 mg)
Lo/Ovral	Low-ogestrel, Cryselle	Ethinyl estradiol (30 μg)	Norgestrel (0.3 mg)
Desogen, Ortho-cept	Apri	Ethinyl estradiol (30 μg)	Desogestrel (0.15 mg)
Loestrin 21 1/5/30	Microgestin, Junel Fe	Ethinyl estradiol (30 μg)	Norethindrone acetate (1.5 mg)
Yasmin		Ethinyl estradiol (30 μg)	Drospirenone (3 mg)
Ovcon 35		Ethinyl estradiol (35 μg)	Norethindrone (0.4 mg)
Ortho-Cyclen	Mononesessa, Sprintec	Ethinyl estradiol (35 μg)	Norgestimate (0.25 mg)
Brevicon, Modicon	Nortrel, Necon 0.5/35	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg)
Demulen 1/35	Zovia 1/35	Ethinyl estradiol (35 μg)	Ethynodiol diacetate (1 mg)
Ortho-Novum 1/35, Norinyl 1+35	Necon 1/35, Nortrel	Ethinyl estradiol (35 μg)	Norethindrone (1 mg)
Ortho-Novum 1/50	Necon 1/50	Ethinyl estradiol (50 μg)	Norethindrone (1 mg)
Ovral	Ogestrel	Ethinyl estradiol (50 μg)	Norgestrel (0.5 mg)
Ovcon 50		Ethinyl estradiol (50 μg)	Norethindrone (1 mg)
Demulen 1/50	Zovia 1/50	Ethinyl estradiol (50 μg)	Ethynodiol diacetate (1 mg)
Norinyl 1/50		Mestranol (50 μg)	Norethindrone (1 mg)
BIPHASIC
Ortho-Novum 10/11, Jenest	Necon 10/11, Nelova 10/11	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 10 days, 1 mg × 11 days)
TRIPHASIC
Ortho Tri-Cyclen Lo		Ethinyl estradiol (25 μg)	Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)
Cyclessa	Velivet	Ethinyl estradiol (25 μg)	Desogestrel (0.1 mg × 7 days, 0.125 mg × 7 days, 0.15 mg × 7 days)
Triphasil, Tri-Levlen	Trivora, Enpresse	Ethinyl estradiol (30 μg × 6 days, 40 μg × 5 days, 30 μg × 10 days)	Levonorgestrel (0.05 mg × 6 days, 0.075 mg × 5 days, 0.125 mg × 10 days)
Tri-Norinyl		Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 7 days, 1 mg × 9 days, 0.5 mg × 5 days)
Ortho Tri-Cyclen	Tri-Sprintec, TriNessa	Ethinyl estradiol (35 μg)	Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)
Ortho-Novum 7/7/7	Nortrel 7/7/7, Necon 7/7/7	Ethinyl estradiol (35 μg)	Norethindrone (0.5 mg × 7 days, 0.75 mg × 7 days, 1 mg × 7 days)
Estrostep FE		Ethinyl estradiol (20 μg × 5 days, 30 μg × 7 days, 35 μg × 9 days)	Norethindrone acetate (1 mg)
EXTENDED CYCLE
Seasonale		Ethinyl estradiol (30 μg × 84 days followed by 7 placebo pills)	Levonorgestrel (0.15 mg)
Seasonique		Ethinyl estradiol (30 μg × 84 days followed by 10 μg × 7 days)	Levonorgestrel (0.15 mg)

Type of progestin may affect breakthrough bleeding.

All combination OCs contain either EE or mestranol. However, a variety of progestins have come into use. The 2 most common contraceptive progestins are derived from 19-nortestosterone, and are classified as gonanes or estranes.²³

Estranes include norethindrone and its derivatives, norethindrone acetate and ethinyodiol diacetate. Gonanes include levonorgestrel, norgestrel, desogestrel, gestodene, and norgestimate.

Each progestin differs in half-life, estrogenic, progestogenic, and androgenic properties, and these variations may explain differing rates of breakthrough bleeding among formulations.⁴ As shown by Endrikat et al,¹² pills with the same quantity of EE but different progestins can have marked differences in breakthrough bleeding rates.

Although gonanes have greater progestational activity, no trial has determined which progestin has the best bleeding profile. A recent Cochrane review comparing different progestins did find that, compared with pills containing levonorgestrel, those containing gestodene may be associated with less intermenstrual bleeding.²⁴

Regardless of the progestin used or the quantity of EE, breakthrough bleeding generally decreases with each successive cycle. One study that compared 2 combination OCs composed of EE/norgestimate and EE/norgestrel demonstrated bleeding rates of 11.3% and 10.6% during the first 6 cycles, which decreased to 5.1% and 6.3% in cycles 13 to 24, respectively.²⁵ Additionally, all women using OCs can experience some cycles without a withdrawal bleed—a menstrual abnormality that may be concerning to those who desire a menstrual period as confirmation that they are not pregnant.

Comparing regimens. OC regimens are available as biphasic, triphasic, extended-cycle, and continuous use. Women using extended-cycle contraceptives may experience more breakthrough bleeding than those using a standard 28-day pill. However, in a 3-month cycle, there are only 7 days of planned bleeding. This is in contrast to 28-day cycles during 3 months in which there are 21 days of planned bleeding.

Though women on extended-cycle regimens may initially experience more breakthrough bleeding than women using 28-day regimens, the total number of planned and unplanned bleeding days may still decrease. Women using a 3-month cycle OC (30 μg EE/150 μg levonorgestrel) experienced more unscheduled bleeding than women using a standard 28-day cycle OC of the same formulation and dose.²⁶ The number of bleeding days decreased with each cycle. Another study examined continuous OC use (20 μg EE/100 μg levonorgestrel) over a period of 1 year, and reported a decreasing number of bleeding days over time.²⁷ In the case of continuous use, all bleeding is unscheduled, and any bleeding is considered breakthrough bleeding.

 

Multiphasic OC regimens were developed with the intention of decreasing breakthrough bleeding by mimicking the rising and falling pattern of estrogen and progesterone in the normal menstrual cycle.²⁸ After the introduction of the biphasic pill, an increase in breakthrough bleeding was noted, which led to the development of the triphasic pill.²⁹ Though the multiphasic hypothesis is physiologically plausible, recent reviews of the literature have found the evidence for its efficacy too limited and methodologically flawed to draw any definitive conclusions about a decrease in breakthrough bleeding.^30,31

Patient behaviors are contributory

Skipping a pill is a common cause of breakthrough bleeding.⁵ Compliance with any OC regimen is crucial to achieving a regular and predictable bleeding pattern. Of 6,676 women surveyed retrospectively, 19% reported missing 1 or more pills per cycle, and 10% reported missing 2 or more pills per cycle.³² Prospective studies have found even higher rates of inconsistent use.

TABLE 2

What to review with patients who are starting a combination OC

Breakthrough bleeding is common in the initial months after starting OCs Breakthrough bleeding, if experienced, usually diminishes over the first 3 months of OC use and abates by the 4th cycle Skipping even 1 pill can result in breakthrough bleeding Avoidance of breakthrough bleeding can be aided by taking your pill at the same time every day; you may find it helpful to make pill-taking part of another daily routine such as tooth brushing Tell me about other medications you are taking, including over-the-counter preparations and herbal supplements If you smoke, the chances of breakthrough bleeding are increased If bleeding continues beyond the 4th cycle, there are diagnostic tests available to explore possible underlying causes If bleeding continues without adequate explanation and despite adherence to the regimen, we can try switching you to a different formulation to see if that helps

When an electronic device was used to monitor pill ingestion, as many as 81% of women were found to miss at least 1 pill per cycle and up to 51% missed 3 or more pills per cycle.³³

Other side effects also undermine adherence. For example, women experiencing nausea may skip pills, which leads to breakthrough bleeding and, ultimately, discontinuation.³⁴ Patients need to understand the impact of skipping pills. Women who report irregular bleeding are 1.6 to 1.7 times more likely than those not reporting this side effect to miss 2 or more pills per cycle.⁵ Even 1 missed pill can increase the risk of bleeding irregularities.³⁵

Failure to take the pill at the same time every day and poor comprehension of pill-taking instructions are other strong predictors of inconsistent use and breakthrough bleeding.³²

Taking some prescription and over-the-counter medications, as well as herbal supplements, may interfere with the activity of OCs to alter bleeding patterns and contraceptive efficacy.³⁶ Medications that induce the cytochrome P-450 system (CYP450) in the liver increase the metabolism of OCs. Anticonvulsants, the antituberculosis agent rifampin, and antifungals such as griseofulvin can increase the clearance of steroid hormones and thus lead to breakthrough bleeding. the herbal supplement St. John’s wort, commonly used for mild or moderate depression, is associated with CYP450 induction. It has been shown to increase the incidence of breakthrough bleeding and probably ovulation in women taking an OC.³⁷

Smoking is associated with such anti-estrogenic effects as early menopause, osteoporosis, and menstrual abnormalities.³⁸ these effects may be related to induction of hepatic estrogen and progesterone metabolism by smoking.^39,40

Before receiving OCs, women are made aware of the relationship between smoking, OCs, and an increased risk of myocardial infarction, stroke, and venous thromboembolism.⁴¹ They should also understand that the anti-estrogenic effect of smoking may lower estrogen levels and lead to breakthrough bleeding, even in women who are reliable pill-takers.^42,43

Smoking appears to have a dose-response relationship with breakthrough bleeding. Increasing levels of smoking have been associated with an increased risk of spotting or bleeding in each cycle.⁴⁴ The difference in cycle control between smokers and nonsmokers appears to be more pronounced with each cycle. Smokers demonstrate a 30% elevation in the risk of bleeding irregularities compared with nonsmokers in the first cycle of use, which rises to an 86% increased risk by the sixth cycle.

Reports conflict regarding the relationship between smoking and contraceptive efficacy, suggesting that confounding factors like compliance may be more important than the antihormonal effect of cigarettes.⁴⁵ Nevertheless, women who smoke should be informed of this potential complicating factor to OC use and as yet another reason to encourage smoking cessation.

Bleeding is sometimes pathologic

When a woman experiences difficult cycle control after the first 3 to 4 months of OC use, consider the possibility of benign and malignant growths, including endometrial polyps, submucous myomas, and cervical or endometrial cancer.⁴⁶ Additionally, contraceptive failure must always be a consideration, and what appears to be breakthrough bleeding may actually represent bleeding in early pregnancy.

 

Cervicitis is an important but largely unrecognized source of unplanned bleeding in women using OCs. Causative organisms include Chlamydia trachomatis Neisseria gonorrhoeae, and Trichomonas vaginalis.²² Intermenstrual bleeding in women previously well controlled on OCs is particularly suggestive of asymptomatic chlamydial cervicitis.

Krettek et al⁴⁷ found that 29.2% of women who had been taking OCs for more than 3 months and presented with intermenstrual spotting had a positive test for C. trachomatis. By comparison, chlamydial cervicitis was found in 10.7% of matched controls taking OCs without spotting who were screened for symptoms of vaginitis or high-risk sexual behavior, and in just 6.1% of women undergoing routine screening before the initiation of contraception.

Three-pronged management

Managing breakthrough bleeding involves effective pretreatment; ongoing counseling and reassurance; and timely and appropriate testing (TABLE 2). In some cases, pill-switching or other forms of medical management may be helpful, but these options are largely unproven.

Counseling reduces anxiety, improves satisfaction, adherence

In a recent survey, 649 Canadian women who were picking up prescriptions for OCs were asked to complete a questionnaire at the pharmacy while they waited.⁴⁸ Over one third (34.5%) reported they had not received counseling from their healthcare provider about breakthrough bleeding. Furthermore, only 28.3% of women who were counseled, and 26.1% of women who were not counseled, gave the optimal response to breakthrough bleeding as defined in this study (“continue taking pill and not call my doctor”).

Lack of counseling can lead to poor method satisfaction and significant cost expenditures because of visits and phone calls by women experiencing unexpected bothersome side effects.⁵ Compared with women who reported the highest satisfaction with the care they received from their provider, those reporting the lowest scores were 1.6 to 2.2 times as likely to be dissatisfied with the pill.

Inform women that breakthrough bleeding is common in the first 3 or 4 cycles of OC use, that bleeding irregularities tend to decline with each successive cycle, and that they should not discontinue pill use without discussing their concerns with you. Remind women to keep sanitary protection with them during the first few months.

The impact of poor counseling was underscored in a study of women enrolled in clinical trials of OCs, contraceptive vaginal rings, and Depo-Provera. Women taking an OC were the least likely to have been warned of menstrual irregularities and thus tended to stop using that method more often than those using a ring or Depo-Provera.⁴⁹ Of women who discontinue OCs, 47% use a less effective method and 19% use no method at all.¹

Give specific instructions for specific regimens. Given the array of OC regimens available, make sure women know how to take them properly. This will help ensure contraceptive efficacy and cycle control. Women who do not understand pill-package instructions are up to 2.8 times more likely to miss pills, which increases the risk of breakthrough bleeding and impacts contraceptive efficacy.⁵ Among women who were counseled about the consequences of missed pills, 76% reported knowing what to do in response (“use another form of birth control that month”). Of women who received no such counseling, only 48% gave the appropriate response (P<.001>48

To improve adherence, advise women to establish a routine for pill-taking: taking the pill at the same time each day or linking pill ingestion with another daily activity, such as tooth brushing. Women without an established routine were 3.6 times more likely to miss 2 or more pills per cycle than women with a routine.⁵

Reassurance regarding efficacy

Reassure users who take their pills routinely that breakthrough bleeding and contraceptive efficacy are not linked.⁵⁰ Breakthrough bleeding is not a sign that OCs are not working.⁴ On the other hand, approximately 1 million unintended pregnancies in the United States each year are associated with misuse or discontinuation of OCs.⁵¹

When to consider diagnostic testing

For OC users who continue to experience breakthrough bleeding beyond 3 to 4 cycles, other potential causes must be ruled out using appropriate diagnostic tests. A pregnancy test, appropriate testing for cervical infection, pelvic ultrasonography, Pap smear, or endometrial biopsy may be warranted, depending on clinical circumstances.

Fall-back options

If breakthrough bleeding continues beyond 3 months, and other reasons, including poor adherence and pathologic processes, are excluded, one option would be to provide the patient with estrogen or switch her to a different pill, though no clinical trials support definitive recommendations.

Aside from changing from a multiphasic to a monophasic formulation, altering the progestin component is often a first step in trying to control breakthrough bleeding.⁴⁶ An OC with a gonane rather than an estrane progestin may be beneficial as this class of progestins may provide more consistent hormonal effects on the endometrium.

 

Choosing an OC with a higher quantity of ee may also help, particularly for women using 20 μg pills. When possible, the same progestin should be used.

You may want to start a trial of conjugated estrogen, 1.25 mg, or estradiol, 2 mg, administered for 7 days when bleeding occurs. This can be repeated if necessary; however, if breakthrough bleeding continues despite this treatment, consideration of a different pill or method should be undertaken.

For many decades, chronic pelvic pain has been discussed, investigated, and treated as if it were caused by 1) a disorder of one of the visceral organ systems in the pelvis (gastrointestinal, urologic, or reproductive), or of somatic structures (pelvic floor muscles, etc) or 2) psychological dysfunction (depression, past abuse, personality disorder, anxiety, sexual dysfunction, and so on). Now, these assumptions are beginning to change.

Thanks to recent clinical investigation and experience, we are gaining a more complex understanding of the interactions among organ systems and the interplay between visceral and somatic structures and their contributions to pain. Understanding the interactions among these components should lead to more informed therapeutic approaches.

In this article, I focus on 2 common complaints that appear to have multiple components: vulvar vestibulitis and endometriosis.

I also explore the role of myofascial tissue in pelvic pain disorders.

Conspicuously absent from this discussion is any review of surgical technique—be it robotic, laparoscopic, or other minimally invasive surgery. As beneficial as these approaches are, in general, surgical details in the case of pelvic pain matter less than the need to integrate surgery with other aspects of treatment.

Vulvar vestibulitis is a chronic pain disorder

Zolnoun D, Hartmann K, Lamvu G, As-Sanie S, Maixner W, Steege J. A conceptual model for the pathophysiology of vulvar vestibulitis syndrome. Obstet Gynecol Surv. 2006;61:395–401.

Erythema and hypersensitivity of the predominantly posterior vulvar vestibule are now widely recognized as a common cause of introital dyspareunia, as well as pain during daily activities. In patients with vulvar vestibulitis, a cotton-tipped applicator touched to the posterior vestibule commonly elicits allodynia (pain in response to a typically nonpainful stimulus).

Although vulvar vestibulitis often involves muscular contraction, it now seems likely that many cases labeled as vaginismus in the past were in fact more complex, attributable to what we increasingly understand as a neuroinflammatory disorder, as Zolnoun and colleagues observe. Research suggests that the pathophysiology of vulvar vestibulitis involves abnormalities in 3 interdependent systems:

• vestibular mucosa
  
• pelvic floor muscles
  
• central nervous system pain regulatory pathways.
  

How this view affects treatment

A modest literature search and extensive clinical experience suggest that pelvic floor muscular spasm can accompany vestibulitis, so treating the pelvic floor with biofeedback or physical therapy or both is helpful.¹ The presence of muscular spasm is sometimes interpreted to mean that muscle dysfunction is the primary disorder and the vestibular response secondary, but my clinical experience favors the opposite view: Vestibulitis happens first, and then the muscles become involved. For many patients, both aspects require treatment.

Vulvar vestibulitis is now often viewed as neuropathic pain—that is, the activation of local pain fibers that appears to be strikingly out of proportion to any demonstrable tissue damage. Overnight application of 5% lidocaine to the vestibule for 4 weeks or more has substantially reduced dyspareunia.² (Compounded preparations of pH-neutral media are often better tolerated than the commercially available medications, which tend to be mildly acidic.) A randomized, controlled trial of this approach is under way.

Multiple studies have reported high success rates (85–95%) for vestibuloplasty. Most surgeons seem to favor excision of the posterior vestibule and posterior hymeneal ring, covering the defect with the leading edge of advanced vaginal mucosa. This surgery is sometimes the first treatment for vestibulitis, but usually is a last resort after other therapies have failed.

Few clinical studies have explored nonsurgical treatments. Tricyclic antidepressants, long used to treat chronic pain in general, have proved helpful in treating generalized vulvodynia, as well as the more localized syndrome of vestibulitis.³

Anti-epileptic drugs, including gabapentin, carbamazepine, and lamotrigine, have been used in other pain disorders, and have recently met with some success when used for vestibulitis.

Success of different treatments highlights complexity of vestibulitis

At first glance, it would seem puzzling that treatment of the pelvic floor muscles, medical therapy for neuropathic pain, and surgical revision of the posterior vestibule would all be beneficial. This finding makes more sense if vestibulitis is viewed as one example of the interaction of several systems.

Early studies suggest potential overlap between interstitial cystitis and vulvar vestibulitis, and there may be an association between vestibulitis and temporomandibular joint disorder, supporting the notion that these conditions are members of a family of neurosensory disorders that share a common genetic susceptibility.⁴

Focus on endometriosis implants may not fully address the disease

 

Practice Committee, American Society for Reprodutive Medicine. Treatment of pelvic pain associated with edometriosis. Fertil Steril. 2006;86:S156–S160.

Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-releasing hormone system—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol. 2006;125:9–28.

Because endometriosis involves the ectopic presence of endometrium in the pelvis or beyond, medical and surgical treatments have traditionally targeted the implants. However, American Fertility Society staging of the disease, based on a fundamentally oncologic model (volume and distribution), is poorly predictive of the 2 major clinical morbidities of endometriosis: pain and infertility. Hence, the mechanisms of pain remain obscure.

Three aspects of endometriosis deserve comment here:

• Successful treatment with a gonadotropin-releasing hormone (GnRH) agonist does not necessarily mean endometriosis is present
  
• The levonorgestrel-releasing intrauterine system (LNG-IUS) eases pain, suggesting uterine involvement
  
• Surrounding organ systems appear to contribute to the disease.
  

Is a presumptive diagnosis accurate?

When treatment of pelvic pain with first-line agents such as NSAIDs or oral contraceptives fails, it is common practice to make a presumptive diagnosis of endometriosis and administer a GnRH agonist. If pain is relieved, it is assumed that endometriosis was the cause, but data do not support this conclusion. In the study most often cited in support of preemptive GnRH-agonist treatment without laparoscopic diagnosis,⁵ women with and without endometriosis experienced pain relief with equal frequency. The ASRM concluded in its recent guideline that relief of pelvic pain in response to a GnRH agonist does not make the diagnosis of endometriosis. This agent interrupts the hypothalamic–pituitary–ovarian axis, causing hypoestrogenism and amenorrhea, and may alter pain by

• reducing contractility of intestinal muscle
  
• eliminating the physiologic perimenstrual rise in pain sensitivity
  
• quieting uterine contractions.
  

Evidence suggests a uterine link

According to Varma and colleagues, the easing of endometriosis-related pain with the LNG-IUS suggests that the uterus itself—as opposed to the peritoneal implants—plays an important role. (Women with chronic pelvic pain, with or without endometriosis, have increased nerve-fiber density in the lower uterine segment.⁶) Therefore, the benefits of progestins may be at least partly attributable to their quieting effect on uterine contractility, in addition to their direct impact on endometriosis implants, and therapies thought to target implants may relieve pain in part through their impact on the uterus.

In a randomized trial, the LNG-IUS relieved endometriosis-related pain as effectively as depot leuprolide.⁷ Given that this device may remain in place for 5 years, it offers substantial benefit.

What interstitial cystitis may reveal about endometriosis

Clinical evidence suggests that endometriosis and disorders of surrounding visceral systems (eg, interstitial cystitis and irritable bowel syndrome) share some morbidities. Assuming these associations are validated by epidemiologic investigations, the common denominator may be vulnerability to inflammation (or a deficit in counterinflammatory systems), nonspecific stress responses to the primary illness, genetically determined deficits in neuromodulation of nociceptive signals reaching the spinal chord,⁴ and other mechanisms awaiting discovery.

How myofascial tissue contributes to pelvic pain

Tu FF, As-Sanie S, Steege JF. Prevalence of pelvic musculoskeletal disorders in a female chronic pelvic pain clinic. J Reprod Med. 2006;51:185–189.

More than 20 years ago, Lipscomb and colleagues⁸ identified pelvic floor dysfunction as an important component of pelvic pain in women, and Slocumb⁹ described abdominal wall trigger points as another. We continue to gain appreciation of myofascial contributions to pelvic pain, although systematic study is lacking.

Tu and colleagues retrospectively studied the records of 987 women who presented to a chronic pelvic pain clinic for evaluation. Single-digit, intravaginal palpation revealed tenderness in the levator ani and piriformis muscles in 22% and 14% of women, respectively. Tenderness at these sites was associated with a higher total number of pain sites, previous surgery for pelvic pain, higher scores on the Beck Depression Inventory and McGill Pain Inventory, and worsening pain with bowel movements.

Muscles that are tender to palpation may, on occasion, be the prime movers in a pain syndrome, but my experience suggests that muscle problems often develop secondary to some other condition. For example, a woman with endometriosis may, over time, develop pelvic floor dysfunction as an important part of her dyspareunia, as a reaction to the tenderness in the posterior cul-de-sac. In a similar manner, muscle dysfunction may follow in the wake of pelvic infection or uterine enlargement, or after gynecologic surgery.

Suboptimal response to generally effective treatments is a common clue to the presence of myofascial and other factors. In this circumstance, rather than escalating treatment (eg, by operating repeatedly to treat endometriosis), the gynecologist should broaden the clinical inquiry by palpating the pelvic muscle groups during physical examination.

 

Can myofascial pain be treated?

Physical therapy has moved enthusiastically into the area of pelvic pain in general. Many clinicians and physical therapists have begun to look beyond the pelvic floor and recognize contributions from the hip external rotator muscles (piriformis, obturator), the sacroiliac joints, and the abdominal wall muscles. These muscle groups seem to communicate with each other at times. For example, palpation of the pelvic floor may refer pain to the ipsilateral lower abdominal wall, and palpation of the sacroiliac joint, which may be painful itself, may also refer pain to the corresponding anterior lower quadrant. The gynecologist can readily screen for these dysfunctions, with treatment provided by the physical therapist. Follow-up by the gynecologist then permits integration of all medical, surgical, and physical therapy.

Systematic studies are needed

At present, comparisons across treatment centers are complicated by variations in clinical assessment techniques. For example, the literature describing how the bladder contributes to pelvic pain often fails to describe assessment techniques for disorders in other systems (gastrointestinal, pelvic floor, etc). When increased bladder sensitivity is then demonstrated, the reader is left to wonder whether it is the prime mover in the problem or an epiphenomenon, secondary to some other disorder.

Dr. Steege reports no financial relationships with any company whose products are mentioned in this article.

For many decades, chronic pelvic pain has been discussed, investigated, and treated as if it were caused by 1) a disorder of one of the visceral organ systems in the pelvis (gastrointestinal, urologic, or reproductive), or of somatic structures (pelvic floor muscles, etc) or 2) psychological dysfunction (depression, past abuse, personality disorder, anxiety, sexual dysfunction, and so on). Now, these assumptions are beginning to change.

Thanks to recent clinical investigation and experience, we are gaining a more complex understanding of the interactions among organ systems and the interplay between visceral and somatic structures and their contributions to pain. Understanding the interactions among these components should lead to more informed therapeutic approaches.

In this article, I focus on 2 common complaints that appear to have multiple components: vulvar vestibulitis and endometriosis.

I also explore the role of myofascial tissue in pelvic pain disorders.

Conspicuously absent from this discussion is any review of surgical technique—be it robotic, laparoscopic, or other minimally invasive surgery. As beneficial as these approaches are, in general, surgical details in the case of pelvic pain matter less than the need to integrate surgery with other aspects of treatment.

Vulvar vestibulitis is a chronic pain disorder

Zolnoun D, Hartmann K, Lamvu G, As-Sanie S, Maixner W, Steege J. A conceptual model for the pathophysiology of vulvar vestibulitis syndrome. Obstet Gynecol Surv. 2006;61:395–401.

Erythema and hypersensitivity of the predominantly posterior vulvar vestibule are now widely recognized as a common cause of introital dyspareunia, as well as pain during daily activities. In patients with vulvar vestibulitis, a cotton-tipped applicator touched to the posterior vestibule commonly elicits allodynia (pain in response to a typically nonpainful stimulus).

Although vulvar vestibulitis often involves muscular contraction, it now seems likely that many cases labeled as vaginismus in the past were in fact more complex, attributable to what we increasingly understand as a neuroinflammatory disorder, as Zolnoun and colleagues observe. Research suggests that the pathophysiology of vulvar vestibulitis involves abnormalities in 3 interdependent systems:

• vestibular mucosa
  
• pelvic floor muscles
  
• central nervous system pain regulatory pathways.
  

How this view affects treatment

A modest literature search and extensive clinical experience suggest that pelvic floor muscular spasm can accompany vestibulitis, so treating the pelvic floor with biofeedback or physical therapy or both is helpful.¹ The presence of muscular spasm is sometimes interpreted to mean that muscle dysfunction is the primary disorder and the vestibular response secondary, but my clinical experience favors the opposite view: Vestibulitis happens first, and then the muscles become involved. For many patients, both aspects require treatment.

Vulvar vestibulitis is now often viewed as neuropathic pain—that is, the activation of local pain fibers that appears to be strikingly out of proportion to any demonstrable tissue damage. Overnight application of 5% lidocaine to the vestibule for 4 weeks or more has substantially reduced dyspareunia.² (Compounded preparations of pH-neutral media are often better tolerated than the commercially available medications, which tend to be mildly acidic.) A randomized, controlled trial of this approach is under way.

Multiple studies have reported high success rates (85–95%) for vestibuloplasty. Most surgeons seem to favor excision of the posterior vestibule and posterior hymeneal ring, covering the defect with the leading edge of advanced vaginal mucosa. This surgery is sometimes the first treatment for vestibulitis, but usually is a last resort after other therapies have failed.

Few clinical studies have explored nonsurgical treatments. Tricyclic antidepressants, long used to treat chronic pain in general, have proved helpful in treating generalized vulvodynia, as well as the more localized syndrome of vestibulitis.³

Anti-epileptic drugs, including gabapentin, carbamazepine, and lamotrigine, have been used in other pain disorders, and have recently met with some success when used for vestibulitis.

Success of different treatments highlights complexity of vestibulitis

At first glance, it would seem puzzling that treatment of the pelvic floor muscles, medical therapy for neuropathic pain, and surgical revision of the posterior vestibule would all be beneficial. This finding makes more sense if vestibulitis is viewed as one example of the interaction of several systems.

Early studies suggest potential overlap between interstitial cystitis and vulvar vestibulitis, and there may be an association between vestibulitis and temporomandibular joint disorder, supporting the notion that these conditions are members of a family of neurosensory disorders that share a common genetic susceptibility.⁴

Focus on endometriosis implants may not fully address the disease

 

Practice Committee, American Society for Reprodutive Medicine. Treatment of pelvic pain associated with edometriosis. Fertil Steril. 2006;86:S156–S160.

Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-releasing hormone system—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol. 2006;125:9–28.

Because endometriosis involves the ectopic presence of endometrium in the pelvis or beyond, medical and surgical treatments have traditionally targeted the implants. However, American Fertility Society staging of the disease, based on a fundamentally oncologic model (volume and distribution), is poorly predictive of the 2 major clinical morbidities of endometriosis: pain and infertility. Hence, the mechanisms of pain remain obscure.

Three aspects of endometriosis deserve comment here:

• Successful treatment with a gonadotropin-releasing hormone (GnRH) agonist does not necessarily mean endometriosis is present
  
• The levonorgestrel-releasing intrauterine system (LNG-IUS) eases pain, suggesting uterine involvement
  
• Surrounding organ systems appear to contribute to the disease.
  

Is a presumptive diagnosis accurate?

When treatment of pelvic pain with first-line agents such as NSAIDs or oral contraceptives fails, it is common practice to make a presumptive diagnosis of endometriosis and administer a GnRH agonist. If pain is relieved, it is assumed that endometriosis was the cause, but data do not support this conclusion. In the study most often cited in support of preemptive GnRH-agonist treatment without laparoscopic diagnosis,⁵ women with and without endometriosis experienced pain relief with equal frequency. The ASRM concluded in its recent guideline that relief of pelvic pain in response to a GnRH agonist does not make the diagnosis of endometriosis. This agent interrupts the hypothalamic–pituitary–ovarian axis, causing hypoestrogenism and amenorrhea, and may alter pain by

• reducing contractility of intestinal muscle
  
• eliminating the physiologic perimenstrual rise in pain sensitivity
  
• quieting uterine contractions.
  

Evidence suggests a uterine link

According to Varma and colleagues, the easing of endometriosis-related pain with the LNG-IUS suggests that the uterus itself—as opposed to the peritoneal implants—plays an important role. (Women with chronic pelvic pain, with or without endometriosis, have increased nerve-fiber density in the lower uterine segment.⁶) Therefore, the benefits of progestins may be at least partly attributable to their quieting effect on uterine contractility, in addition to their direct impact on endometriosis implants, and therapies thought to target implants may relieve pain in part through their impact on the uterus.

In a randomized trial, the LNG-IUS relieved endometriosis-related pain as effectively as depot leuprolide.⁷ Given that this device may remain in place for 5 years, it offers substantial benefit.

What interstitial cystitis may reveal about endometriosis

Clinical evidence suggests that endometriosis and disorders of surrounding visceral systems (eg, interstitial cystitis and irritable bowel syndrome) share some morbidities. Assuming these associations are validated by epidemiologic investigations, the common denominator may be vulnerability to inflammation (or a deficit in counterinflammatory systems), nonspecific stress responses to the primary illness, genetically determined deficits in neuromodulation of nociceptive signals reaching the spinal chord,⁴ and other mechanisms awaiting discovery.

How myofascial tissue contributes to pelvic pain

Tu FF, As-Sanie S, Steege JF. Prevalence of pelvic musculoskeletal disorders in a female chronic pelvic pain clinic. J Reprod Med. 2006;51:185–189.

More than 20 years ago, Lipscomb and colleagues⁸ identified pelvic floor dysfunction as an important component of pelvic pain in women, and Slocumb⁹ described abdominal wall trigger points as another. We continue to gain appreciation of myofascial contributions to pelvic pain, although systematic study is lacking.

Tu and colleagues retrospectively studied the records of 987 women who presented to a chronic pelvic pain clinic for evaluation. Single-digit, intravaginal palpation revealed tenderness in the levator ani and piriformis muscles in 22% and 14% of women, respectively. Tenderness at these sites was associated with a higher total number of pain sites, previous surgery for pelvic pain, higher scores on the Beck Depression Inventory and McGill Pain Inventory, and worsening pain with bowel movements.

Muscles that are tender to palpation may, on occasion, be the prime movers in a pain syndrome, but my experience suggests that muscle problems often develop secondary to some other condition. For example, a woman with endometriosis may, over time, develop pelvic floor dysfunction as an important part of her dyspareunia, as a reaction to the tenderness in the posterior cul-de-sac. In a similar manner, muscle dysfunction may follow in the wake of pelvic infection or uterine enlargement, or after gynecologic surgery.

Suboptimal response to generally effective treatments is a common clue to the presence of myofascial and other factors. In this circumstance, rather than escalating treatment (eg, by operating repeatedly to treat endometriosis), the gynecologist should broaden the clinical inquiry by palpating the pelvic muscle groups during physical examination.

 

Can myofascial pain be treated?

Physical therapy has moved enthusiastically into the area of pelvic pain in general. Many clinicians and physical therapists have begun to look beyond the pelvic floor and recognize contributions from the hip external rotator muscles (piriformis, obturator), the sacroiliac joints, and the abdominal wall muscles. These muscle groups seem to communicate with each other at times. For example, palpation of the pelvic floor may refer pain to the ipsilateral lower abdominal wall, and palpation of the sacroiliac joint, which may be painful itself, may also refer pain to the corresponding anterior lower quadrant. The gynecologist can readily screen for these dysfunctions, with treatment provided by the physical therapist. Follow-up by the gynecologist then permits integration of all medical, surgical, and physical therapy.

Systematic studies are needed

At present, comparisons across treatment centers are complicated by variations in clinical assessment techniques. For example, the literature describing how the bladder contributes to pelvic pain often fails to describe assessment techniques for disorders in other systems (gastrointestinal, pelvic floor, etc). When increased bladder sensitivity is then demonstrated, the reader is left to wonder whether it is the prime mover in the problem or an epiphenomenon, secondary to some other disorder.

Dr. Steege reports no financial relationships with any company whose products are mentioned in this article.

For many decades, chronic pelvic pain has been discussed, investigated, and treated as if it were caused by 1) a disorder of one of the visceral organ systems in the pelvis (gastrointestinal, urologic, or reproductive), or of somatic structures (pelvic floor muscles, etc) or 2) psychological dysfunction (depression, past abuse, personality disorder, anxiety, sexual dysfunction, and so on). Now, these assumptions are beginning to change.

Thanks to recent clinical investigation and experience, we are gaining a more complex understanding of the interactions among organ systems and the interplay between visceral and somatic structures and their contributions to pain. Understanding the interactions among these components should lead to more informed therapeutic approaches.

In this article, I focus on 2 common complaints that appear to have multiple components: vulvar vestibulitis and endometriosis.

I also explore the role of myofascial tissue in pelvic pain disorders.

Conspicuously absent from this discussion is any review of surgical technique—be it robotic, laparoscopic, or other minimally invasive surgery. As beneficial as these approaches are, in general, surgical details in the case of pelvic pain matter less than the need to integrate surgery with other aspects of treatment.

Vulvar vestibulitis is a chronic pain disorder

Zolnoun D, Hartmann K, Lamvu G, As-Sanie S, Maixner W, Steege J. A conceptual model for the pathophysiology of vulvar vestibulitis syndrome. Obstet Gynecol Surv. 2006;61:395–401.

Erythema and hypersensitivity of the predominantly posterior vulvar vestibule are now widely recognized as a common cause of introital dyspareunia, as well as pain during daily activities. In patients with vulvar vestibulitis, a cotton-tipped applicator touched to the posterior vestibule commonly elicits allodynia (pain in response to a typically nonpainful stimulus).

Although vulvar vestibulitis often involves muscular contraction, it now seems likely that many cases labeled as vaginismus in the past were in fact more complex, attributable to what we increasingly understand as a neuroinflammatory disorder, as Zolnoun and colleagues observe. Research suggests that the pathophysiology of vulvar vestibulitis involves abnormalities in 3 interdependent systems:

• vestibular mucosa
  
• pelvic floor muscles
  
• central nervous system pain regulatory pathways.
  

How this view affects treatment

A modest literature search and extensive clinical experience suggest that pelvic floor muscular spasm can accompany vestibulitis, so treating the pelvic floor with biofeedback or physical therapy or both is helpful.¹ The presence of muscular spasm is sometimes interpreted to mean that muscle dysfunction is the primary disorder and the vestibular response secondary, but my clinical experience favors the opposite view: Vestibulitis happens first, and then the muscles become involved. For many patients, both aspects require treatment.

Vulvar vestibulitis is now often viewed as neuropathic pain—that is, the activation of local pain fibers that appears to be strikingly out of proportion to any demonstrable tissue damage. Overnight application of 5% lidocaine to the vestibule for 4 weeks or more has substantially reduced dyspareunia.² (Compounded preparations of pH-neutral media are often better tolerated than the commercially available medications, which tend to be mildly acidic.) A randomized, controlled trial of this approach is under way.

Multiple studies have reported high success rates (85–95%) for vestibuloplasty. Most surgeons seem to favor excision of the posterior vestibule and posterior hymeneal ring, covering the defect with the leading edge of advanced vaginal mucosa. This surgery is sometimes the first treatment for vestibulitis, but usually is a last resort after other therapies have failed.

Few clinical studies have explored nonsurgical treatments. Tricyclic antidepressants, long used to treat chronic pain in general, have proved helpful in treating generalized vulvodynia, as well as the more localized syndrome of vestibulitis.³

Anti-epileptic drugs, including gabapentin, carbamazepine, and lamotrigine, have been used in other pain disorders, and have recently met with some success when used for vestibulitis.

Success of different treatments highlights complexity of vestibulitis

At first glance, it would seem puzzling that treatment of the pelvic floor muscles, medical therapy for neuropathic pain, and surgical revision of the posterior vestibule would all be beneficial. This finding makes more sense if vestibulitis is viewed as one example of the interaction of several systems.

Early studies suggest potential overlap between interstitial cystitis and vulvar vestibulitis, and there may be an association between vestibulitis and temporomandibular joint disorder, supporting the notion that these conditions are members of a family of neurosensory disorders that share a common genetic susceptibility.⁴

Focus on endometriosis implants may not fully address the disease

 

Practice Committee, American Society for Reprodutive Medicine. Treatment of pelvic pain associated with edometriosis. Fertil Steril. 2006;86:S156–S160.

Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-releasing hormone system—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol. 2006;125:9–28.

Because endometriosis involves the ectopic presence of endometrium in the pelvis or beyond, medical and surgical treatments have traditionally targeted the implants. However, American Fertility Society staging of the disease, based on a fundamentally oncologic model (volume and distribution), is poorly predictive of the 2 major clinical morbidities of endometriosis: pain and infertility. Hence, the mechanisms of pain remain obscure.

Three aspects of endometriosis deserve comment here:

• Successful treatment with a gonadotropin-releasing hormone (GnRH) agonist does not necessarily mean endometriosis is present
  
• The levonorgestrel-releasing intrauterine system (LNG-IUS) eases pain, suggesting uterine involvement
  
• Surrounding organ systems appear to contribute to the disease.
  

Is a presumptive diagnosis accurate?

When treatment of pelvic pain with first-line agents such as NSAIDs or oral contraceptives fails, it is common practice to make a presumptive diagnosis of endometriosis and administer a GnRH agonist. If pain is relieved, it is assumed that endometriosis was the cause, but data do not support this conclusion. In the study most often cited in support of preemptive GnRH-agonist treatment without laparoscopic diagnosis,⁵ women with and without endometriosis experienced pain relief with equal frequency. The ASRM concluded in its recent guideline that relief of pelvic pain in response to a GnRH agonist does not make the diagnosis of endometriosis. This agent interrupts the hypothalamic–pituitary–ovarian axis, causing hypoestrogenism and amenorrhea, and may alter pain by

• reducing contractility of intestinal muscle
  
• eliminating the physiologic perimenstrual rise in pain sensitivity
  
• quieting uterine contractions.
  

Evidence suggests a uterine link

According to Varma and colleagues, the easing of endometriosis-related pain with the LNG-IUS suggests that the uterus itself—as opposed to the peritoneal implants—plays an important role. (Women with chronic pelvic pain, with or without endometriosis, have increased nerve-fiber density in the lower uterine segment.⁶) Therefore, the benefits of progestins may be at least partly attributable to their quieting effect on uterine contractility, in addition to their direct impact on endometriosis implants, and therapies thought to target implants may relieve pain in part through their impact on the uterus.

In a randomized trial, the LNG-IUS relieved endometriosis-related pain as effectively as depot leuprolide.⁷ Given that this device may remain in place for 5 years, it offers substantial benefit.

What interstitial cystitis may reveal about endometriosis

Clinical evidence suggests that endometriosis and disorders of surrounding visceral systems (eg, interstitial cystitis and irritable bowel syndrome) share some morbidities. Assuming these associations are validated by epidemiologic investigations, the common denominator may be vulnerability to inflammation (or a deficit in counterinflammatory systems), nonspecific stress responses to the primary illness, genetically determined deficits in neuromodulation of nociceptive signals reaching the spinal chord,⁴ and other mechanisms awaiting discovery.

How myofascial tissue contributes to pelvic pain

Tu FF, As-Sanie S, Steege JF. Prevalence of pelvic musculoskeletal disorders in a female chronic pelvic pain clinic. J Reprod Med. 2006;51:185–189.

More than 20 years ago, Lipscomb and colleagues⁸ identified pelvic floor dysfunction as an important component of pelvic pain in women, and Slocumb⁹ described abdominal wall trigger points as another. We continue to gain appreciation of myofascial contributions to pelvic pain, although systematic study is lacking.

Tu and colleagues retrospectively studied the records of 987 women who presented to a chronic pelvic pain clinic for evaluation. Single-digit, intravaginal palpation revealed tenderness in the levator ani and piriformis muscles in 22% and 14% of women, respectively. Tenderness at these sites was associated with a higher total number of pain sites, previous surgery for pelvic pain, higher scores on the Beck Depression Inventory and McGill Pain Inventory, and worsening pain with bowel movements.

Muscles that are tender to palpation may, on occasion, be the prime movers in a pain syndrome, but my experience suggests that muscle problems often develop secondary to some other condition. For example, a woman with endometriosis may, over time, develop pelvic floor dysfunction as an important part of her dyspareunia, as a reaction to the tenderness in the posterior cul-de-sac. In a similar manner, muscle dysfunction may follow in the wake of pelvic infection or uterine enlargement, or after gynecologic surgery.

Suboptimal response to generally effective treatments is a common clue to the presence of myofascial and other factors. In this circumstance, rather than escalating treatment (eg, by operating repeatedly to treat endometriosis), the gynecologist should broaden the clinical inquiry by palpating the pelvic muscle groups during physical examination.

 

Can myofascial pain be treated?

Physical therapy has moved enthusiastically into the area of pelvic pain in general. Many clinicians and physical therapists have begun to look beyond the pelvic floor and recognize contributions from the hip external rotator muscles (piriformis, obturator), the sacroiliac joints, and the abdominal wall muscles. These muscle groups seem to communicate with each other at times. For example, palpation of the pelvic floor may refer pain to the ipsilateral lower abdominal wall, and palpation of the sacroiliac joint, which may be painful itself, may also refer pain to the corresponding anterior lower quadrant. The gynecologist can readily screen for these dysfunctions, with treatment provided by the physical therapist. Follow-up by the gynecologist then permits integration of all medical, surgical, and physical therapy.

Systematic studies are needed

At present, comparisons across treatment centers are complicated by variations in clinical assessment techniques. For example, the literature describing how the bladder contributes to pelvic pain often fails to describe assessment techniques for disorders in other systems (gastrointestinal, pelvic floor, etc). When increased bladder sensitivity is then demonstrated, the reader is left to wonder whether it is the prime mover in the problem or an epiphenomenon, secondary to some other disorder.

Dr. Steege reports no financial relationships with any company whose products are mentioned in this article.

CASE 1: Uterine atony leads to heavy bleeding

A 21-year-old nulliparous patient at 41 weeks’ gestation delivers vaginally after a prolonged second stage and chorioamnionitis. After placental separation, profound uterine atony is noted, and the patient begins to hemorrhage. The atony is unresponsive to bimanual massage, intravenous oxytocin, and intramuscular methylergonovine.

What can be done to stanch the flow?

Postpartum hemorrhage remains a leading cause of maternal death in the United States, and most cases are the direct consequence of uterine atony. As such, they generally respond to the timely administration of IV oxytocin or uterotonics. In this article, we focus on uncommon aspects of postpartum hemorrhage—such as bleeding that persists despite these basic maneuvers, as happened in Case 1.

STEP 1: Identify source of bleeding, administer uterotonic drugs

Three prostaglandins are among the uterotonic drugs available to clinicians for treating uterine atony (TABLE 1):

Carboprost tromethamine, a synthetic derivative of prostaglandin F, acts as a smooth-muscle constrictor. It can be injected intramuscularly or directly into the myometrium. Avoid carboprost tromethamine in patients with reactive airway disease, because it can cause bronchial smooth muscle to constrict.

Prostaglandin E₂, also known as dinoprostone, is available as a 20-mg vaginal suppository that should be administered rectally for postpartum hemorrhage to prevent the dose from being washed away by excessive blood flow. Dinoprostone is approved by the Food and Drug Administration (FDA) as an abortifacient and works by causing contraction of the smooth muscle of the uterus. Limitations include its high prevalence of side effects, including nausea, vomiting, fever, and diarrhea.

Misoprostol, a synthetic analogue of prostaglandin E₁, is FDA-approved for prevention of gastric ulcers. It is highly potent, stable at room temperature, inexpensive, and rapidly absorbed through oral, vaginal, and rectal routes of administration.¹ For treatment of postpartum uterine atony, place a dose of 1,000 μg (five 200-μg tablets) rectally. Uterine tone should improve within 3 minutes.²

For a list of other drugs and devices recommended for the labor and delivery suite, see TABLE 2.

TABLE 1

Uterotonic drugs: Instructions and cautions

DRUG	DOSAGE AND ROUTE	PRECAUTIONS
Oxytocin	10 U IM or 10–40 U in 1,000 mL of a balanced salt solution by IV infusion	Avoid infusing large doses 10–20 mL/min) for long periods due to antidiuretic effects of oxytocin
Methylergonovine	0.2 mg IM	Avoid if hypertension is present; avoid IV administration
Carboprost tromethamine	0.25 mg IM	Avoid in patients with asthma, cardiac, renal, or hepatic disease
Dinoprostone	20 mg rectally or intravaginally	Avoid in patients with cardiac, renal, or hepatic disease
Misoprostol	1,000 μg rectally	Avoid in patients with renal or hepatic failure

TABLE 2

Tools for the well-prepared labor and delivery unit

ITEM	APPLICATION
Uterotonic drugs (see TABLE 1)	Pharmacotherapy for uterine atony
Gauze rolls and sterile Mayo stand cover	Uterine packing
Bakri balloon	Intrauterine tamponade
Long size 1 chromic suture on larged curved needles	B-Lynch sutures (see FIGURE 1)
Long straight free needles and size 0 chromic suture	Hemostatic square sutures (see FIGURE 2)
Topical hemostatic agents: Gelfoam, thrombin, Tisseel, FloSeal	Topical hemostasis

STEP 2: Apply direct pressure to the uterine cavity

If uterotonic medications fail to control bleeding and improve uterine tone, apply direct pressure to the uterine cavity by packing it with gauze^3,4 or inserting a Bakri tamponade balloon device (Cook Women’s Health, Spencer, Ind).⁵

Uterine packing. The goal is to place direct pressure on all surfaces of the uterine cavity. This can be accomplished easily when the cervix has been fully dilated after vaginal delivery. Unfurl multiple rolls of moistened Kerlix gauze and evenly pack and cover the entire uterine cavity. Be sure to place the initial rolls of gauze high in the fundus, or blood may accumulate undetected behind the packing.

We begin by placing a sterile Mayo stand cover into the uterus, then apply packing inside the stand cover. This technique facilitates removal of the gauze and minimizes trauma to the endometrium (the packing does not stick to the uterine cavity when it is removed). Be sure to tie the ends of the gauze rolls together when using more than 1 roll.

Remove the packing 24 to 36 hours after placement. We remove the gauze in an operating room in case additional maneuvers are needed to control recurrent hemorrhage.

 

The Bakri balloon is a large Silastic balloon with a capacity of 500 mL that is designed to provide intrauterine tamponade for bleeding caused by atony, placenta previa, or focal placenta accreta. It has also been used to control hemorrhage associated with cervical ectopic pregnancy.⁵

A port with a lumen on the device makes it possible to assess the state of hemorrhage. The balloon is placed through the cervix and into the uterus after vaginal delivery, or in reverse fashion during cesarean delivery. It is then filled with saline to apply pressure to the bleeding surfaces of the endometrium.

Once the balloon is inflated, observe the catheter port for signs of continued hemorrhage. If bleeding remains brisk, further intervention will be necessary to control the hemorrhage. If bleeding slows appreciably, the balloon tamponade is likely to be successful and the patient can be observed.

Leave the balloon in place for 24 to 36 hours, then deflate it incrementally. If bleeding recurs when you deflate the balloon, reinflate it and leave it in place longer.

STEP 3: Control the blood supply to the uterus

If packing or tamponade is unsuccessful, the next step is radiographic uterine artery embolization or surgical ligation of the uterine blood supply with O’Leary sutures,⁶ followed by utero-ovarian vessel ligation, if necessary.⁷

Uterine artery embolization is an effective method of decreasing blood flow to the uterus. Only facilities with readily available interventional radiology services can perform the procedure, however, and the patient must be stable enough for transfer to the radiology suite. Because most cases of postpartum hemorrhage involve profuse blood loss, radiographic embolization is limited to cases of slow but continuing uterine blood loss.

Surgical ligation of the uterine blood supply is particularly useful. It requires a laparotomy incision after vaginal delivery but is easily performed at the time of cesarean delivery:

1. Create the bladder flap and mobilize the bladder inferiorly
2. Place a suture approximately 1 to 2 cm inferior to the level at which a low transverse uterine incision would be placed during cesarean delivery. This is done by pulling the broad ligament laterally using the thumb and index and middle fingers, and placing size 0 chromic suture, anterior to posterior, through the myometrium at the lateral margin of the uterus
3. Pass the suture through the broad ligament, posterior to anterior, staying well medial to the course of the ureter
4. Tie the suture to occlude the uterine vessels
5. Repeat on the opposite side.

 

If this procedure does not reduce the hemorrhage substantially, perform a high uterine artery ligation. This technique is identical to the inferior vessel ligation, but is performed approximately 5 cm superior to the first ligation site.

If these steps fail to reduce bleeding significantly, ligate the utero-ovarian blood supply bilaterally in similar fashion.

STEP 4: Place uterine compression sutures

The uterus can be externally compressed by the strategic placement of sutures.

The B-Lynch technique. This method⁸ begins with placement of a long size 1 chromic suture on a large curved needle through the anterior lateral aspect of the myometrium just below the repaired uterine incision during a cesarean delivery (FIGURE 1). (It is placed in the same anatomic location in the absence of a hysterotomy.) The suture then exits just above the uterine incision.

The suture is directed over the anterior surface of the myometrium, over the fundus, and down the posterior wall of the uterus, before reentering the myometrium at the inferior posterior lateral edge of the uterus and crossing horizontally to the opposite edge. The suture is then brought up over the posterior myometrium, over the fundus, and back across the anterior myometrium. It then reenters the anterior myometrium just above the uterine incision and exits just below it. The 2 free ends are tied together under tension while a surgical assistant manually compresses the uterus.

To determine the degree of blood loss, visually inspect the vagina. If the technique has been successful, close the abdomen and give the patient a uterotonic for 24 hours. Also, monitor urine output, hemoglobin, and hematocrit carefully and inspect the vagina frequently for blood loss.

FIGURE 1 Compress the uterus with the B-Lynch technique

Pass long size 1 chromic suture through the anterior uterine wall just below and above the usual site of a low-transverse incision, wrap the suture around the anterior and posterior uterine walls, and pass through the posterior wall opposite the entry point. Wrap the suture again and finish near the entry point on the anterior wall. Tie the ends tightly with the uterus under compression.The square-suture technique, described by Cho and colleagues,⁹ is also useful (FIGURE 2). It involves placement of size 1 chromic catgut suture using a free, long, straight Keith needle in the following steps:

1. Pass the suture through the myometrium, anterior to posterior
2. Pass the suture through the myometrium again, posterior to anterior, approximately 4 to 6 cm medial to the exit point of the first pass
3. Place the suture 4 to 6 cm inferior and pass it through the myometrium yet again, anterior to posterior
4. Pass the suture through the myometrium, posterior to anterior, 4 to 6 cm lateral to the last exit point
5. Tie the 2 free ends together under tension while a surgical assistant compresses the uterus in the anterior-to-posterior direction.

Place 3 to 5 of these sutures across the surface of the uterus until the resulting compression relieves the hemorrhage. Before closing the abdomen, inspect the vagina carefully to confirm the success of the procedure.

Both the B-Lynch and square-suture techniques are intended to preserve the patient’s fertility. If the patient has completed childbearing, consider prompt hysterectomy instead.

FIGURE 2 Compression option: Square-suture technique

Using size 1 chromic catgut suture on a free, long, straight Keith needle, stitch the anterior and posterior uterine walls together in 3 to 5 small squares. The ends of each square are then tied tightly while an assistant compresses the uterus from anterior to posterior.

STEP 5: Perform hysterectomy

If compression sutures and devascularization of the uterus fail to control the hemorrhage, hysterectomy is the next step.

CASE 2: Attached placenta exacerbates bleeding

A 36-year-old gravida 4 para 3 with 3 prior cesarean deliveries presents at 36 weeks’ gestation with heavy vaginal bleeding. A sonogram performed earlier in the pregnancy revealed an anterior placenta previa. The patient undergoes emergent cesarean delivery for continued brisk bleeding, but the placenta fails to detach from the uterus.

How would you proceed?

STEP 1: Attempt to separate the placenta from the uterus

Gently attempt to manually develop a separation plane between the placenta and uterus. If this proves impossible at all surfaces of the placenta, the accreta is global, and hysterectomy is warranted in most cases.

If placenta accreta or percreta is strongly suspected before delivery, avoid attempts to deliver the placenta and proceed to hysterectomy or planned retention.

STEP 2: Perform hysterectomy or planned retention

If a separation plane can be developed between the placenta and uterus, and only a small area is firmly adherent, the accreta is focal. An attempt to remove or excise the focally adherent placenta is reasonable. The attachment site can be oversewn to control bleeding, and the hemostatic square-suture technique or Bakri balloon may be helpful.

 

In a case series, Nishijima and colleagues¹⁰ described successful removal of the adherent placenta in 2 patients under direct visualization by inverting the uterus through a large midline uterine incision.

Kayem and colleagues¹¹ described ligation of the umbilical cord close to the placental insertion, with the placenta left in the uterus. They reviewed the records of all patients with the diagnosis of placenta accreta during 2 time frames:

• when management involved immediate hysterectomy
• when management was conservative with the placenta left in utero.

During conservative management, 3 of 20 patients underwent hysterectomy—1 at the patient’s request, 1 at the time of delivery due to hemorrhage, and 1 for bleeding on postoperative day 26 due to endometritis. The rates of disseminated intravascular coagulation and transfusion were lower during conservative management. Two women who underwent conservative management had subsequent successful pregnancies. One of these patients had 2 subsequent pregnancies, both complicated by placenta accreta that was again managed conservatively.

Long-term morbidity of conservative management is unclear

Because of the small number of cases reported, long-term morbidity and mortality rates due to hemorrhage or infection are unknown. Therefore, conservative management should be undertaken with extreme caution! Patients who have completed childbearing should be managed by hysterectomy.

In some cases, conservative management of placenta accreta may serve as a temporizing measure to allow for transfer to a higher level of care when immediate postpartum hysterectomy is not safe or feasible.

When the bladder is involved

When placenta percreta involves the urinary bladder, conservative management may be the only safe option because of the irreparable harm that could occur to the lower urinary tract during hysterectomy.¹² (Imagine the urinary tract injuries that could occur during hysterectomy for the patients in FIGURE 3 A and B!)

In these cases, conservative management involves delivering the fetus through a classical uterine incision, ligating the umbilical cord close to the placental insertion, and closing the uterine incision. Avoid attempts to remove the placenta. Give the patient a broad-spectrum prophylactic antibiotic such as amoxicillin/clavulanic acid for 10 days.¹¹ Assess the patient weekly for 6 weeks with ultrasonography, clinical examination, and a white blood cell count with differential (to assess for signs of infection). It may take 6 to 10 months for the placenta to be entirely reabsorbed.

FIGURE 3A Bladder wall involvement

This ultrasonographic image shows placenta percreta involving the posterior bladder wall.

FIGURE 3B Bladder wall involvement

Placenta percreta that has eroded through the entire lower uterine segment and into the bladder. Photo from Stoehr E, Stitely M. Placenta percreta diagnosed antenatally with magnetic resonance imaging. The Female Patient. 2005;30:37–39. Used with permission.

Manage blood replacement

Few community hospitals keep a large reserve of blood products in stock. A massive obstetric hemorrhage can rapidly deplete blood-bank stores and necessitate transferring the patient or obtaining products from other hospitals or facilities. For this reason, the blood bank should be notified of postpartum hemorrhage as soon as possible, and the possibility of using emergency-release, type-specific blood should be discussed with blood-bank medical personnel.

When to transfuse red blood cells

Administer packed red blood cells (RBCs) if the hemorrhage is profuse and ongoing or if the patient is hemodynamically unstable. Each unit of packed RBCs increases the hematocrit by approximately 3% and raises the hemoglobin level by approximately 1 g.

If coagulopathy is suspected, or the patient has received more than 6 to 8 U of packed RBCs, consider transfusing fresh frozen plasma.

 

Blood studies are also indicated

Send blood to the laboratory for measurement of prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen. If the hospital is not equipped to measure fibrinogen, perform a rapidclot observation test¹³ by filling a plain, red-top tube with blood and observing it for clotting. If a clot forms in 8 to 10 minutes and remains intact, the test is normal. When the fibrinogen level is less than 150 mg/dL, the blood will not clot or the clot will dissolve in 30 to 60 minutes.

This rapid test can guide the decision to infuse fresh frozen plasma. Each unit of fresh frozen plasma raises the fibrinogen level by 10 mg/dL. The goal is to keep the fibrinogen level above 100 mg/dL.

Platelet count often declines during hemorrhage

When blood loss is ongoing, try to keep the platelet count above 50×10³/μL. Each unit of platelets will increase the platelet count by 5–10×10³/μL. However, platelets are rapidly destroyed after transfusion, so continue to assess hemoglobin level, hematocrit, platelet count, and coagulation parameters. Also, check calcium and electrolyte levels, and correct levels after the transfusion of every 4 U of blood.

Cell-saver technology is an option for management of postpartum hemorrhage, once the surgical field has been cleared of amniotic fluid.¹⁴

Volume replacement can be accomplished with concurrent administration of crystalloid or other volume expanders, such as hetastarch (Hespan) or albumin. Monitor urine output to gauge the adequacy of volume replenishment.

Consider contacting a referral center about patient transfer or additional blood products if bleeding is ongoing or coagulation defects persist.

The authors report no financial relationships relevant to this article.

CASE 1: Uterine atony leads to heavy bleeding

A 21-year-old nulliparous patient at 41 weeks’ gestation delivers vaginally after a prolonged second stage and chorioamnionitis. After placental separation, profound uterine atony is noted, and the patient begins to hemorrhage. The atony is unresponsive to bimanual massage, intravenous oxytocin, and intramuscular methylergonovine.

What can be done to stanch the flow?

Postpartum hemorrhage remains a leading cause of maternal death in the United States, and most cases are the direct consequence of uterine atony. As such, they generally respond to the timely administration of IV oxytocin or uterotonics. In this article, we focus on uncommon aspects of postpartum hemorrhage—such as bleeding that persists despite these basic maneuvers, as happened in Case 1.

STEP 1: Identify source of bleeding, administer uterotonic drugs

Three prostaglandins are among the uterotonic drugs available to clinicians for treating uterine atony (TABLE 1):

Carboprost tromethamine, a synthetic derivative of prostaglandin F, acts as a smooth-muscle constrictor. It can be injected intramuscularly or directly into the myometrium. Avoid carboprost tromethamine in patients with reactive airway disease, because it can cause bronchial smooth muscle to constrict.

Prostaglandin E₂, also known as dinoprostone, is available as a 20-mg vaginal suppository that should be administered rectally for postpartum hemorrhage to prevent the dose from being washed away by excessive blood flow. Dinoprostone is approved by the Food and Drug Administration (FDA) as an abortifacient and works by causing contraction of the smooth muscle of the uterus. Limitations include its high prevalence of side effects, including nausea, vomiting, fever, and diarrhea.

Misoprostol, a synthetic analogue of prostaglandin E₁, is FDA-approved for prevention of gastric ulcers. It is highly potent, stable at room temperature, inexpensive, and rapidly absorbed through oral, vaginal, and rectal routes of administration.¹ For treatment of postpartum uterine atony, place a dose of 1,000 μg (five 200-μg tablets) rectally. Uterine tone should improve within 3 minutes.²

For a list of other drugs and devices recommended for the labor and delivery suite, see TABLE 2.

TABLE 1

Uterotonic drugs: Instructions and cautions

DRUG	DOSAGE AND ROUTE	PRECAUTIONS
Oxytocin	10 U IM or 10–40 U in 1,000 mL of a balanced salt solution by IV infusion	Avoid infusing large doses 10–20 mL/min) for long periods due to antidiuretic effects of oxytocin
Methylergonovine	0.2 mg IM	Avoid if hypertension is present; avoid IV administration
Carboprost tromethamine	0.25 mg IM	Avoid in patients with asthma, cardiac, renal, or hepatic disease
Dinoprostone	20 mg rectally or intravaginally	Avoid in patients with cardiac, renal, or hepatic disease
Misoprostol	1,000 μg rectally	Avoid in patients with renal or hepatic failure

TABLE 2

Tools for the well-prepared labor and delivery unit

ITEM	APPLICATION
Uterotonic drugs (see TABLE 1)	Pharmacotherapy for uterine atony
Gauze rolls and sterile Mayo stand cover	Uterine packing
Bakri balloon	Intrauterine tamponade
Long size 1 chromic suture on larged curved needles	B-Lynch sutures (see FIGURE 1)
Long straight free needles and size 0 chromic suture	Hemostatic square sutures (see FIGURE 2)
Topical hemostatic agents: Gelfoam, thrombin, Tisseel, FloSeal	Topical hemostasis

STEP 2: Apply direct pressure to the uterine cavity

If uterotonic medications fail to control bleeding and improve uterine tone, apply direct pressure to the uterine cavity by packing it with gauze^3,4 or inserting a Bakri tamponade balloon device (Cook Women’s Health, Spencer, Ind).⁵

Uterine packing. The goal is to place direct pressure on all surfaces of the uterine cavity. This can be accomplished easily when the cervix has been fully dilated after vaginal delivery. Unfurl multiple rolls of moistened Kerlix gauze and evenly pack and cover the entire uterine cavity. Be sure to place the initial rolls of gauze high in the fundus, or blood may accumulate undetected behind the packing.

We begin by placing a sterile Mayo stand cover into the uterus, then apply packing inside the stand cover. This technique facilitates removal of the gauze and minimizes trauma to the endometrium (the packing does not stick to the uterine cavity when it is removed). Be sure to tie the ends of the gauze rolls together when using more than 1 roll.

Remove the packing 24 to 36 hours after placement. We remove the gauze in an operating room in case additional maneuvers are needed to control recurrent hemorrhage.

 

The Bakri balloon is a large Silastic balloon with a capacity of 500 mL that is designed to provide intrauterine tamponade for bleeding caused by atony, placenta previa, or focal placenta accreta. It has also been used to control hemorrhage associated with cervical ectopic pregnancy.⁵

A port with a lumen on the device makes it possible to assess the state of hemorrhage. The balloon is placed through the cervix and into the uterus after vaginal delivery, or in reverse fashion during cesarean delivery. It is then filled with saline to apply pressure to the bleeding surfaces of the endometrium.

Once the balloon is inflated, observe the catheter port for signs of continued hemorrhage. If bleeding remains brisk, further intervention will be necessary to control the hemorrhage. If bleeding slows appreciably, the balloon tamponade is likely to be successful and the patient can be observed.

Leave the balloon in place for 24 to 36 hours, then deflate it incrementally. If bleeding recurs when you deflate the balloon, reinflate it and leave it in place longer.

STEP 3: Control the blood supply to the uterus

If packing or tamponade is unsuccessful, the next step is radiographic uterine artery embolization or surgical ligation of the uterine blood supply with O’Leary sutures,⁶ followed by utero-ovarian vessel ligation, if necessary.⁷

Uterine artery embolization is an effective method of decreasing blood flow to the uterus. Only facilities with readily available interventional radiology services can perform the procedure, however, and the patient must be stable enough for transfer to the radiology suite. Because most cases of postpartum hemorrhage involve profuse blood loss, radiographic embolization is limited to cases of slow but continuing uterine blood loss.

Surgical ligation of the uterine blood supply is particularly useful. It requires a laparotomy incision after vaginal delivery but is easily performed at the time of cesarean delivery:

1. Create the bladder flap and mobilize the bladder inferiorly
2. Place a suture approximately 1 to 2 cm inferior to the level at which a low transverse uterine incision would be placed during cesarean delivery. This is done by pulling the broad ligament laterally using the thumb and index and middle fingers, and placing size 0 chromic suture, anterior to posterior, through the myometrium at the lateral margin of the uterus
3. Pass the suture through the broad ligament, posterior to anterior, staying well medial to the course of the ureter
4. Tie the suture to occlude the uterine vessels
5. Repeat on the opposite side.

 

If this procedure does not reduce the hemorrhage substantially, perform a high uterine artery ligation. This technique is identical to the inferior vessel ligation, but is performed approximately 5 cm superior to the first ligation site.

If these steps fail to reduce bleeding significantly, ligate the utero-ovarian blood supply bilaterally in similar fashion.

STEP 4: Place uterine compression sutures

The uterus can be externally compressed by the strategic placement of sutures.

The B-Lynch technique. This method⁸ begins with placement of a long size 1 chromic suture on a large curved needle through the anterior lateral aspect of the myometrium just below the repaired uterine incision during a cesarean delivery (FIGURE 1). (It is placed in the same anatomic location in the absence of a hysterotomy.) The suture then exits just above the uterine incision.

The suture is directed over the anterior surface of the myometrium, over the fundus, and down the posterior wall of the uterus, before reentering the myometrium at the inferior posterior lateral edge of the uterus and crossing horizontally to the opposite edge. The suture is then brought up over the posterior myometrium, over the fundus, and back across the anterior myometrium. It then reenters the anterior myometrium just above the uterine incision and exits just below it. The 2 free ends are tied together under tension while a surgical assistant manually compresses the uterus.

To determine the degree of blood loss, visually inspect the vagina. If the technique has been successful, close the abdomen and give the patient a uterotonic for 24 hours. Also, monitor urine output, hemoglobin, and hematocrit carefully and inspect the vagina frequently for blood loss.

FIGURE 1 Compress the uterus with the B-Lynch technique

Pass long size 1 chromic suture through the anterior uterine wall just below and above the usual site of a low-transverse incision, wrap the suture around the anterior and posterior uterine walls, and pass through the posterior wall opposite the entry point. Wrap the suture again and finish near the entry point on the anterior wall. Tie the ends tightly with the uterus under compression.The square-suture technique, described by Cho and colleagues,⁹ is also useful (FIGURE 2). It involves placement of size 1 chromic catgut suture using a free, long, straight Keith needle in the following steps:

1. Pass the suture through the myometrium, anterior to posterior
2. Pass the suture through the myometrium again, posterior to anterior, approximately 4 to 6 cm medial to the exit point of the first pass
3. Place the suture 4 to 6 cm inferior and pass it through the myometrium yet again, anterior to posterior
4. Pass the suture through the myometrium, posterior to anterior, 4 to 6 cm lateral to the last exit point
5. Tie the 2 free ends together under tension while a surgical assistant compresses the uterus in the anterior-to-posterior direction.

Place 3 to 5 of these sutures across the surface of the uterus until the resulting compression relieves the hemorrhage. Before closing the abdomen, inspect the vagina carefully to confirm the success of the procedure.

Both the B-Lynch and square-suture techniques are intended to preserve the patient’s fertility. If the patient has completed childbearing, consider prompt hysterectomy instead.

FIGURE 2 Compression option: Square-suture technique

Using size 1 chromic catgut suture on a free, long, straight Keith needle, stitch the anterior and posterior uterine walls together in 3 to 5 small squares. The ends of each square are then tied tightly while an assistant compresses the uterus from anterior to posterior.

STEP 5: Perform hysterectomy

If compression sutures and devascularization of the uterus fail to control the hemorrhage, hysterectomy is the next step.

CASE 2: Attached placenta exacerbates bleeding

A 36-year-old gravida 4 para 3 with 3 prior cesarean deliveries presents at 36 weeks’ gestation with heavy vaginal bleeding. A sonogram performed earlier in the pregnancy revealed an anterior placenta previa. The patient undergoes emergent cesarean delivery for continued brisk bleeding, but the placenta fails to detach from the uterus.

How would you proceed?

STEP 1: Attempt to separate the placenta from the uterus

Gently attempt to manually develop a separation plane between the placenta and uterus. If this proves impossible at all surfaces of the placenta, the accreta is global, and hysterectomy is warranted in most cases.

If placenta accreta or percreta is strongly suspected before delivery, avoid attempts to deliver the placenta and proceed to hysterectomy or planned retention.

STEP 2: Perform hysterectomy or planned retention

If a separation plane can be developed between the placenta and uterus, and only a small area is firmly adherent, the accreta is focal. An attempt to remove or excise the focally adherent placenta is reasonable. The attachment site can be oversewn to control bleeding, and the hemostatic square-suture technique or Bakri balloon may be helpful.

 

In a case series, Nishijima and colleagues¹⁰ described successful removal of the adherent placenta in 2 patients under direct visualization by inverting the uterus through a large midline uterine incision.

Kayem and colleagues¹¹ described ligation of the umbilical cord close to the placental insertion, with the placenta left in the uterus. They reviewed the records of all patients with the diagnosis of placenta accreta during 2 time frames:

• when management involved immediate hysterectomy
• when management was conservative with the placenta left in utero.

During conservative management, 3 of 20 patients underwent hysterectomy—1 at the patient’s request, 1 at the time of delivery due to hemorrhage, and 1 for bleeding on postoperative day 26 due to endometritis. The rates of disseminated intravascular coagulation and transfusion were lower during conservative management. Two women who underwent conservative management had subsequent successful pregnancies. One of these patients had 2 subsequent pregnancies, both complicated by placenta accreta that was again managed conservatively.

Long-term morbidity of conservative management is unclear

Because of the small number of cases reported, long-term morbidity and mortality rates due to hemorrhage or infection are unknown. Therefore, conservative management should be undertaken with extreme caution! Patients who have completed childbearing should be managed by hysterectomy.

In some cases, conservative management of placenta accreta may serve as a temporizing measure to allow for transfer to a higher level of care when immediate postpartum hysterectomy is not safe or feasible.

When the bladder is involved

When placenta percreta involves the urinary bladder, conservative management may be the only safe option because of the irreparable harm that could occur to the lower urinary tract during hysterectomy.¹² (Imagine the urinary tract injuries that could occur during hysterectomy for the patients in FIGURE 3 A and B!)

In these cases, conservative management involves delivering the fetus through a classical uterine incision, ligating the umbilical cord close to the placental insertion, and closing the uterine incision. Avoid attempts to remove the placenta. Give the patient a broad-spectrum prophylactic antibiotic such as amoxicillin/clavulanic acid for 10 days.¹¹ Assess the patient weekly for 6 weeks with ultrasonography, clinical examination, and a white blood cell count with differential (to assess for signs of infection). It may take 6 to 10 months for the placenta to be entirely reabsorbed.

FIGURE 3A Bladder wall involvement

This ultrasonographic image shows placenta percreta involving the posterior bladder wall.

FIGURE 3B Bladder wall involvement

Placenta percreta that has eroded through the entire lower uterine segment and into the bladder. Photo from Stoehr E, Stitely M. Placenta percreta diagnosed antenatally with magnetic resonance imaging. The Female Patient. 2005;30:37–39. Used with permission.

Manage blood replacement

Few community hospitals keep a large reserve of blood products in stock. A massive obstetric hemorrhage can rapidly deplete blood-bank stores and necessitate transferring the patient or obtaining products from other hospitals or facilities. For this reason, the blood bank should be notified of postpartum hemorrhage as soon as possible, and the possibility of using emergency-release, type-specific blood should be discussed with blood-bank medical personnel.

When to transfuse red blood cells

Administer packed red blood cells (RBCs) if the hemorrhage is profuse and ongoing or if the patient is hemodynamically unstable. Each unit of packed RBCs increases the hematocrit by approximately 3% and raises the hemoglobin level by approximately 1 g.

If coagulopathy is suspected, or the patient has received more than 6 to 8 U of packed RBCs, consider transfusing fresh frozen plasma.

 

Blood studies are also indicated

Send blood to the laboratory for measurement of prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen. If the hospital is not equipped to measure fibrinogen, perform a rapidclot observation test¹³ by filling a plain, red-top tube with blood and observing it for clotting. If a clot forms in 8 to 10 minutes and remains intact, the test is normal. When the fibrinogen level is less than 150 mg/dL, the blood will not clot or the clot will dissolve in 30 to 60 minutes.

This rapid test can guide the decision to infuse fresh frozen plasma. Each unit of fresh frozen plasma raises the fibrinogen level by 10 mg/dL. The goal is to keep the fibrinogen level above 100 mg/dL.

Platelet count often declines during hemorrhage

When blood loss is ongoing, try to keep the platelet count above 50×10³/μL. Each unit of platelets will increase the platelet count by 5–10×10³/μL. However, platelets are rapidly destroyed after transfusion, so continue to assess hemoglobin level, hematocrit, platelet count, and coagulation parameters. Also, check calcium and electrolyte levels, and correct levels after the transfusion of every 4 U of blood.

Cell-saver technology is an option for management of postpartum hemorrhage, once the surgical field has been cleared of amniotic fluid.¹⁴

Volume replacement can be accomplished with concurrent administration of crystalloid or other volume expanders, such as hetastarch (Hespan) or albumin. Monitor urine output to gauge the adequacy of volume replenishment.

Consider contacting a referral center about patient transfer or additional blood products if bleeding is ongoing or coagulation defects persist.

The authors report no financial relationships relevant to this article.

CASE 1: Uterine atony leads to heavy bleeding

A 21-year-old nulliparous patient at 41 weeks’ gestation delivers vaginally after a prolonged second stage and chorioamnionitis. After placental separation, profound uterine atony is noted, and the patient begins to hemorrhage. The atony is unresponsive to bimanual massage, intravenous oxytocin, and intramuscular methylergonovine.

What can be done to stanch the flow?

Postpartum hemorrhage remains a leading cause of maternal death in the United States, and most cases are the direct consequence of uterine atony. As such, they generally respond to the timely administration of IV oxytocin or uterotonics. In this article, we focus on uncommon aspects of postpartum hemorrhage—such as bleeding that persists despite these basic maneuvers, as happened in Case 1.

STEP 1: Identify source of bleeding, administer uterotonic drugs

Three prostaglandins are among the uterotonic drugs available to clinicians for treating uterine atony (TABLE 1):

Carboprost tromethamine, a synthetic derivative of prostaglandin F, acts as a smooth-muscle constrictor. It can be injected intramuscularly or directly into the myometrium. Avoid carboprost tromethamine in patients with reactive airway disease, because it can cause bronchial smooth muscle to constrict.

Prostaglandin E₂, also known as dinoprostone, is available as a 20-mg vaginal suppository that should be administered rectally for postpartum hemorrhage to prevent the dose from being washed away by excessive blood flow. Dinoprostone is approved by the Food and Drug Administration (FDA) as an abortifacient and works by causing contraction of the smooth muscle of the uterus. Limitations include its high prevalence of side effects, including nausea, vomiting, fever, and diarrhea.

Misoprostol, a synthetic analogue of prostaglandin E₁, is FDA-approved for prevention of gastric ulcers. It is highly potent, stable at room temperature, inexpensive, and rapidly absorbed through oral, vaginal, and rectal routes of administration.¹ For treatment of postpartum uterine atony, place a dose of 1,000 μg (five 200-μg tablets) rectally. Uterine tone should improve within 3 minutes.²

For a list of other drugs and devices recommended for the labor and delivery suite, see TABLE 2.

TABLE 1

Uterotonic drugs: Instructions and cautions

DRUG	DOSAGE AND ROUTE	PRECAUTIONS
Oxytocin	10 U IM or 10–40 U in 1,000 mL of a balanced salt solution by IV infusion	Avoid infusing large doses 10–20 mL/min) for long periods due to antidiuretic effects of oxytocin
Methylergonovine	0.2 mg IM	Avoid if hypertension is present; avoid IV administration
Carboprost tromethamine	0.25 mg IM	Avoid in patients with asthma, cardiac, renal, or hepatic disease
Dinoprostone	20 mg rectally or intravaginally	Avoid in patients with cardiac, renal, or hepatic disease
Misoprostol	1,000 μg rectally	Avoid in patients with renal or hepatic failure

TABLE 2

Tools for the well-prepared labor and delivery unit

ITEM	APPLICATION
Uterotonic drugs (see TABLE 1)	Pharmacotherapy for uterine atony
Gauze rolls and sterile Mayo stand cover	Uterine packing
Bakri balloon	Intrauterine tamponade
Long size 1 chromic suture on larged curved needles	B-Lynch sutures (see FIGURE 1)
Long straight free needles and size 0 chromic suture	Hemostatic square sutures (see FIGURE 2)
Topical hemostatic agents: Gelfoam, thrombin, Tisseel, FloSeal	Topical hemostasis

STEP 2: Apply direct pressure to the uterine cavity

If uterotonic medications fail to control bleeding and improve uterine tone, apply direct pressure to the uterine cavity by packing it with gauze^3,4 or inserting a Bakri tamponade balloon device (Cook Women’s Health, Spencer, Ind).⁵

Uterine packing. The goal is to place direct pressure on all surfaces of the uterine cavity. This can be accomplished easily when the cervix has been fully dilated after vaginal delivery. Unfurl multiple rolls of moistened Kerlix gauze and evenly pack and cover the entire uterine cavity. Be sure to place the initial rolls of gauze high in the fundus, or blood may accumulate undetected behind the packing.

We begin by placing a sterile Mayo stand cover into the uterus, then apply packing inside the stand cover. This technique facilitates removal of the gauze and minimizes trauma to the endometrium (the packing does not stick to the uterine cavity when it is removed). Be sure to tie the ends of the gauze rolls together when using more than 1 roll.

Remove the packing 24 to 36 hours after placement. We remove the gauze in an operating room in case additional maneuvers are needed to control recurrent hemorrhage.

 

The Bakri balloon is a large Silastic balloon with a capacity of 500 mL that is designed to provide intrauterine tamponade for bleeding caused by atony, placenta previa, or focal placenta accreta. It has also been used to control hemorrhage associated with cervical ectopic pregnancy.⁵

A port with a lumen on the device makes it possible to assess the state of hemorrhage. The balloon is placed through the cervix and into the uterus after vaginal delivery, or in reverse fashion during cesarean delivery. It is then filled with saline to apply pressure to the bleeding surfaces of the endometrium.

Once the balloon is inflated, observe the catheter port for signs of continued hemorrhage. If bleeding remains brisk, further intervention will be necessary to control the hemorrhage. If bleeding slows appreciably, the balloon tamponade is likely to be successful and the patient can be observed.

Leave the balloon in place for 24 to 36 hours, then deflate it incrementally. If bleeding recurs when you deflate the balloon, reinflate it and leave it in place longer.

STEP 3: Control the blood supply to the uterus

If packing or tamponade is unsuccessful, the next step is radiographic uterine artery embolization or surgical ligation of the uterine blood supply with O’Leary sutures,⁶ followed by utero-ovarian vessel ligation, if necessary.⁷

Uterine artery embolization is an effective method of decreasing blood flow to the uterus. Only facilities with readily available interventional radiology services can perform the procedure, however, and the patient must be stable enough for transfer to the radiology suite. Because most cases of postpartum hemorrhage involve profuse blood loss, radiographic embolization is limited to cases of slow but continuing uterine blood loss.

Surgical ligation of the uterine blood supply is particularly useful. It requires a laparotomy incision after vaginal delivery but is easily performed at the time of cesarean delivery:

1. Create the bladder flap and mobilize the bladder inferiorly
2. Place a suture approximately 1 to 2 cm inferior to the level at which a low transverse uterine incision would be placed during cesarean delivery. This is done by pulling the broad ligament laterally using the thumb and index and middle fingers, and placing size 0 chromic suture, anterior to posterior, through the myometrium at the lateral margin of the uterus
3. Pass the suture through the broad ligament, posterior to anterior, staying well medial to the course of the ureter
4. Tie the suture to occlude the uterine vessels
5. Repeat on the opposite side.

 

If this procedure does not reduce the hemorrhage substantially, perform a high uterine artery ligation. This technique is identical to the inferior vessel ligation, but is performed approximately 5 cm superior to the first ligation site.

If these steps fail to reduce bleeding significantly, ligate the utero-ovarian blood supply bilaterally in similar fashion.

STEP 4: Place uterine compression sutures

The uterus can be externally compressed by the strategic placement of sutures.

The B-Lynch technique. This method⁸ begins with placement of a long size 1 chromic suture on a large curved needle through the anterior lateral aspect of the myometrium just below the repaired uterine incision during a cesarean delivery (FIGURE 1). (It is placed in the same anatomic location in the absence of a hysterotomy.) The suture then exits just above the uterine incision.

The suture is directed over the anterior surface of the myometrium, over the fundus, and down the posterior wall of the uterus, before reentering the myometrium at the inferior posterior lateral edge of the uterus and crossing horizontally to the opposite edge. The suture is then brought up over the posterior myometrium, over the fundus, and back across the anterior myometrium. It then reenters the anterior myometrium just above the uterine incision and exits just below it. The 2 free ends are tied together under tension while a surgical assistant manually compresses the uterus.

To determine the degree of blood loss, visually inspect the vagina. If the technique has been successful, close the abdomen and give the patient a uterotonic for 24 hours. Also, monitor urine output, hemoglobin, and hematocrit carefully and inspect the vagina frequently for blood loss.

FIGURE 1 Compress the uterus with the B-Lynch technique

Pass long size 1 chromic suture through the anterior uterine wall just below and above the usual site of a low-transverse incision, wrap the suture around the anterior and posterior uterine walls, and pass through the posterior wall opposite the entry point. Wrap the suture again and finish near the entry point on the anterior wall. Tie the ends tightly with the uterus under compression.The square-suture technique, described by Cho and colleagues,⁹ is also useful (FIGURE 2). It involves placement of size 1 chromic catgut suture using a free, long, straight Keith needle in the following steps:

1. Pass the suture through the myometrium, anterior to posterior
2. Pass the suture through the myometrium again, posterior to anterior, approximately 4 to 6 cm medial to the exit point of the first pass
3. Place the suture 4 to 6 cm inferior and pass it through the myometrium yet again, anterior to posterior
4. Pass the suture through the myometrium, posterior to anterior, 4 to 6 cm lateral to the last exit point
5. Tie the 2 free ends together under tension while a surgical assistant compresses the uterus in the anterior-to-posterior direction.

Place 3 to 5 of these sutures across the surface of the uterus until the resulting compression relieves the hemorrhage. Before closing the abdomen, inspect the vagina carefully to confirm the success of the procedure.

Both the B-Lynch and square-suture techniques are intended to preserve the patient’s fertility. If the patient has completed childbearing, consider prompt hysterectomy instead.

FIGURE 2 Compression option: Square-suture technique

Using size 1 chromic catgut suture on a free, long, straight Keith needle, stitch the anterior and posterior uterine walls together in 3 to 5 small squares. The ends of each square are then tied tightly while an assistant compresses the uterus from anterior to posterior.

STEP 5: Perform hysterectomy

If compression sutures and devascularization of the uterus fail to control the hemorrhage, hysterectomy is the next step.

CASE 2: Attached placenta exacerbates bleeding

A 36-year-old gravida 4 para 3 with 3 prior cesarean deliveries presents at 36 weeks’ gestation with heavy vaginal bleeding. A sonogram performed earlier in the pregnancy revealed an anterior placenta previa. The patient undergoes emergent cesarean delivery for continued brisk bleeding, but the placenta fails to detach from the uterus.

How would you proceed?

STEP 1: Attempt to separate the placenta from the uterus

Gently attempt to manually develop a separation plane between the placenta and uterus. If this proves impossible at all surfaces of the placenta, the accreta is global, and hysterectomy is warranted in most cases.

If placenta accreta or percreta is strongly suspected before delivery, avoid attempts to deliver the placenta and proceed to hysterectomy or planned retention.

STEP 2: Perform hysterectomy or planned retention

If a separation plane can be developed between the placenta and uterus, and only a small area is firmly adherent, the accreta is focal. An attempt to remove or excise the focally adherent placenta is reasonable. The attachment site can be oversewn to control bleeding, and the hemostatic square-suture technique or Bakri balloon may be helpful.

 

In a case series, Nishijima and colleagues¹⁰ described successful removal of the adherent placenta in 2 patients under direct visualization by inverting the uterus through a large midline uterine incision.

Kayem and colleagues¹¹ described ligation of the umbilical cord close to the placental insertion, with the placenta left in the uterus. They reviewed the records of all patients with the diagnosis of placenta accreta during 2 time frames:

• when management involved immediate hysterectomy
• when management was conservative with the placenta left in utero.

During conservative management, 3 of 20 patients underwent hysterectomy—1 at the patient’s request, 1 at the time of delivery due to hemorrhage, and 1 for bleeding on postoperative day 26 due to endometritis. The rates of disseminated intravascular coagulation and transfusion were lower during conservative management. Two women who underwent conservative management had subsequent successful pregnancies. One of these patients had 2 subsequent pregnancies, both complicated by placenta accreta that was again managed conservatively.

Long-term morbidity of conservative management is unclear

Because of the small number of cases reported, long-term morbidity and mortality rates due to hemorrhage or infection are unknown. Therefore, conservative management should be undertaken with extreme caution! Patients who have completed childbearing should be managed by hysterectomy.

In some cases, conservative management of placenta accreta may serve as a temporizing measure to allow for transfer to a higher level of care when immediate postpartum hysterectomy is not safe or feasible.

When the bladder is involved

When placenta percreta involves the urinary bladder, conservative management may be the only safe option because of the irreparable harm that could occur to the lower urinary tract during hysterectomy.¹² (Imagine the urinary tract injuries that could occur during hysterectomy for the patients in FIGURE 3 A and B!)

In these cases, conservative management involves delivering the fetus through a classical uterine incision, ligating the umbilical cord close to the placental insertion, and closing the uterine incision. Avoid attempts to remove the placenta. Give the patient a broad-spectrum prophylactic antibiotic such as amoxicillin/clavulanic acid for 10 days.¹¹ Assess the patient weekly for 6 weeks with ultrasonography, clinical examination, and a white blood cell count with differential (to assess for signs of infection). It may take 6 to 10 months for the placenta to be entirely reabsorbed.

FIGURE 3A Bladder wall involvement

This ultrasonographic image shows placenta percreta involving the posterior bladder wall.

FIGURE 3B Bladder wall involvement

Placenta percreta that has eroded through the entire lower uterine segment and into the bladder. Photo from Stoehr E, Stitely M. Placenta percreta diagnosed antenatally with magnetic resonance imaging. The Female Patient. 2005;30:37–39. Used with permission.

Manage blood replacement

Few community hospitals keep a large reserve of blood products in stock. A massive obstetric hemorrhage can rapidly deplete blood-bank stores and necessitate transferring the patient or obtaining products from other hospitals or facilities. For this reason, the blood bank should be notified of postpartum hemorrhage as soon as possible, and the possibility of using emergency-release, type-specific blood should be discussed with blood-bank medical personnel.

When to transfuse red blood cells

Administer packed red blood cells (RBCs) if the hemorrhage is profuse and ongoing or if the patient is hemodynamically unstable. Each unit of packed RBCs increases the hematocrit by approximately 3% and raises the hemoglobin level by approximately 1 g.

If coagulopathy is suspected, or the patient has received more than 6 to 8 U of packed RBCs, consider transfusing fresh frozen plasma.

 

Blood studies are also indicated

Send blood to the laboratory for measurement of prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen. If the hospital is not equipped to measure fibrinogen, perform a rapidclot observation test¹³ by filling a plain, red-top tube with blood and observing it for clotting. If a clot forms in 8 to 10 minutes and remains intact, the test is normal. When the fibrinogen level is less than 150 mg/dL, the blood will not clot or the clot will dissolve in 30 to 60 minutes.

This rapid test can guide the decision to infuse fresh frozen plasma. Each unit of fresh frozen plasma raises the fibrinogen level by 10 mg/dL. The goal is to keep the fibrinogen level above 100 mg/dL.

Platelet count often declines during hemorrhage

When blood loss is ongoing, try to keep the platelet count above 50×10³/μL. Each unit of platelets will increase the platelet count by 5–10×10³/μL. However, platelets are rapidly destroyed after transfusion, so continue to assess hemoglobin level, hematocrit, platelet count, and coagulation parameters. Also, check calcium and electrolyte levels, and correct levels after the transfusion of every 4 U of blood.

Cell-saver technology is an option for management of postpartum hemorrhage, once the surgical field has been cleared of amniotic fluid.¹⁴

Volume replacement can be accomplished with concurrent administration of crystalloid or other volume expanders, such as hetastarch (Hespan) or albumin. Monitor urine output to gauge the adequacy of volume replenishment.

Consider contacting a referral center about patient transfer or additional blood products if bleeding is ongoing or coagulation defects persist.

The authors report no financial relationships relevant to this article.