Clinical Review

Dr. Mitwally holds patents licensed to Serono for use of aromatase inhibitors for infertility treatment.

Dr. Casper has a licensing agreement with Ares-Serono for use of aromatase inhibitors in assisted reproduction.

CASE 1 Ovulation begins, but pregnancy does not follow

U.Y. is a 32-year-old woman who has been trying to conceive for 3 years. Her infertility is caused by anovulation associated with polycystic ovary syndrome (PCOS). All other variables are within physiologic limits—she has patent tubes and an unremarkable uterus, and her partner has a normal semen analysis.

She has undergone six cycles of treatment with clomiphene citrate, with ovulation documented each time by ultrasonography (US) and measurement of luteal-phase progesterone levels. Her endometrial thickness is 4 to 6 mm around the day of ovulation.

Would an aromatase inhibitor increase her chances of conceiving?

This patient is an excellent candidate for ovulation induction using an aromatase inhibitor (AI).

The primary reason? She is unlikely to benefit from an increased dosage of clomiphene citrate because the dosage that triggers ovulation is believed to be most appropriate—an increase above that level is not expected to improve the chance of pregnancy. Moreover, conception is less likely after more than six cycles of clomiphene citrate.^1,2

In this article, we describe the induction of ovulation using AIs—a relatively new, and off-label, application (TABLES 1 and 2). The strategies presented here are suitable for general ObGyns and do not require sophisticated technology such as rapid hormonal assays or transvaginal US.

Because this application is so new, with limited data published so far, much of the information presented here is based on our personal experience rather than level-1 evidence, which is sorely needed.

Of course, induction of ovulation is appropriate only after other specific causes of anovulation or ovulatory dysfunction are excluded, such as thyroid disorders, hyperprolactinemia, severe insulin resistance, and ovarian failure.

Concerns about teratogenicity of AIs appear to be largely unfounded (see below).

TABLE 1

Aromatase inhibitors work best in these applications

TABLE 2

Avoid AIs in these situations

Ovulation is good, but pregnancy is better

In women undergoing induction of ovulation, there are two levels of success: ovulation and pregnancy.

Clearly, the presence of other, nonovulatory infertility factors—e.g., male infertility and tubal-uterine problems—can prevent successful ovulation induction from translating into pregnancy.

We have reported^3-9 on the successful use of AIs to stimulate the ovary and achieve pregnancy—even in women who fail to conceive after several treatment trials with clomiphene citrate.⁴

Other authors have conducted further investigations that have confirmed our findings and have recommended use of these agents for other aspects of infertility treatment, such as assisted reproduction.^10-19

Latest generation of AIs is more benign

Many AIs have been developed over the past 30 years. The most recent are third-generation agents that were approved mainly to suppress estrogen production in postmenopausal women with breast cancer. Clinical failure of earlier generations of AIs for their approved indication was mainly due to significant adverse effects, lack of satisfactory potency, or lack of specificity in inhibiting the aromatase enzyme without inhibiting other enzymes of steroidogenesis.²⁰

Third-generation AIs that are commercially available in North America, Europe, and other parts of the world include:

• two nonsteroidal preparations: anastrozole (Arimidex) and letrozole (Femara)
• one steroidal agent: exemestane (Aromasin).

Letrozole and anastrozole are reversible, competitive agents with considerably greater potency (more than 1,000 times greater) than the first-generation AI aminoglutethimide. At a dosage of 1 to 5 mg/day, they reduce estrogen levels by 97% to more than 99%.

AIs are completely absorbed after oral administration, with a mean terminal half-life of approximately 45 hours (range: 30–60 hours). Exemestane has a shorter circulating half-life of approximately 9 hours, but may have a longer effect because it is irreversible.²¹

Mild gastrointestinal (GI) disturbances account for most of the adverse events, and rarely limit therapy.

How AIs work

Although we continue to accrue data on the use of AIs to induce ovulation, the underlying mechanism of action has not been studied. However, we believe that AIs work both centrally (at the level of the hypothalamus and pituitary) and peripherally (at the level of the ovaries).^22-28

At the central level, AIs suppress estrogen production by directly, specifically, and potently inhibiting the aromatase enzyme (i.e., estrogen synthase, the enzyme responsible for the synthesis of estrogen). Because the aromatase enzyme is expressed in various tissues and organs—most notably, the ovaries, brain, and fat²⁹—AIs suppress estrogen production in all of those tissues, leading to a low serum estrogen level and low local estrogen level. Low estrogen levels are thought to release the hypothalamus and pituitary gland from their negative-feedback mechanism, thereby increasing production of endogenous gonadotropins from the pituitary gland and stimulating ovarian follicular development and ovulation (FIGURE).

At the peripheral level, the aromatase enzyme catalyzes the terminal step in the steroidogenesis cascade that converts androgens into estrogen. When that enzyme is inhibited, enzyme substrate (androgens) is thought to accumulate. Contrary to the general belief that androgens are deleterious to ovarian follicles, studies in primates have demonstrated that androgens actually up-regulate the expression of gonadotropin receptors, particularly follicle-stimulating hormone (FSH) receptors.³⁰ This renders the ovaries more sensitive to gonadotropin stimulation—whether the gonadotropins are endogenous or exogenous.^22-28

FIGURE Aromatase inhibitors promote follicle development, then fade from the scene in time to prevent hyperovulation

Administration of an aromatase inhibitor (AI) on cycle days 3 to 7 suppresses ovarian estradiol (E2) secretion, as shown in A, which reduces estrogen-negative feedback at the hypothalamus and pituitary. As a result, follicle-stimulating hormone (FSH) secretion increases, fostering growth of multiple ovarian follicles. The growing follicles, shown in B, cause estrogen levels to rise again, depressing FSH, and leading to monofollicular ovulation in most cases.

Why AIs are superior to clomiphene

Clomiphene citrate is a selective estrogen receptor modulator (SERM) that is believed to induce ovulation through its antiestrogenic properties at the level of the hypothalamus or pituitary gland, or both. Clomiphene down-regulates estrogen receptors at this level, and the hypothalamus and pituitary gland react as though the estrogen level is very low. This reverses the suppression of endogenous gonadotropins by estrogen, and gonadotropin levels rise, stimulating ovarian follicular development.

The down-regulation of estrogen receptors with clomiphene administration is not limited to the hypothalamus and pituitary gland, but also occurs peripherally at the endometrium and cervix, where it is not so desirable. When the cervix is affected, it becomes an unfavorable environment for sperm to penetrate, and when the endometrium is affected, its hypoestrogenic status may reduce the likelihood of embryo implantation—or may increase the risk of pregnancy loss if implantation occurs.

These peripheral antiestrogenic prop erties of clomiphene citrate may account for the discrepancy between high ovulation and low pregnancy rates.^22-28 Several strategies to overcome this problem—e.g., adding estrogen, starting clomiphene citrate earlier in the menstrual period, or using another SERM, such as tamoxifen—have been largely unsuccessful. With clomiphene citrate, depletion of estrogen receptors has long-term effects because of the drug’s relatively long half-life (several days).³¹

In contrast, AIs do not appear to affect the expression of estrogen receptors in different body tissues, such as the endometrium and cervix. AIs have a shorter half-life (8 hours to 2 days), and nonsteroidal third-generation agents have a reversible inhibitory effect on the aromatase enzyme. Moreover, the rise in endogenous gonadotropins stimulates the production of more aromatase enzyme. This newly formed aromatase enzyme, and the return of a normal aromatase level after a short half-life of AI, leads the maturing ovarian follicles to secrete estrogen, which reaches a physiologic level soon after the last administration of AI. The rising estrogen level allows development of a more hospitable uterine environment (endometrium and cervical mucus).^22-28

Early evidence confirms efficacy of AIs

After our pioneering reports of successful ovulation induction^3-9 and improved ovarian response to stimulation by gonadotropins^5-7 using AIs in small, nonrandomized, controlled trials, several larger and better designed clinical trials followed and supported our findings.^10-19

Clinical trials comparing AIs with clomiphene citrate have consistently reported a universal “trend” toward superiority of AIs in achieving pregnancy despite comparable levels of success in achieving ovulation.^{10,11,14,16-19} However, these published clinical trials lacked adequate sample size to definitively confirm the superiority of AIs in achieving clinical pregnancy. We believe AIs are superior because, in our experience, they have helped women achieve pregnancy even after failure of several cycles of clomiphene treatment.^4,15

Should an AI follow a trial of clomiphene?

U.Y., the patient described at the opening of this article, has two main options now that she has completed six cycles of clomiphene citrate without conceiving. The usual strategy would be a shift to more sophisticated treatment using gonadotropin injection. However, exogenous gonadotropins have several disadvantages:

• the drugs must be injected (orally inactive)
• they are more expensive than clomiphene citrate and AIs
• they require close monitoring by an infertility specialist with expensive and sophisticated technology
• they carry a risk of severe ovarian hyperstimulation, which is unlikely with clomiphene citrate and unreported with AIs
• multiple pregnancy is likely, particularly in conjunction with intrauterine insemination
• the risk of ovarian hyperstimulation with gonadotropin injection is much higher in women with PCOS, such as U.Y., as is the likelihood of multiple pregnancy.

The reason U.Y. has not conceived after six cycles of clomiphene citrate is likely related to the drug’s antiestrogenic effects on the endometrium, which appeared to be very thin (4–6 mm) on US imaging around the day of ovulation. If she fails to conceive with AIs, she will probably not become pregnant after a switch to gonadotropin injection unless more advanced treatment is included, such as in vitro fertilization (IVF) and embryo transfer. Other causes of her infertility—besides ovulatory dysfunction—may explain the failure to conceive.

Comparable pregnancy rates have been observed for AIs and gonadotropin injection, although further study is needed—specifically, clinical trials comparing gonadotropin and AIs in conjunction with timed intercourse or intrauterine insemination, or both.

CASE 2 No response to clomiphene citrate

G.A., 28 years old, has been trying to conceive for 3 years. She reports having irregular menstrual periods indicative of anovulation, and body temperature charts and progesterone levels support that diagnosis. She undergoes three cycles of clomiphene citrate at dosages ranging from 50 to 150 mg/day for 5 days starting on day 3 of the menstrual cycle. Despite treatment, she fails to ovulate.

Would an AI increase her chance of ovulating and conceiving?

Failure to ovulate after treatment with clomiphene citrate may have any of several causes, including inappropriate patient selection and resistance to the drug.

An example of inappropriate patient selection would be a woman with hypothalamic/hypopituitary anovulation; this type of patient often has insufficient levels of endogenous gonadotropins (luteinizing hormone and FSH). Another example would be a woman with reduced ovarian reserve; this type of patient is often unresponsive to clomiphene citrate and may have substantially elevated gonadotropin levels, most notably high FSH on day 3 of the menstrual cycle.

AIs are unlikely to induce ovulation in either of these patients. For the first type of patient, exogenous gonadotropin injection would be appropriate, as would be a gonadotropin-releasing hormone (GnRH) pump. For a woman with reduced ovarian reserve, an oocyte donor and IVF are the best treatment option.

Success with an AI is unlikely when there is no appropriate indication for clomiphene citrate. For example, a woman with severe insulin resistance who fails to ovulate in response to clomiphene citrate is unlikely to ovulate in response to an AI. In that case, an insulin sensitizer—alone or in combination with clomiphene citrate or an AI—would be the appropriate option. Other measures to reduce insulin resistance, such as weight loss, exercise, and dietary modification, may also be helpful.

CASE 3 Ovulatory patient with endometriosis fails to conceive on clomiphene

R.C., 34 years old, has been trying to conceive for 2 years. Her basic infertility workup, which included a hysterosalpingogram and semen analysis, did not reveal any abnormalities. She has regular menstrual cycles suggestive of ovulation. In addition, luteal-phase progesterone levels and biphasic body temperature charts both indicate regular ovulation.

After six cycles of clomiphene citrate, her gynecologist performs diagnostic laparoscopy. Other than minimal, stage 1 endometriosis, confirmed by pathologic examination of peritoneal biopsies, there are no remarkable findings. Methylene blue tubal perfusion confirms patent fallopian tubes during the operation. The gynecologist fulgurates the minimal endometriotic implants using carbon dioxide laser. Two months after the procedure, the patient undergoes three more cycles of clomiphene citrate, without success.

Would an AI help her conceive?

Most of the data on successful treatment with clomiphene citrate come from anovulatory women with PCOS in whom anovulation is the main cause of infertility. Evidence is weaker when the patient is ovulatory and has unexplained or endometriosis-associated infertility.³²

A recent nonrandomized, controlled study that included women with a medical history comparable to R.C.’s found treatment with clomiphene citrate to significantly reduce the chance of pregnancy, compared with timed intercourse without clomiphene or other forms of ovarian stimulation, following conservative laparoscopic surgery for their endometriosis.³³ We believe that clomiphene citrate is in-appropriate in women with endometriosis-related infertility—and may activate underlying endometriotic lesions.

For R.C., treatment with an AI is a viable option, particularly in light of recent data showing that the aromatase enzyme is expressed in endometriotic lesions.³⁴ An AI could also enhance conception by further suppressing endometriosis through its effects on circulating estrogen levels and local estrogen production. This is an unproven extrapolation that seems scientifically appropriate to us, but needs confirmation by randomized clinical trials.

CASE 4 Woman with unexplained—and uninvestigated—infertility

E.D., 31 years old, has been trying to conceive for 1 year. Neither she nor her husband has undergone any study of their infertility problem.

Would empiric treatment with an AI be appropriate?

No treatment should begin until the patient and her partner have undergone the basic workup (TABLE 3). If a specific cause of infertility is determined, the patient should be treated accordingly. If no explanation for the infertility can be found, or anovulation is the likely cause, empirical ovarian stimulation with timed intercourse or intrauterine insemination is reasonable, provided:

• semen analysis is within normal limits
• ovarian function is present—i.e., the patient is expected to ovulate in response to ovarian stimulation
• at least one tube is patent and functional
• uterus has no serious abnormalities.

If ovarian stimulation fails to trigger ovulation or pregnancy, consider the options listed in TABLE 4

TABLE 3

Basic infertility workup

TABLE 4

When ovarian stimulation fails, next step depends on several variables

Minimal adverse effects

AIs are generally well tolerated. The most common adverse effects are hot flushes, GI disturbances (nausea and vomiting), and leg cramps. In clinical trials involving postmenopausal women with breast cancer who were taking an AI, very few withdrew because of drug-related adverse effects.³⁵ Those women took an AI on a daily basis over several months. Fewer adverse effects would be expected among usually healthy younger women administered a short course (a few days) for ovarian stimulation. In addition, our clinical experience has been that fewer women experience side effects such as mild hot flushes and symptoms similar to premenstrual syndrome when taking an AI, compared with clomiphene citrate.^3-9

Are AIs teratogenic?

When any medication is given during pregnancy, there are concerns about its effects. Drugs used to induce ovulation are no exception. In fact, clomiphene citrate is classified as pregnancy category X—a fact frequently overlooked by treating physicians. As for AIs, recent studies found no evidence of teratogenicity or clastogenicity in animal embryos when anastrozole was given. The picture is murkier for letrozole.

When used for ovarian stimulation, the short half-life of AIs and administration in the early follicular phase (several days before ovulation and fertilization occur) should ensure clearance of the drugs before implantation. Nevertheless, it is important to confirm that the patient is not pregnant before an AI is given. We recommend a pregnancy test before administering an AI for ovulation induction.

Mixed bag of data on pregnancy outcomes

Three large studies recently reported on pregnancy outcomes after infertility treatment with AIs.^9,36,37 The first was a cohort study comparing outcomes of 394 pregnancies achieved after treatment with letrozole (133 pregnancies) and other ovarian-stimulation agents, including clomiphene citrate (113 pregnancies) and gonadotropins (110 pregnancies), with a control group of 38 pregnancies achieved without ovarian stimulation.⁹ The study encompassed three tertiary referral centers over 2 years. Pregnancies conceived after treatment with an AI had rates of miscarriage and ectopic pregnancy comparable to all other groups. In addition, letrozole was associated with a significantly lower rate of multiple gestation than was clomiphene citrate.⁹

The second study, presented in abstract form, compared the outcome of 150 births after treatment with letrozole to a database of 36,050 normal deliveries.³⁶ Although the authors themselves stated that there was no statistically significant difference in the overall incidence of congenital malformation, they reported a higher incidence of locomotor malformation and cardiac anomaly in the infants conceived after treatment with letrozole.³⁶ They did not address this discrepancy or explain how locomotor malformation was assessed.

A closer look at the abstract reveals major methodological flaws that weaken the data and conclusions presented:

• The study was not well controlled. The treated patients (n=130) were infertile women, mainly suffering from PCOS and unexplained infertility, who had a mean age of 35.2 years. The control group included a database of spontaneously conceiving women who were significantly younger (mean age: 30.5 years). The control group also included deliveries in a low-risk hospital that refers out high-risk pregnancies to secondary and tertiary hospitals. These are important distinctions because women of advanced maternal age have an increased incidence of medical illnesses, making their pregnancies higher in risk.
• The incidence of multiple gestation was significantly higher among women treated for infertility than among women in the control group. It is well known that multiple gestations are at increased risk of fetal malformation compared with singleton pregnancies.
• The incidence of cardiac anomaly among women treated with letrozole did not differ significantly from the known incidence of cardiac malformation in the general population, but the authors concluded that the rate of cardiac malformation was significantly higher in the letrozole group than among controls. This is misleading because it was the control group that developed cardiac malformation at a significantly lower rate than in the general population. Such a low incidence of cardiac anomaly in a low-risk hospital setting is not surprising, because mothers would be transferred to a tertiary-care center once an anomaly was detected.
• Data on congenital malformation in the control group were collected from delivery records available in the maternity ward of the hospital. However, a significant percentage of congenital malformations, such as cardiac anomaly, are not detected until after the neonatal period.³⁶

It is also interesting that the results of this abstract have not been published in a peer-reviewed journal more than a year after its presentation.

The third study, which is more recent, compared the incidence of congenital malformation in 911 newborns conceived after treatment with letrozole (n=514) or clomiphene citrate (n=397).³⁷ It found no statistically significant difference between the groups. Congenital malformation was diagnosed in 2.4% and 4.8% of the letrozole- and clomiphene-treated groups, respectively, and major malformation occurred in 1.2% and 3% of the letrozole- and clomiphene-treated groups, respectively. These differences were not statistically significant, but there was a sevenfold increase in overall cardiac anomalies in the clomiphene-treated group, compared with the letrozole-treated group—and this difference was statistically significant. These findings warrant further investigation into the use of clomiphene citrate for induction of ovulation.

Dr. Mitwally holds patents licensed to Serono for use of aromatase inhibitors for infertility treatment.

Dr. Casper has a licensing agreement with Ares-Serono for use of aromatase inhibitors in assisted reproduction.

CASE 1 Ovulation begins, but pregnancy does not follow

U.Y. is a 32-year-old woman who has been trying to conceive for 3 years. Her infertility is caused by anovulation associated with polycystic ovary syndrome (PCOS). All other variables are within physiologic limits—she has patent tubes and an unremarkable uterus, and her partner has a normal semen analysis.

She has undergone six cycles of treatment with clomiphene citrate, with ovulation documented each time by ultrasonography (US) and measurement of luteal-phase progesterone levels. Her endometrial thickness is 4 to 6 mm around the day of ovulation.

Would an aromatase inhibitor increase her chances of conceiving?

This patient is an excellent candidate for ovulation induction using an aromatase inhibitor (AI).

The primary reason? She is unlikely to benefit from an increased dosage of clomiphene citrate because the dosage that triggers ovulation is believed to be most appropriate—an increase above that level is not expected to improve the chance of pregnancy. Moreover, conception is less likely after more than six cycles of clomiphene citrate.^1,2

In this article, we describe the induction of ovulation using AIs—a relatively new, and off-label, application (TABLES 1 and 2). The strategies presented here are suitable for general ObGyns and do not require sophisticated technology such as rapid hormonal assays or transvaginal US.

Because this application is so new, with limited data published so far, much of the information presented here is based on our personal experience rather than level-1 evidence, which is sorely needed.

Of course, induction of ovulation is appropriate only after other specific causes of anovulation or ovulatory dysfunction are excluded, such as thyroid disorders, hyperprolactinemia, severe insulin resistance, and ovarian failure.

Concerns about teratogenicity of AIs appear to be largely unfounded (see below).

TABLE 1

Aromatase inhibitors work best in these applications

TABLE 2

Avoid AIs in these situations

Ovulation is good, but pregnancy is better

In women undergoing induction of ovulation, there are two levels of success: ovulation and pregnancy.

Clearly, the presence of other, nonovulatory infertility factors—e.g., male infertility and tubal-uterine problems—can prevent successful ovulation induction from translating into pregnancy.

We have reported^3-9 on the successful use of AIs to stimulate the ovary and achieve pregnancy—even in women who fail to conceive after several treatment trials with clomiphene citrate.⁴

Other authors have conducted further investigations that have confirmed our findings and have recommended use of these agents for other aspects of infertility treatment, such as assisted reproduction.^10-19

Latest generation of AIs is more benign

Many AIs have been developed over the past 30 years. The most recent are third-generation agents that were approved mainly to suppress estrogen production in postmenopausal women with breast cancer. Clinical failure of earlier generations of AIs for their approved indication was mainly due to significant adverse effects, lack of satisfactory potency, or lack of specificity in inhibiting the aromatase enzyme without inhibiting other enzymes of steroidogenesis.²⁰

Third-generation AIs that are commercially available in North America, Europe, and other parts of the world include:

• two nonsteroidal preparations: anastrozole (Arimidex) and letrozole (Femara)
• one steroidal agent: exemestane (Aromasin).

Letrozole and anastrozole are reversible, competitive agents with considerably greater potency (more than 1,000 times greater) than the first-generation AI aminoglutethimide. At a dosage of 1 to 5 mg/day, they reduce estrogen levels by 97% to more than 99%.

AIs are completely absorbed after oral administration, with a mean terminal half-life of approximately 45 hours (range: 30–60 hours). Exemestane has a shorter circulating half-life of approximately 9 hours, but may have a longer effect because it is irreversible.²¹

Mild gastrointestinal (GI) disturbances account for most of the adverse events, and rarely limit therapy.

How AIs work

Although we continue to accrue data on the use of AIs to induce ovulation, the underlying mechanism of action has not been studied. However, we believe that AIs work both centrally (at the level of the hypothalamus and pituitary) and peripherally (at the level of the ovaries).^22-28

At the central level, AIs suppress estrogen production by directly, specifically, and potently inhibiting the aromatase enzyme (i.e., estrogen synthase, the enzyme responsible for the synthesis of estrogen). Because the aromatase enzyme is expressed in various tissues and organs—most notably, the ovaries, brain, and fat²⁹—AIs suppress estrogen production in all of those tissues, leading to a low serum estrogen level and low local estrogen level. Low estrogen levels are thought to release the hypothalamus and pituitary gland from their negative-feedback mechanism, thereby increasing production of endogenous gonadotropins from the pituitary gland and stimulating ovarian follicular development and ovulation (FIGURE).

At the peripheral level, the aromatase enzyme catalyzes the terminal step in the steroidogenesis cascade that converts androgens into estrogen. When that enzyme is inhibited, enzyme substrate (androgens) is thought to accumulate. Contrary to the general belief that androgens are deleterious to ovarian follicles, studies in primates have demonstrated that androgens actually up-regulate the expression of gonadotropin receptors, particularly follicle-stimulating hormone (FSH) receptors.³⁰ This renders the ovaries more sensitive to gonadotropin stimulation—whether the gonadotropins are endogenous or exogenous.^22-28

FIGURE Aromatase inhibitors promote follicle development, then fade from the scene in time to prevent hyperovulation

Administration of an aromatase inhibitor (AI) on cycle days 3 to 7 suppresses ovarian estradiol (E2) secretion, as shown in A, which reduces estrogen-negative feedback at the hypothalamus and pituitary. As a result, follicle-stimulating hormone (FSH) secretion increases, fostering growth of multiple ovarian follicles. The growing follicles, shown in B, cause estrogen levels to rise again, depressing FSH, and leading to monofollicular ovulation in most cases.

Why AIs are superior to clomiphene

Clomiphene citrate is a selective estrogen receptor modulator (SERM) that is believed to induce ovulation through its antiestrogenic properties at the level of the hypothalamus or pituitary gland, or both. Clomiphene down-regulates estrogen receptors at this level, and the hypothalamus and pituitary gland react as though the estrogen level is very low. This reverses the suppression of endogenous gonadotropins by estrogen, and gonadotropin levels rise, stimulating ovarian follicular development.

The down-regulation of estrogen receptors with clomiphene administration is not limited to the hypothalamus and pituitary gland, but also occurs peripherally at the endometrium and cervix, where it is not so desirable. When the cervix is affected, it becomes an unfavorable environment for sperm to penetrate, and when the endometrium is affected, its hypoestrogenic status may reduce the likelihood of embryo implantation—or may increase the risk of pregnancy loss if implantation occurs.

These peripheral antiestrogenic prop erties of clomiphene citrate may account for the discrepancy between high ovulation and low pregnancy rates.^22-28 Several strategies to overcome this problem—e.g., adding estrogen, starting clomiphene citrate earlier in the menstrual period, or using another SERM, such as tamoxifen—have been largely unsuccessful. With clomiphene citrate, depletion of estrogen receptors has long-term effects because of the drug’s relatively long half-life (several days).³¹

In contrast, AIs do not appear to affect the expression of estrogen receptors in different body tissues, such as the endometrium and cervix. AIs have a shorter half-life (8 hours to 2 days), and nonsteroidal third-generation agents have a reversible inhibitory effect on the aromatase enzyme. Moreover, the rise in endogenous gonadotropins stimulates the production of more aromatase enzyme. This newly formed aromatase enzyme, and the return of a normal aromatase level after a short half-life of AI, leads the maturing ovarian follicles to secrete estrogen, which reaches a physiologic level soon after the last administration of AI. The rising estrogen level allows development of a more hospitable uterine environment (endometrium and cervical mucus).^22-28

Early evidence confirms efficacy of AIs

After our pioneering reports of successful ovulation induction^3-9 and improved ovarian response to stimulation by gonadotropins^5-7 using AIs in small, nonrandomized, controlled trials, several larger and better designed clinical trials followed and supported our findings.^10-19

Clinical trials comparing AIs with clomiphene citrate have consistently reported a universal “trend” toward superiority of AIs in achieving pregnancy despite comparable levels of success in achieving ovulation.^{10,11,14,16-19} However, these published clinical trials lacked adequate sample size to definitively confirm the superiority of AIs in achieving clinical pregnancy. We believe AIs are superior because, in our experience, they have helped women achieve pregnancy even after failure of several cycles of clomiphene treatment.^4,15

Should an AI follow a trial of clomiphene?

U.Y., the patient described at the opening of this article, has two main options now that she has completed six cycles of clomiphene citrate without conceiving. The usual strategy would be a shift to more sophisticated treatment using gonadotropin injection. However, exogenous gonadotropins have several disadvantages:

• the drugs must be injected (orally inactive)
• they are more expensive than clomiphene citrate and AIs
• they require close monitoring by an infertility specialist with expensive and sophisticated technology
• they carry a risk of severe ovarian hyperstimulation, which is unlikely with clomiphene citrate and unreported with AIs
• multiple pregnancy is likely, particularly in conjunction with intrauterine insemination
• the risk of ovarian hyperstimulation with gonadotropin injection is much higher in women with PCOS, such as U.Y., as is the likelihood of multiple pregnancy.

The reason U.Y. has not conceived after six cycles of clomiphene citrate is likely related to the drug’s antiestrogenic effects on the endometrium, which appeared to be very thin (4–6 mm) on US imaging around the day of ovulation. If she fails to conceive with AIs, she will probably not become pregnant after a switch to gonadotropin injection unless more advanced treatment is included, such as in vitro fertilization (IVF) and embryo transfer. Other causes of her infertility—besides ovulatory dysfunction—may explain the failure to conceive.

Comparable pregnancy rates have been observed for AIs and gonadotropin injection, although further study is needed—specifically, clinical trials comparing gonadotropin and AIs in conjunction with timed intercourse or intrauterine insemination, or both.

CASE 2 No response to clomiphene citrate

G.A., 28 years old, has been trying to conceive for 3 years. She reports having irregular menstrual periods indicative of anovulation, and body temperature charts and progesterone levels support that diagnosis. She undergoes three cycles of clomiphene citrate at dosages ranging from 50 to 150 mg/day for 5 days starting on day 3 of the menstrual cycle. Despite treatment, she fails to ovulate.

Would an AI increase her chance of ovulating and conceiving?

Failure to ovulate after treatment with clomiphene citrate may have any of several causes, including inappropriate patient selection and resistance to the drug.

An example of inappropriate patient selection would be a woman with hypothalamic/hypopituitary anovulation; this type of patient often has insufficient levels of endogenous gonadotropins (luteinizing hormone and FSH). Another example would be a woman with reduced ovarian reserve; this type of patient is often unresponsive to clomiphene citrate and may have substantially elevated gonadotropin levels, most notably high FSH on day 3 of the menstrual cycle.

AIs are unlikely to induce ovulation in either of these patients. For the first type of patient, exogenous gonadotropin injection would be appropriate, as would be a gonadotropin-releasing hormone (GnRH) pump. For a woman with reduced ovarian reserve, an oocyte donor and IVF are the best treatment option.

Success with an AI is unlikely when there is no appropriate indication for clomiphene citrate. For example, a woman with severe insulin resistance who fails to ovulate in response to clomiphene citrate is unlikely to ovulate in response to an AI. In that case, an insulin sensitizer—alone or in combination with clomiphene citrate or an AI—would be the appropriate option. Other measures to reduce insulin resistance, such as weight loss, exercise, and dietary modification, may also be helpful.

CASE 3 Ovulatory patient with endometriosis fails to conceive on clomiphene

R.C., 34 years old, has been trying to conceive for 2 years. Her basic infertility workup, which included a hysterosalpingogram and semen analysis, did not reveal any abnormalities. She has regular menstrual cycles suggestive of ovulation. In addition, luteal-phase progesterone levels and biphasic body temperature charts both indicate regular ovulation.

After six cycles of clomiphene citrate, her gynecologist performs diagnostic laparoscopy. Other than minimal, stage 1 endometriosis, confirmed by pathologic examination of peritoneal biopsies, there are no remarkable findings. Methylene blue tubal perfusion confirms patent fallopian tubes during the operation. The gynecologist fulgurates the minimal endometriotic implants using carbon dioxide laser. Two months after the procedure, the patient undergoes three more cycles of clomiphene citrate, without success.

Would an AI help her conceive?

Most of the data on successful treatment with clomiphene citrate come from anovulatory women with PCOS in whom anovulation is the main cause of infertility. Evidence is weaker when the patient is ovulatory and has unexplained or endometriosis-associated infertility.³²

A recent nonrandomized, controlled study that included women with a medical history comparable to R.C.’s found treatment with clomiphene citrate to significantly reduce the chance of pregnancy, compared with timed intercourse without clomiphene or other forms of ovarian stimulation, following conservative laparoscopic surgery for their endometriosis.³³ We believe that clomiphene citrate is in-appropriate in women with endometriosis-related infertility—and may activate underlying endometriotic lesions.

For R.C., treatment with an AI is a viable option, particularly in light of recent data showing that the aromatase enzyme is expressed in endometriotic lesions.³⁴ An AI could also enhance conception by further suppressing endometriosis through its effects on circulating estrogen levels and local estrogen production. This is an unproven extrapolation that seems scientifically appropriate to us, but needs confirmation by randomized clinical trials.

CASE 4 Woman with unexplained—and uninvestigated—infertility

E.D., 31 years old, has been trying to conceive for 1 year. Neither she nor her husband has undergone any study of their infertility problem.

Would empiric treatment with an AI be appropriate?

No treatment should begin until the patient and her partner have undergone the basic workup (TABLE 3). If a specific cause of infertility is determined, the patient should be treated accordingly. If no explanation for the infertility can be found, or anovulation is the likely cause, empirical ovarian stimulation with timed intercourse or intrauterine insemination is reasonable, provided:

• semen analysis is within normal limits
• ovarian function is present—i.e., the patient is expected to ovulate in response to ovarian stimulation
• at least one tube is patent and functional
• uterus has no serious abnormalities.

If ovarian stimulation fails to trigger ovulation or pregnancy, consider the options listed in TABLE 4

TABLE 3

Basic infertility workup

TABLE 4

When ovarian stimulation fails, next step depends on several variables

Minimal adverse effects

AIs are generally well tolerated. The most common adverse effects are hot flushes, GI disturbances (nausea and vomiting), and leg cramps. In clinical trials involving postmenopausal women with breast cancer who were taking an AI, very few withdrew because of drug-related adverse effects.³⁵ Those women took an AI on a daily basis over several months. Fewer adverse effects would be expected among usually healthy younger women administered a short course (a few days) for ovarian stimulation. In addition, our clinical experience has been that fewer women experience side effects such as mild hot flushes and symptoms similar to premenstrual syndrome when taking an AI, compared with clomiphene citrate.^3-9

Are AIs teratogenic?

When any medication is given during pregnancy, there are concerns about its effects. Drugs used to induce ovulation are no exception. In fact, clomiphene citrate is classified as pregnancy category X—a fact frequently overlooked by treating physicians. As for AIs, recent studies found no evidence of teratogenicity or clastogenicity in animal embryos when anastrozole was given. The picture is murkier for letrozole.

When used for ovarian stimulation, the short half-life of AIs and administration in the early follicular phase (several days before ovulation and fertilization occur) should ensure clearance of the drugs before implantation. Nevertheless, it is important to confirm that the patient is not pregnant before an AI is given. We recommend a pregnancy test before administering an AI for ovulation induction.

Mixed bag of data on pregnancy outcomes

Three large studies recently reported on pregnancy outcomes after infertility treatment with AIs.^9,36,37 The first was a cohort study comparing outcomes of 394 pregnancies achieved after treatment with letrozole (133 pregnancies) and other ovarian-stimulation agents, including clomiphene citrate (113 pregnancies) and gonadotropins (110 pregnancies), with a control group of 38 pregnancies achieved without ovarian stimulation.⁹ The study encompassed three tertiary referral centers over 2 years. Pregnancies conceived after treatment with an AI had rates of miscarriage and ectopic pregnancy comparable to all other groups. In addition, letrozole was associated with a significantly lower rate of multiple gestation than was clomiphene citrate.⁹

The second study, presented in abstract form, compared the outcome of 150 births after treatment with letrozole to a database of 36,050 normal deliveries.³⁶ Although the authors themselves stated that there was no statistically significant difference in the overall incidence of congenital malformation, they reported a higher incidence of locomotor malformation and cardiac anomaly in the infants conceived after treatment with letrozole.³⁶ They did not address this discrepancy or explain how locomotor malformation was assessed.

A closer look at the abstract reveals major methodological flaws that weaken the data and conclusions presented:

• The study was not well controlled. The treated patients (n=130) were infertile women, mainly suffering from PCOS and unexplained infertility, who had a mean age of 35.2 years. The control group included a database of spontaneously conceiving women who were significantly younger (mean age: 30.5 years). The control group also included deliveries in a low-risk hospital that refers out high-risk pregnancies to secondary and tertiary hospitals. These are important distinctions because women of advanced maternal age have an increased incidence of medical illnesses, making their pregnancies higher in risk.
• The incidence of multiple gestation was significantly higher among women treated for infertility than among women in the control group. It is well known that multiple gestations are at increased risk of fetal malformation compared with singleton pregnancies.
• The incidence of cardiac anomaly among women treated with letrozole did not differ significantly from the known incidence of cardiac malformation in the general population, but the authors concluded that the rate of cardiac malformation was significantly higher in the letrozole group than among controls. This is misleading because it was the control group that developed cardiac malformation at a significantly lower rate than in the general population. Such a low incidence of cardiac anomaly in a low-risk hospital setting is not surprising, because mothers would be transferred to a tertiary-care center once an anomaly was detected.
• Data on congenital malformation in the control group were collected from delivery records available in the maternity ward of the hospital. However, a significant percentage of congenital malformations, such as cardiac anomaly, are not detected until after the neonatal period.³⁶

It is also interesting that the results of this abstract have not been published in a peer-reviewed journal more than a year after its presentation.

The third study, which is more recent, compared the incidence of congenital malformation in 911 newborns conceived after treatment with letrozole (n=514) or clomiphene citrate (n=397).³⁷ It found no statistically significant difference between the groups. Congenital malformation was diagnosed in 2.4% and 4.8% of the letrozole- and clomiphene-treated groups, respectively, and major malformation occurred in 1.2% and 3% of the letrozole- and clomiphene-treated groups, respectively. These differences were not statistically significant, but there was a sevenfold increase in overall cardiac anomalies in the clomiphene-treated group, compared with the letrozole-treated group—and this difference was statistically significant. These findings warrant further investigation into the use of clomiphene citrate for induction of ovulation.

Dr. Mitwally holds patents licensed to Serono for use of aromatase inhibitors for infertility treatment.

Dr. Casper has a licensing agreement with Ares-Serono for use of aromatase inhibitors in assisted reproduction.

CASE 1 Ovulation begins, but pregnancy does not follow

U.Y. is a 32-year-old woman who has been trying to conceive for 3 years. Her infertility is caused by anovulation associated with polycystic ovary syndrome (PCOS). All other variables are within physiologic limits—she has patent tubes and an unremarkable uterus, and her partner has a normal semen analysis.

She has undergone six cycles of treatment with clomiphene citrate, with ovulation documented each time by ultrasonography (US) and measurement of luteal-phase progesterone levels. Her endometrial thickness is 4 to 6 mm around the day of ovulation.

Would an aromatase inhibitor increase her chances of conceiving?

This patient is an excellent candidate for ovulation induction using an aromatase inhibitor (AI).

The primary reason? She is unlikely to benefit from an increased dosage of clomiphene citrate because the dosage that triggers ovulation is believed to be most appropriate—an increase above that level is not expected to improve the chance of pregnancy. Moreover, conception is less likely after more than six cycles of clomiphene citrate.^1,2

In this article, we describe the induction of ovulation using AIs—a relatively new, and off-label, application (TABLES 1 and 2). The strategies presented here are suitable for general ObGyns and do not require sophisticated technology such as rapid hormonal assays or transvaginal US.

Because this application is so new, with limited data published so far, much of the information presented here is based on our personal experience rather than level-1 evidence, which is sorely needed.

Of course, induction of ovulation is appropriate only after other specific causes of anovulation or ovulatory dysfunction are excluded, such as thyroid disorders, hyperprolactinemia, severe insulin resistance, and ovarian failure.

Concerns about teratogenicity of AIs appear to be largely unfounded (see below).

TABLE 1

Aromatase inhibitors work best in these applications

TABLE 2

Avoid AIs in these situations

Ovulation is good, but pregnancy is better

In women undergoing induction of ovulation, there are two levels of success: ovulation and pregnancy.

Clearly, the presence of other, nonovulatory infertility factors—e.g., male infertility and tubal-uterine problems—can prevent successful ovulation induction from translating into pregnancy.

We have reported^3-9 on the successful use of AIs to stimulate the ovary and achieve pregnancy—even in women who fail to conceive after several treatment trials with clomiphene citrate.⁴

Other authors have conducted further investigations that have confirmed our findings and have recommended use of these agents for other aspects of infertility treatment, such as assisted reproduction.^10-19

Latest generation of AIs is more benign

Many AIs have been developed over the past 30 years. The most recent are third-generation agents that were approved mainly to suppress estrogen production in postmenopausal women with breast cancer. Clinical failure of earlier generations of AIs for their approved indication was mainly due to significant adverse effects, lack of satisfactory potency, or lack of specificity in inhibiting the aromatase enzyme without inhibiting other enzymes of steroidogenesis.²⁰

Third-generation AIs that are commercially available in North America, Europe, and other parts of the world include:

• two nonsteroidal preparations: anastrozole (Arimidex) and letrozole (Femara)
• one steroidal agent: exemestane (Aromasin).

Letrozole and anastrozole are reversible, competitive agents with considerably greater potency (more than 1,000 times greater) than the first-generation AI aminoglutethimide. At a dosage of 1 to 5 mg/day, they reduce estrogen levels by 97% to more than 99%.

AIs are completely absorbed after oral administration, with a mean terminal half-life of approximately 45 hours (range: 30–60 hours). Exemestane has a shorter circulating half-life of approximately 9 hours, but may have a longer effect because it is irreversible.²¹

Mild gastrointestinal (GI) disturbances account for most of the adverse events, and rarely limit therapy.

How AIs work

Although we continue to accrue data on the use of AIs to induce ovulation, the underlying mechanism of action has not been studied. However, we believe that AIs work both centrally (at the level of the hypothalamus and pituitary) and peripherally (at the level of the ovaries).^22-28

At the central level, AIs suppress estrogen production by directly, specifically, and potently inhibiting the aromatase enzyme (i.e., estrogen synthase, the enzyme responsible for the synthesis of estrogen). Because the aromatase enzyme is expressed in various tissues and organs—most notably, the ovaries, brain, and fat²⁹—AIs suppress estrogen production in all of those tissues, leading to a low serum estrogen level and low local estrogen level. Low estrogen levels are thought to release the hypothalamus and pituitary gland from their negative-feedback mechanism, thereby increasing production of endogenous gonadotropins from the pituitary gland and stimulating ovarian follicular development and ovulation (FIGURE).

At the peripheral level, the aromatase enzyme catalyzes the terminal step in the steroidogenesis cascade that converts androgens into estrogen. When that enzyme is inhibited, enzyme substrate (androgens) is thought to accumulate. Contrary to the general belief that androgens are deleterious to ovarian follicles, studies in primates have demonstrated that androgens actually up-regulate the expression of gonadotropin receptors, particularly follicle-stimulating hormone (FSH) receptors.³⁰ This renders the ovaries more sensitive to gonadotropin stimulation—whether the gonadotropins are endogenous or exogenous.^22-28

FIGURE Aromatase inhibitors promote follicle development, then fade from the scene in time to prevent hyperovulation

Administration of an aromatase inhibitor (AI) on cycle days 3 to 7 suppresses ovarian estradiol (E2) secretion, as shown in A, which reduces estrogen-negative feedback at the hypothalamus and pituitary. As a result, follicle-stimulating hormone (FSH) secretion increases, fostering growth of multiple ovarian follicles. The growing follicles, shown in B, cause estrogen levels to rise again, depressing FSH, and leading to monofollicular ovulation in most cases.

Why AIs are superior to clomiphene

Clomiphene citrate is a selective estrogen receptor modulator (SERM) that is believed to induce ovulation through its antiestrogenic properties at the level of the hypothalamus or pituitary gland, or both. Clomiphene down-regulates estrogen receptors at this level, and the hypothalamus and pituitary gland react as though the estrogen level is very low. This reverses the suppression of endogenous gonadotropins by estrogen, and gonadotropin levels rise, stimulating ovarian follicular development.

The down-regulation of estrogen receptors with clomiphene administration is not limited to the hypothalamus and pituitary gland, but also occurs peripherally at the endometrium and cervix, where it is not so desirable. When the cervix is affected, it becomes an unfavorable environment for sperm to penetrate, and when the endometrium is affected, its hypoestrogenic status may reduce the likelihood of embryo implantation—or may increase the risk of pregnancy loss if implantation occurs.

These peripheral antiestrogenic prop erties of clomiphene citrate may account for the discrepancy between high ovulation and low pregnancy rates.^22-28 Several strategies to overcome this problem—e.g., adding estrogen, starting clomiphene citrate earlier in the menstrual period, or using another SERM, such as tamoxifen—have been largely unsuccessful. With clomiphene citrate, depletion of estrogen receptors has long-term effects because of the drug’s relatively long half-life (several days).³¹

In contrast, AIs do not appear to affect the expression of estrogen receptors in different body tissues, such as the endometrium and cervix. AIs have a shorter half-life (8 hours to 2 days), and nonsteroidal third-generation agents have a reversible inhibitory effect on the aromatase enzyme. Moreover, the rise in endogenous gonadotropins stimulates the production of more aromatase enzyme. This newly formed aromatase enzyme, and the return of a normal aromatase level after a short half-life of AI, leads the maturing ovarian follicles to secrete estrogen, which reaches a physiologic level soon after the last administration of AI. The rising estrogen level allows development of a more hospitable uterine environment (endometrium and cervical mucus).^22-28

Early evidence confirms efficacy of AIs

After our pioneering reports of successful ovulation induction^3-9 and improved ovarian response to stimulation by gonadotropins^5-7 using AIs in small, nonrandomized, controlled trials, several larger and better designed clinical trials followed and supported our findings.^10-19

Clinical trials comparing AIs with clomiphene citrate have consistently reported a universal “trend” toward superiority of AIs in achieving pregnancy despite comparable levels of success in achieving ovulation.^{10,11,14,16-19} However, these published clinical trials lacked adequate sample size to definitively confirm the superiority of AIs in achieving clinical pregnancy. We believe AIs are superior because, in our experience, they have helped women achieve pregnancy even after failure of several cycles of clomiphene treatment.^4,15

Should an AI follow a trial of clomiphene?

U.Y., the patient described at the opening of this article, has two main options now that she has completed six cycles of clomiphene citrate without conceiving. The usual strategy would be a shift to more sophisticated treatment using gonadotropin injection. However, exogenous gonadotropins have several disadvantages:

• the drugs must be injected (orally inactive)
• they are more expensive than clomiphene citrate and AIs
• they require close monitoring by an infertility specialist with expensive and sophisticated technology
• they carry a risk of severe ovarian hyperstimulation, which is unlikely with clomiphene citrate and unreported with AIs
• multiple pregnancy is likely, particularly in conjunction with intrauterine insemination
• the risk of ovarian hyperstimulation with gonadotropin injection is much higher in women with PCOS, such as U.Y., as is the likelihood of multiple pregnancy.

The reason U.Y. has not conceived after six cycles of clomiphene citrate is likely related to the drug’s antiestrogenic effects on the endometrium, which appeared to be very thin (4–6 mm) on US imaging around the day of ovulation. If she fails to conceive with AIs, she will probably not become pregnant after a switch to gonadotropin injection unless more advanced treatment is included, such as in vitro fertilization (IVF) and embryo transfer. Other causes of her infertility—besides ovulatory dysfunction—may explain the failure to conceive.

Comparable pregnancy rates have been observed for AIs and gonadotropin injection, although further study is needed—specifically, clinical trials comparing gonadotropin and AIs in conjunction with timed intercourse or intrauterine insemination, or both.

CASE 2 No response to clomiphene citrate

G.A., 28 years old, has been trying to conceive for 3 years. She reports having irregular menstrual periods indicative of anovulation, and body temperature charts and progesterone levels support that diagnosis. She undergoes three cycles of clomiphene citrate at dosages ranging from 50 to 150 mg/day for 5 days starting on day 3 of the menstrual cycle. Despite treatment, she fails to ovulate.

Would an AI increase her chance of ovulating and conceiving?

Failure to ovulate after treatment with clomiphene citrate may have any of several causes, including inappropriate patient selection and resistance to the drug.

An example of inappropriate patient selection would be a woman with hypothalamic/hypopituitary anovulation; this type of patient often has insufficient levels of endogenous gonadotropins (luteinizing hormone and FSH). Another example would be a woman with reduced ovarian reserve; this type of patient is often unresponsive to clomiphene citrate and may have substantially elevated gonadotropin levels, most notably high FSH on day 3 of the menstrual cycle.

AIs are unlikely to induce ovulation in either of these patients. For the first type of patient, exogenous gonadotropin injection would be appropriate, as would be a gonadotropin-releasing hormone (GnRH) pump. For a woman with reduced ovarian reserve, an oocyte donor and IVF are the best treatment option.

Success with an AI is unlikely when there is no appropriate indication for clomiphene citrate. For example, a woman with severe insulin resistance who fails to ovulate in response to clomiphene citrate is unlikely to ovulate in response to an AI. In that case, an insulin sensitizer—alone or in combination with clomiphene citrate or an AI—would be the appropriate option. Other measures to reduce insulin resistance, such as weight loss, exercise, and dietary modification, may also be helpful.

CASE 3 Ovulatory patient with endometriosis fails to conceive on clomiphene

R.C., 34 years old, has been trying to conceive for 2 years. Her basic infertility workup, which included a hysterosalpingogram and semen analysis, did not reveal any abnormalities. She has regular menstrual cycles suggestive of ovulation. In addition, luteal-phase progesterone levels and biphasic body temperature charts both indicate regular ovulation.

After six cycles of clomiphene citrate, her gynecologist performs diagnostic laparoscopy. Other than minimal, stage 1 endometriosis, confirmed by pathologic examination of peritoneal biopsies, there are no remarkable findings. Methylene blue tubal perfusion confirms patent fallopian tubes during the operation. The gynecologist fulgurates the minimal endometriotic implants using carbon dioxide laser. Two months after the procedure, the patient undergoes three more cycles of clomiphene citrate, without success.

Would an AI help her conceive?

Most of the data on successful treatment with clomiphene citrate come from anovulatory women with PCOS in whom anovulation is the main cause of infertility. Evidence is weaker when the patient is ovulatory and has unexplained or endometriosis-associated infertility.³²

A recent nonrandomized, controlled study that included women with a medical history comparable to R.C.’s found treatment with clomiphene citrate to significantly reduce the chance of pregnancy, compared with timed intercourse without clomiphene or other forms of ovarian stimulation, following conservative laparoscopic surgery for their endometriosis.³³ We believe that clomiphene citrate is in-appropriate in women with endometriosis-related infertility—and may activate underlying endometriotic lesions.

For R.C., treatment with an AI is a viable option, particularly in light of recent data showing that the aromatase enzyme is expressed in endometriotic lesions.³⁴ An AI could also enhance conception by further suppressing endometriosis through its effects on circulating estrogen levels and local estrogen production. This is an unproven extrapolation that seems scientifically appropriate to us, but needs confirmation by randomized clinical trials.

CASE 4 Woman with unexplained—and uninvestigated—infertility

E.D., 31 years old, has been trying to conceive for 1 year. Neither she nor her husband has undergone any study of their infertility problem.

Would empiric treatment with an AI be appropriate?

No treatment should begin until the patient and her partner have undergone the basic workup (TABLE 3). If a specific cause of infertility is determined, the patient should be treated accordingly. If no explanation for the infertility can be found, or anovulation is the likely cause, empirical ovarian stimulation with timed intercourse or intrauterine insemination is reasonable, provided:

• semen analysis is within normal limits
• ovarian function is present—i.e., the patient is expected to ovulate in response to ovarian stimulation
• at least one tube is patent and functional
• uterus has no serious abnormalities.

If ovarian stimulation fails to trigger ovulation or pregnancy, consider the options listed in TABLE 4

TABLE 3

Basic infertility workup

TABLE 4

When ovarian stimulation fails, next step depends on several variables

Minimal adverse effects

AIs are generally well tolerated. The most common adverse effects are hot flushes, GI disturbances (nausea and vomiting), and leg cramps. In clinical trials involving postmenopausal women with breast cancer who were taking an AI, very few withdrew because of drug-related adverse effects.³⁵ Those women took an AI on a daily basis over several months. Fewer adverse effects would be expected among usually healthy younger women administered a short course (a few days) for ovarian stimulation. In addition, our clinical experience has been that fewer women experience side effects such as mild hot flushes and symptoms similar to premenstrual syndrome when taking an AI, compared with clomiphene citrate.^3-9

Are AIs teratogenic?

When any medication is given during pregnancy, there are concerns about its effects. Drugs used to induce ovulation are no exception. In fact, clomiphene citrate is classified as pregnancy category X—a fact frequently overlooked by treating physicians. As for AIs, recent studies found no evidence of teratogenicity or clastogenicity in animal embryos when anastrozole was given. The picture is murkier for letrozole.

When used for ovarian stimulation, the short half-life of AIs and administration in the early follicular phase (several days before ovulation and fertilization occur) should ensure clearance of the drugs before implantation. Nevertheless, it is important to confirm that the patient is not pregnant before an AI is given. We recommend a pregnancy test before administering an AI for ovulation induction.

Mixed bag of data on pregnancy outcomes

Three large studies recently reported on pregnancy outcomes after infertility treatment with AIs.^9,36,37 The first was a cohort study comparing outcomes of 394 pregnancies achieved after treatment with letrozole (133 pregnancies) and other ovarian-stimulation agents, including clomiphene citrate (113 pregnancies) and gonadotropins (110 pregnancies), with a control group of 38 pregnancies achieved without ovarian stimulation.⁹ The study encompassed three tertiary referral centers over 2 years. Pregnancies conceived after treatment with an AI had rates of miscarriage and ectopic pregnancy comparable to all other groups. In addition, letrozole was associated with a significantly lower rate of multiple gestation than was clomiphene citrate.⁹

The second study, presented in abstract form, compared the outcome of 150 births after treatment with letrozole to a database of 36,050 normal deliveries.³⁶ Although the authors themselves stated that there was no statistically significant difference in the overall incidence of congenital malformation, they reported a higher incidence of locomotor malformation and cardiac anomaly in the infants conceived after treatment with letrozole.³⁶ They did not address this discrepancy or explain how locomotor malformation was assessed.

A closer look at the abstract reveals major methodological flaws that weaken the data and conclusions presented:

• The study was not well controlled. The treated patients (n=130) were infertile women, mainly suffering from PCOS and unexplained infertility, who had a mean age of 35.2 years. The control group included a database of spontaneously conceiving women who were significantly younger (mean age: 30.5 years). The control group also included deliveries in a low-risk hospital that refers out high-risk pregnancies to secondary and tertiary hospitals. These are important distinctions because women of advanced maternal age have an increased incidence of medical illnesses, making their pregnancies higher in risk.
• The incidence of multiple gestation was significantly higher among women treated for infertility than among women in the control group. It is well known that multiple gestations are at increased risk of fetal malformation compared with singleton pregnancies.
• The incidence of cardiac anomaly among women treated with letrozole did not differ significantly from the known incidence of cardiac malformation in the general population, but the authors concluded that the rate of cardiac malformation was significantly higher in the letrozole group than among controls. This is misleading because it was the control group that developed cardiac malformation at a significantly lower rate than in the general population. Such a low incidence of cardiac anomaly in a low-risk hospital setting is not surprising, because mothers would be transferred to a tertiary-care center once an anomaly was detected.
• Data on congenital malformation in the control group were collected from delivery records available in the maternity ward of the hospital. However, a significant percentage of congenital malformations, such as cardiac anomaly, are not detected until after the neonatal period.³⁶

It is also interesting that the results of this abstract have not been published in a peer-reviewed journal more than a year after its presentation.

The third study, which is more recent, compared the incidence of congenital malformation in 911 newborns conceived after treatment with letrozole (n=514) or clomiphene citrate (n=397).³⁷ It found no statistically significant difference between the groups. Congenital malformation was diagnosed in 2.4% and 4.8% of the letrozole- and clomiphene-treated groups, respectively, and major malformation occurred in 1.2% and 3% of the letrozole- and clomiphene-treated groups, respectively. These differences were not statistically significant, but there was a sevenfold increase in overall cardiac anomalies in the clomiphene-treated group, compared with the letrozole-treated group—and this difference was statistically significant. These findings warrant further investigation into the use of clomiphene citrate for induction of ovulation.

The author reports no financial relationships relevant to this article.

CASE Multiple morbidities complicate choice of contraceptive

D.M. is a 27-year-old woman who has sickle cell disease, which led to a mild stroke during adolescence. She also has mild renal insufficiency and was given a diagnosis in adulthood of systemic lupus erythematosus, for which she takes prednisone on a maintenance basis.

D.M. is sexually active with her long-term boyfriend, and has undergone salpingectomy for ectopic pregnancy. Recently, she underwent exploratory laparotomy after a ruptured hemorrhagic ovarian cyst caused an intraperitoneal hemorrhage.

What method of birth control would be most appropriate for this patient?

The question is a daunting one, but it’s imperative for health-care providers to understand the nature and magnitude of contraceptive risks in medically complex women and provide the answers that these patients need.

In this article, I describe important considerations and sift the evidence regarding each of what I refer to here as highly effective contraceptive methods:

• safe hormonal contraceptives
• intrauterine contraceptives
• minimally invasive surgical sterilization.

These methods have given medically complex women greater control over their reproductive function and health, and a number of them offer benefits beyond contraception.

With some methods, such as progestin-only contraception, prospective data are lacking but retrospective studies show no elevated risk of cardiovascular events. And although combination hormonal contraceptives carry an elevated relative risk of cardiovascular events, absolute risk is very low.

First, who are these patients?

Women who have an extreme chronic medical condition, such as pulmonary hypertension, cardiomyopathy, or a dilated aortic root (>40 mm), face pregnancy-associated mortality as high as 10% to 50%—making unplanned pregnancy significantly more dangerous than any contraceptive. And even women who have a less severe medical condition stand to benefit from careful pregnancy timing: Those who have diabetes, lupus, or inflammatory bowel disease often need to optimize their medical condition before becoming pregnant. Still others may need to discontinue a teratogenic medication or treatment.

As for women who have multiple serious medical conditions, such as the patient described above, there is critical need to understand and prepare for the risks of pregnancy. These women deserve a contraceptive that has an efficacy rate approaching 100%.

All too often, however, these women settle for less effective barrier methods— or no method at all—out of concern that contraceptive and personal medical risks may interact adversely. Medical interests may drive these choices, but the unplanned pregnancies that result can pose more health risks than the rejected contraceptives.

A tool to weigh contraceptive risks

The World Health Organization (WHO) has categorized a large number of medical conditions according to their level of risk in regard to specific contraceptives.¹ The four categories established by WHO range from no restrictions (category 1) to unacceptable health risks (category 4) (TABLE 1). With this system, you have a streamlined resource for weighing a contraceptive’s risks and benefits and finding an appropriate method for your patients.

TABLE 1

Four levels of risk in WHO categories

Sifting risks and benefits of hormonal contraceptives

With typical use, hormonal contraceptive pills and injections prevent pregnancy in 92% to 97% of women who use one of these methods for 1 year.² They also may decrease dysmenorrhea and menorrhagia, reduce the incidence of functional ovarian cysts, improve menstrual symptoms, and help prevent ovarian and endometrial cancers.^2,3 In surveys in selected developed countries, the majority of women have used hormonal contraceptives at some time in their reproductive lives.²

Hormonal contraceptives also carry rare but potentially serious health risks that may deter their use—at times, inappropriately. Combined oral contraceptives (OCs) may double or triple the risk of myocardial infarction (MI)⁴ and stroke^5,6 and triple or quadruple the risk of deep venous thrombosis (DVT) and venous thromboembolism (VTE).⁷

Recent data on the combined contraceptive patch suggest that it carries a risk of VTE twice as high as combined OCs.⁸ (Rates of MI and stroke were too small to compare accurately.⁸) We lack data on the vaginal ring contraceptive, but its medical risks are assumed to be similar to those of combined oral contraceptives.¹

Putting the risks of OCs in context

It is very important to interpret these risks in light of the overall rarity of cardiovascular events and the opposing risks of pregnancy. TABLE 2 shows the low incidence of MI, stroke, and VTE among nonpregnant and pregnant women.

For every 100,000 woman-years, combined OCs are estimated to contribute three additional cases of MI, four additional cases of stroke, and 10 to 20 additional cases of VTE.^3,5,9 For these severe conditions, the baseline incidence plus additional cases attributed to use of combination OCs still does not approach the risk of pregnancy itself. One study showed that women face a higher risk of cardiovascular death in pregnancy than when taking combined OCs, with the exception of smokers over the age of 35 years.⁹

For most women, combined OCs pose no greater cardiovascular risk than pregnancy does—but baseline cardiovascular risk factors augment that risk. Women who have hypertension, those who smoke, and those over age 35 face higher risks of MI and stroke while taking combined OCs.^4,10 Diabetes and hypercholesterolemia further elevate the risk of MI,⁴ and migraine headache and thrombophilia raise the risk of stroke.^6,11-13 Women with thrombophilia, a history of a clotting disorder, elevated body mass index (BMI), and, possibly, those who smoke face a higher risk of VTE when using a combined hormonal contraceptive.^14-17

Because of these risks, the WHO classifies significant cardiovascular risk factors as category 4 (contraindicated) in regard to combined OCs (TABLE 3).

These risk factors include:

• known vascular disease
• ischemic heart disease
• history of stroke
• known thrombotic mutation
• complicated valvular disease.

When systolic blood pressure exceeds 160 mm Hg or diastolic blood pressure surpasses 100 mm Hg, combined OCs are again contraindicated. Use of combined OCs in women who have milder blood pressure elevations and adequately controlled hypertension is classified as category 3—theoretical or proven risks usually outweigh the advantages of using the method. Individual risk factors such as hyperlipidemia or uncomplicated diabetes are classified as category 3 in regard to combined OCs—unless multiple factors coexist, in which case they fall into category 4.

TABLE 2

Incidence of major cardiovascular events per 100,000 woman-years

TABLE 3

Risk states in which combined hormonal contraceptives are contraindicated

Obese women may benefit from OCs—but efficacy may decline

Although obesity increases the risk of VTE¹⁷ and possibly MI⁴ during use of combined OCs, the WHO classifies it as category 2 in regard to this contraceptive method—advantages generally outweigh the theoretical or proven risks. This rating is based on the low number of major adverse events associated with use of low-dose combined OCs in obese women.¹

However, combined OCs appear to be less effective in obese women than in their normal-weight peers. A recent case-control study showed diminished efficacy for women with a BMI over 27, and an even higher rate of contraceptive failure for those with a BMI over 32.¹⁸ Nevertheless, it is important for clinicians and patients to recognize the benefits likely to accrue from this method—probably at a higher rate than is seen with most barrier methods.

Obese women who suffer from oligoovulation may also benefit from the progestin in combined OCs, which can mitigate the effects of unopposed estrogen.

Nevertheless, it may be wise, when counseling these women, to consider a more effective method that carries less risk, such as a progestin-releasing intrauterine contraceptive.

Stroke risk in migraine sufferers may render OC option unwise

Patients who experience migraine have a higher risk of stroke than their migraine-free peers. The risk is even higher when the migraine is preceded by an aura (a 5- to 10-minute episode of moving lights in a visual field, speech disturbance, paresthesias, or weakness that precedes the headache).^12,19 Risk is especially elevated when women who suffer migraines use a combined OC, with an odds ratio for stroke ranging from 6.6 to 8.7.

Because of these heightened risks, the WHO classifies migraine with aura as category 4 (contraindicated) for combined OCs. When no aura is present, the advisability of OC use depends on the woman’s age and whether her symptoms predate hormone use. Migraine without aura falls into category 4 for women over age 35 whose symptoms develop while on the contraceptive. It falls into category 2 if the woman is under age 35 and her symptoms predate contraceptive use. In other situations, migraine without aura falls into category 3.

Progestin-only options may be safer in women with cardiovascular risk

Women who face an unacceptable level of cardiovascular risk with combined OCs may still be candidates for progestin-only contraceptives. Although data are thin regarding the risks of progestins in the absence of estrogen, an international WHO study found no increased cardiovascular risk with the use of oral or injectable progestins.²⁰

Current breast cancer is the only medical condition in which progestin-only contraception is contraindicated (category 4). Significant or multiple cardiac risk factors are classified as category 3 in regard to depot medroxyprogesterone acetate, and as category 1 or 2 for progestin-only pills.

Current DVT or VTE is classified as category 3 in regard to progestin-only contraception. A history of DVT or VTE is category 2 (TABLE 4).

TABLE 4

Risks of progestin-only contraceptives may outweigh benefits in these conditions

Liver disease, cancer may rule out use of hormones

Estrogens and progestins are metabolized by the liver, and women with significant liver dysfunction may accumulate medication. Hormones are also contraindicated in the setting of hormone-sensitive tumors, such as liver adenomas and breast cancer.

In addition, hormones may interact with—and should be avoided during use of—drugs that affect metabolic enzymes, such as certain anticonvulsants, rifampin, and some antiretrovirals.¹

Intrauterine option is underused

Two types of intrauterine contraception (IUC) are available in the United States: the CuT-380A and the LNG-20. The former uses copper, whereas the latter delivers the progestin levonorgestrel directly to the endometrium. Both methods are extremely effective, with cumulative failure rates below 1% to 2% over 5 to 10 years.²¹ Unlike most hormonal contraceptives, IUCs do not require patient compliance, and the LNG-20 has the additional benefit of decreasing menstrual blood loss.²¹

Despite these advantages, fear of uterine infection has led to underuse of IUC in the United States.²² A worldwide review of prospective studies of IUC revealed that the risk of infection is limited to the first 20 days after insertion, when the risk of pelvic inflammatory disease (PID) is approximately 1%.²³ Thereafter, the risk of infection is significantly lower and can be linked to other PID risk factors, such as young age and multiple partners.^23,24 The risk may be even lower with the LNG-20 than with the copper system.²⁵ The IUC’s safety and high level of effectiveness make it an excellent choice for many women with chronic medical conditions.

Picture is murky in immunocompromised women

Infection caused by IUC may be unlikely in a healthy woman, but use of IUC in immunocompromised patients carries uncertain risk. Data from HIV-infected women in Africa have been reassuring, demonstrating an acceptably low risk of infection.²⁶ However, no studies have evaluated IUC among women on immunosuppressive drugs or those with otherwise impaired immune systems, and the WHO does not make formal recommendations for these patients. Two case reports of IUC failure in transplant patients led some to theorize that immune-mediated inflammation is necessary for IUC function, but this has not been proven.²⁷

When immunocompromised women do not qualify for other highly effective contraceptives, the benefit of IUC may outweigh any theoretical risks. In this case, the LNG-20 may be preferable for its possibly lower risk of infection and decreased reliance on an inflammatory mechanism of action.

Contraindications to IUC include breast cancer, pelvic infection

Although the LNG-20 contains a hormone, the amount of levonorgestrel entering the circulation is very low, so the method is not restricted in women with cardiovascular risk factors. The only contraindications to IUC are:

• pelvic infection or sepsis
• pregnancy
• undiagnosed abnormal uterine bleeding or gynecologic cancer
• distorted uterine cavity
• breast cancer (for the LNG-20)
• Wilson’s disease (for the CuT-380A).

Sterilization is a safe option

For women ready to forego future childbearing, surgical sterilization is an excellent option. It requires no compliance or follow-up on the part of the patient, and efficacy rates approach that of IUC—at 98% to 99% or higher.

Beyond regret and sterilization failure, the risks of sterilization are limited to those of the surgical procedure itself. These may be negligible if tubal ligation is performed at the time of another indicated surgery, such as cesarean section.

Interval sterilization with laparoscopic tubal ligation is usually performed with general anesthesia. The rate of major morbidity is approximately 0.9%, including major bleeding, need for laparotomy, organ injury, and major infection. Complications may be higher in women with diabetes, a history of major surgery, and obesity.²⁸

The WHO advises caution when using this method in the setting of severe diabetes, sickle cell disease, coagulopathy, severe renal disease, cardiovascular disease, or pulmonary disease.¹

Insertion of intratubal coils is less invasive than tubal ligation

Hysteroscopic tubal sterilization with placement of titanium–Dacron intratubal coils (sold by the name Essure) is another option gaining use (FIGURE). Although large-scale studies have yet to be published, data from the largest phase III trial are consistent with smaller studies.²⁹ In that multicenter trial, coil placement was successful in 92% of patients, and 99% of women completed the procedure without general anesthesia. Tubal perforation was identified in 1% of women, who went on to a laparoscopic procedure.

This less invasive method of permanent sterilization increases options for women who are poor laparoscopy candidates, although the 10% of women who experience technical failure will be forced to find an alternative method. Patient compliance is also an issue because the woman must use backup contraception for 3 months following the procedure, until tubal occlusion is confirmed by hysterosalpingography.

FIGURE Sterilization via insertion of intratubal coils

Delivery of the Essure device.
After 3 months, polyethylene (PET) fibers elicit ingrowth and proximal tubal occlusion.

Focusing on the patient’s partner may be the smartest approach

Male sterilization with vasectomy poses no medical risks to a woman with a complex medical history. However, long-term success requires that she keep the same sexual partner throughout her reproductive life or seek another form of contraception.

CASE RESOLVED Patient opts for progestin-only pills

Because of her sickle cell disease, D.M., the patient described at the beginning of this article, is not a good candidate for surgical sterilization, and neither is her boyfriend. According to WHO criteria, her sickle cell disease falls into category 2 in regard to combined OCs and category 1 for IUC—both effective methods. No guidance is available regarding concomitant use of steroids, which she is taking for lupus, with IUC, but her baseline risk for pelvic infection is thought to be relatively low. The noncontraceptive benefit of ovarian cyst suppression makes combined OCs even more attractive for this patient, but her history of stroke contraindicates this method (category 4). Depot medroxyprogesterone acetate may suppress ovarian function and is classified as category 3. She ultimately selects a combination of progestin-only pills and condoms and has successfully avoided pregnancy.

The author reports no financial relationships relevant to this article.

CASE Multiple morbidities complicate choice of contraceptive

D.M. is a 27-year-old woman who has sickle cell disease, which led to a mild stroke during adolescence. She also has mild renal insufficiency and was given a diagnosis in adulthood of systemic lupus erythematosus, for which she takes prednisone on a maintenance basis.

D.M. is sexually active with her long-term boyfriend, and has undergone salpingectomy for ectopic pregnancy. Recently, she underwent exploratory laparotomy after a ruptured hemorrhagic ovarian cyst caused an intraperitoneal hemorrhage.

What method of birth control would be most appropriate for this patient?

The question is a daunting one, but it’s imperative for health-care providers to understand the nature and magnitude of contraceptive risks in medically complex women and provide the answers that these patients need.

In this article, I describe important considerations and sift the evidence regarding each of what I refer to here as highly effective contraceptive methods:

• safe hormonal contraceptives
• intrauterine contraceptives
• minimally invasive surgical sterilization.

These methods have given medically complex women greater control over their reproductive function and health, and a number of them offer benefits beyond contraception.

With some methods, such as progestin-only contraception, prospective data are lacking but retrospective studies show no elevated risk of cardiovascular events. And although combination hormonal contraceptives carry an elevated relative risk of cardiovascular events, absolute risk is very low.

First, who are these patients?

Women who have an extreme chronic medical condition, such as pulmonary hypertension, cardiomyopathy, or a dilated aortic root (>40 mm), face pregnancy-associated mortality as high as 10% to 50%—making unplanned pregnancy significantly more dangerous than any contraceptive. And even women who have a less severe medical condition stand to benefit from careful pregnancy timing: Those who have diabetes, lupus, or inflammatory bowel disease often need to optimize their medical condition before becoming pregnant. Still others may need to discontinue a teratogenic medication or treatment.

As for women who have multiple serious medical conditions, such as the patient described above, there is critical need to understand and prepare for the risks of pregnancy. These women deserve a contraceptive that has an efficacy rate approaching 100%.

All too often, however, these women settle for less effective barrier methods— or no method at all—out of concern that contraceptive and personal medical risks may interact adversely. Medical interests may drive these choices, but the unplanned pregnancies that result can pose more health risks than the rejected contraceptives.

A tool to weigh contraceptive risks

The World Health Organization (WHO) has categorized a large number of medical conditions according to their level of risk in regard to specific contraceptives.¹ The four categories established by WHO range from no restrictions (category 1) to unacceptable health risks (category 4) (TABLE 1). With this system, you have a streamlined resource for weighing a contraceptive’s risks and benefits and finding an appropriate method for your patients.

TABLE 1

Four levels of risk in WHO categories

Sifting risks and benefits of hormonal contraceptives

With typical use, hormonal contraceptive pills and injections prevent pregnancy in 92% to 97% of women who use one of these methods for 1 year.² They also may decrease dysmenorrhea and menorrhagia, reduce the incidence of functional ovarian cysts, improve menstrual symptoms, and help prevent ovarian and endometrial cancers.^2,3 In surveys in selected developed countries, the majority of women have used hormonal contraceptives at some time in their reproductive lives.²

Hormonal contraceptives also carry rare but potentially serious health risks that may deter their use—at times, inappropriately. Combined oral contraceptives (OCs) may double or triple the risk of myocardial infarction (MI)⁴ and stroke^5,6 and triple or quadruple the risk of deep venous thrombosis (DVT) and venous thromboembolism (VTE).⁷

Recent data on the combined contraceptive patch suggest that it carries a risk of VTE twice as high as combined OCs.⁸ (Rates of MI and stroke were too small to compare accurately.⁸) We lack data on the vaginal ring contraceptive, but its medical risks are assumed to be similar to those of combined oral contraceptives.¹

Putting the risks of OCs in context

It is very important to interpret these risks in light of the overall rarity of cardiovascular events and the opposing risks of pregnancy. TABLE 2 shows the low incidence of MI, stroke, and VTE among nonpregnant and pregnant women.

For every 100,000 woman-years, combined OCs are estimated to contribute three additional cases of MI, four additional cases of stroke, and 10 to 20 additional cases of VTE.^3,5,9 For these severe conditions, the baseline incidence plus additional cases attributed to use of combination OCs still does not approach the risk of pregnancy itself. One study showed that women face a higher risk of cardiovascular death in pregnancy than when taking combined OCs, with the exception of smokers over the age of 35 years.⁹

For most women, combined OCs pose no greater cardiovascular risk than pregnancy does—but baseline cardiovascular risk factors augment that risk. Women who have hypertension, those who smoke, and those over age 35 face higher risks of MI and stroke while taking combined OCs.^4,10 Diabetes and hypercholesterolemia further elevate the risk of MI,⁴ and migraine headache and thrombophilia raise the risk of stroke.^6,11-13 Women with thrombophilia, a history of a clotting disorder, elevated body mass index (BMI), and, possibly, those who smoke face a higher risk of VTE when using a combined hormonal contraceptive.^14-17

Because of these risks, the WHO classifies significant cardiovascular risk factors as category 4 (contraindicated) in regard to combined OCs (TABLE 3).

These risk factors include:

• known vascular disease
• ischemic heart disease
• history of stroke
• known thrombotic mutation
• complicated valvular disease.

When systolic blood pressure exceeds 160 mm Hg or diastolic blood pressure surpasses 100 mm Hg, combined OCs are again contraindicated. Use of combined OCs in women who have milder blood pressure elevations and adequately controlled hypertension is classified as category 3—theoretical or proven risks usually outweigh the advantages of using the method. Individual risk factors such as hyperlipidemia or uncomplicated diabetes are classified as category 3 in regard to combined OCs—unless multiple factors coexist, in which case they fall into category 4.

TABLE 2

Incidence of major cardiovascular events per 100,000 woman-years

TABLE 3

Risk states in which combined hormonal contraceptives are contraindicated

Obese women may benefit from OCs—but efficacy may decline

Although obesity increases the risk of VTE¹⁷ and possibly MI⁴ during use of combined OCs, the WHO classifies it as category 2 in regard to this contraceptive method—advantages generally outweigh the theoretical or proven risks. This rating is based on the low number of major adverse events associated with use of low-dose combined OCs in obese women.¹

However, combined OCs appear to be less effective in obese women than in their normal-weight peers. A recent case-control study showed diminished efficacy for women with a BMI over 27, and an even higher rate of contraceptive failure for those with a BMI over 32.¹⁸ Nevertheless, it is important for clinicians and patients to recognize the benefits likely to accrue from this method—probably at a higher rate than is seen with most barrier methods.

Obese women who suffer from oligoovulation may also benefit from the progestin in combined OCs, which can mitigate the effects of unopposed estrogen.

Nevertheless, it may be wise, when counseling these women, to consider a more effective method that carries less risk, such as a progestin-releasing intrauterine contraceptive.

Stroke risk in migraine sufferers may render OC option unwise

Patients who experience migraine have a higher risk of stroke than their migraine-free peers. The risk is even higher when the migraine is preceded by an aura (a 5- to 10-minute episode of moving lights in a visual field, speech disturbance, paresthesias, or weakness that precedes the headache).^12,19 Risk is especially elevated when women who suffer migraines use a combined OC, with an odds ratio for stroke ranging from 6.6 to 8.7.

Because of these heightened risks, the WHO classifies migraine with aura as category 4 (contraindicated) for combined OCs. When no aura is present, the advisability of OC use depends on the woman’s age and whether her symptoms predate hormone use. Migraine without aura falls into category 4 for women over age 35 whose symptoms develop while on the contraceptive. It falls into category 2 if the woman is under age 35 and her symptoms predate contraceptive use. In other situations, migraine without aura falls into category 3.

Progestin-only options may be safer in women with cardiovascular risk

Women who face an unacceptable level of cardiovascular risk with combined OCs may still be candidates for progestin-only contraceptives. Although data are thin regarding the risks of progestins in the absence of estrogen, an international WHO study found no increased cardiovascular risk with the use of oral or injectable progestins.²⁰

Current breast cancer is the only medical condition in which progestin-only contraception is contraindicated (category 4). Significant or multiple cardiac risk factors are classified as category 3 in regard to depot medroxyprogesterone acetate, and as category 1 or 2 for progestin-only pills.

Current DVT or VTE is classified as category 3 in regard to progestin-only contraception. A history of DVT or VTE is category 2 (TABLE 4).

TABLE 4

Risks of progestin-only contraceptives may outweigh benefits in these conditions

Liver disease, cancer may rule out use of hormones

Estrogens and progestins are metabolized by the liver, and women with significant liver dysfunction may accumulate medication. Hormones are also contraindicated in the setting of hormone-sensitive tumors, such as liver adenomas and breast cancer.

In addition, hormones may interact with—and should be avoided during use of—drugs that affect metabolic enzymes, such as certain anticonvulsants, rifampin, and some antiretrovirals.¹

Intrauterine option is underused

Two types of intrauterine contraception (IUC) are available in the United States: the CuT-380A and the LNG-20. The former uses copper, whereas the latter delivers the progestin levonorgestrel directly to the endometrium. Both methods are extremely effective, with cumulative failure rates below 1% to 2% over 5 to 10 years.²¹ Unlike most hormonal contraceptives, IUCs do not require patient compliance, and the LNG-20 has the additional benefit of decreasing menstrual blood loss.²¹

Despite these advantages, fear of uterine infection has led to underuse of IUC in the United States.²² A worldwide review of prospective studies of IUC revealed that the risk of infection is limited to the first 20 days after insertion, when the risk of pelvic inflammatory disease (PID) is approximately 1%.²³ Thereafter, the risk of infection is significantly lower and can be linked to other PID risk factors, such as young age and multiple partners.^23,24 The risk may be even lower with the LNG-20 than with the copper system.²⁵ The IUC’s safety and high level of effectiveness make it an excellent choice for many women with chronic medical conditions.

Picture is murky in immunocompromised women

Infection caused by IUC may be unlikely in a healthy woman, but use of IUC in immunocompromised patients carries uncertain risk. Data from HIV-infected women in Africa have been reassuring, demonstrating an acceptably low risk of infection.²⁶ However, no studies have evaluated IUC among women on immunosuppressive drugs or those with otherwise impaired immune systems, and the WHO does not make formal recommendations for these patients. Two case reports of IUC failure in transplant patients led some to theorize that immune-mediated inflammation is necessary for IUC function, but this has not been proven.²⁷

When immunocompromised women do not qualify for other highly effective contraceptives, the benefit of IUC may outweigh any theoretical risks. In this case, the LNG-20 may be preferable for its possibly lower risk of infection and decreased reliance on an inflammatory mechanism of action.

Contraindications to IUC include breast cancer, pelvic infection

Although the LNG-20 contains a hormone, the amount of levonorgestrel entering the circulation is very low, so the method is not restricted in women with cardiovascular risk factors. The only contraindications to IUC are:

• pelvic infection or sepsis
• pregnancy
• undiagnosed abnormal uterine bleeding or gynecologic cancer
• distorted uterine cavity
• breast cancer (for the LNG-20)
• Wilson’s disease (for the CuT-380A).

Sterilization is a safe option

For women ready to forego future childbearing, surgical sterilization is an excellent option. It requires no compliance or follow-up on the part of the patient, and efficacy rates approach that of IUC—at 98% to 99% or higher.

Beyond regret and sterilization failure, the risks of sterilization are limited to those of the surgical procedure itself. These may be negligible if tubal ligation is performed at the time of another indicated surgery, such as cesarean section.

Interval sterilization with laparoscopic tubal ligation is usually performed with general anesthesia. The rate of major morbidity is approximately 0.9%, including major bleeding, need for laparotomy, organ injury, and major infection. Complications may be higher in women with diabetes, a history of major surgery, and obesity.²⁸

The WHO advises caution when using this method in the setting of severe diabetes, sickle cell disease, coagulopathy, severe renal disease, cardiovascular disease, or pulmonary disease.¹

Insertion of intratubal coils is less invasive than tubal ligation

Hysteroscopic tubal sterilization with placement of titanium–Dacron intratubal coils (sold by the name Essure) is another option gaining use (FIGURE). Although large-scale studies have yet to be published, data from the largest phase III trial are consistent with smaller studies.²⁹ In that multicenter trial, coil placement was successful in 92% of patients, and 99% of women completed the procedure without general anesthesia. Tubal perforation was identified in 1% of women, who went on to a laparoscopic procedure.

This less invasive method of permanent sterilization increases options for women who are poor laparoscopy candidates, although the 10% of women who experience technical failure will be forced to find an alternative method. Patient compliance is also an issue because the woman must use backup contraception for 3 months following the procedure, until tubal occlusion is confirmed by hysterosalpingography.

FIGURE Sterilization via insertion of intratubal coils

Delivery of the Essure device.
After 3 months, polyethylene (PET) fibers elicit ingrowth and proximal tubal occlusion.

Focusing on the patient’s partner may be the smartest approach

Male sterilization with vasectomy poses no medical risks to a woman with a complex medical history. However, long-term success requires that she keep the same sexual partner throughout her reproductive life or seek another form of contraception.

CASE RESOLVED Patient opts for progestin-only pills

Because of her sickle cell disease, D.M., the patient described at the beginning of this article, is not a good candidate for surgical sterilization, and neither is her boyfriend. According to WHO criteria, her sickle cell disease falls into category 2 in regard to combined OCs and category 1 for IUC—both effective methods. No guidance is available regarding concomitant use of steroids, which she is taking for lupus, with IUC, but her baseline risk for pelvic infection is thought to be relatively low. The noncontraceptive benefit of ovarian cyst suppression makes combined OCs even more attractive for this patient, but her history of stroke contraindicates this method (category 4). Depot medroxyprogesterone acetate may suppress ovarian function and is classified as category 3. She ultimately selects a combination of progestin-only pills and condoms and has successfully avoided pregnancy.

The author reports no financial relationships relevant to this article.

CASE Multiple morbidities complicate choice of contraceptive

D.M. is a 27-year-old woman who has sickle cell disease, which led to a mild stroke during adolescence. She also has mild renal insufficiency and was given a diagnosis in adulthood of systemic lupus erythematosus, for which she takes prednisone on a maintenance basis.

D.M. is sexually active with her long-term boyfriend, and has undergone salpingectomy for ectopic pregnancy. Recently, she underwent exploratory laparotomy after a ruptured hemorrhagic ovarian cyst caused an intraperitoneal hemorrhage.

What method of birth control would be most appropriate for this patient?

The question is a daunting one, but it’s imperative for health-care providers to understand the nature and magnitude of contraceptive risks in medically complex women and provide the answers that these patients need.

In this article, I describe important considerations and sift the evidence regarding each of what I refer to here as highly effective contraceptive methods:

• safe hormonal contraceptives
• intrauterine contraceptives
• minimally invasive surgical sterilization.

These methods have given medically complex women greater control over their reproductive function and health, and a number of them offer benefits beyond contraception.

With some methods, such as progestin-only contraception, prospective data are lacking but retrospective studies show no elevated risk of cardiovascular events. And although combination hormonal contraceptives carry an elevated relative risk of cardiovascular events, absolute risk is very low.

First, who are these patients?

Women who have an extreme chronic medical condition, such as pulmonary hypertension, cardiomyopathy, or a dilated aortic root (>40 mm), face pregnancy-associated mortality as high as 10% to 50%—making unplanned pregnancy significantly more dangerous than any contraceptive. And even women who have a less severe medical condition stand to benefit from careful pregnancy timing: Those who have diabetes, lupus, or inflammatory bowel disease often need to optimize their medical condition before becoming pregnant. Still others may need to discontinue a teratogenic medication or treatment.

As for women who have multiple serious medical conditions, such as the patient described above, there is critical need to understand and prepare for the risks of pregnancy. These women deserve a contraceptive that has an efficacy rate approaching 100%.

All too often, however, these women settle for less effective barrier methods— or no method at all—out of concern that contraceptive and personal medical risks may interact adversely. Medical interests may drive these choices, but the unplanned pregnancies that result can pose more health risks than the rejected contraceptives.

A tool to weigh contraceptive risks

The World Health Organization (WHO) has categorized a large number of medical conditions according to their level of risk in regard to specific contraceptives.¹ The four categories established by WHO range from no restrictions (category 1) to unacceptable health risks (category 4) (TABLE 1). With this system, you have a streamlined resource for weighing a contraceptive’s risks and benefits and finding an appropriate method for your patients.

TABLE 1

Four levels of risk in WHO categories

Sifting risks and benefits of hormonal contraceptives

With typical use, hormonal contraceptive pills and injections prevent pregnancy in 92% to 97% of women who use one of these methods for 1 year.² They also may decrease dysmenorrhea and menorrhagia, reduce the incidence of functional ovarian cysts, improve menstrual symptoms, and help prevent ovarian and endometrial cancers.^2,3 In surveys in selected developed countries, the majority of women have used hormonal contraceptives at some time in their reproductive lives.²

Hormonal contraceptives also carry rare but potentially serious health risks that may deter their use—at times, inappropriately. Combined oral contraceptives (OCs) may double or triple the risk of myocardial infarction (MI)⁴ and stroke^5,6 and triple or quadruple the risk of deep venous thrombosis (DVT) and venous thromboembolism (VTE).⁷

Recent data on the combined contraceptive patch suggest that it carries a risk of VTE twice as high as combined OCs.⁸ (Rates of MI and stroke were too small to compare accurately.⁸) We lack data on the vaginal ring contraceptive, but its medical risks are assumed to be similar to those of combined oral contraceptives.¹

Putting the risks of OCs in context

It is very important to interpret these risks in light of the overall rarity of cardiovascular events and the opposing risks of pregnancy. TABLE 2 shows the low incidence of MI, stroke, and VTE among nonpregnant and pregnant women.

For every 100,000 woman-years, combined OCs are estimated to contribute three additional cases of MI, four additional cases of stroke, and 10 to 20 additional cases of VTE.^3,5,9 For these severe conditions, the baseline incidence plus additional cases attributed to use of combination OCs still does not approach the risk of pregnancy itself. One study showed that women face a higher risk of cardiovascular death in pregnancy than when taking combined OCs, with the exception of smokers over the age of 35 years.⁹

For most women, combined OCs pose no greater cardiovascular risk than pregnancy does—but baseline cardiovascular risk factors augment that risk. Women who have hypertension, those who smoke, and those over age 35 face higher risks of MI and stroke while taking combined OCs.^4,10 Diabetes and hypercholesterolemia further elevate the risk of MI,⁴ and migraine headache and thrombophilia raise the risk of stroke.^6,11-13 Women with thrombophilia, a history of a clotting disorder, elevated body mass index (BMI), and, possibly, those who smoke face a higher risk of VTE when using a combined hormonal contraceptive.^14-17

Because of these risks, the WHO classifies significant cardiovascular risk factors as category 4 (contraindicated) in regard to combined OCs (TABLE 3).

These risk factors include:

• known vascular disease
• ischemic heart disease
• history of stroke
• known thrombotic mutation
• complicated valvular disease.

When systolic blood pressure exceeds 160 mm Hg or diastolic blood pressure surpasses 100 mm Hg, combined OCs are again contraindicated. Use of combined OCs in women who have milder blood pressure elevations and adequately controlled hypertension is classified as category 3—theoretical or proven risks usually outweigh the advantages of using the method. Individual risk factors such as hyperlipidemia or uncomplicated diabetes are classified as category 3 in regard to combined OCs—unless multiple factors coexist, in which case they fall into category 4.

TABLE 2

Incidence of major cardiovascular events per 100,000 woman-years

TABLE 3

Risk states in which combined hormonal contraceptives are contraindicated

Obese women may benefit from OCs—but efficacy may decline

Although obesity increases the risk of VTE¹⁷ and possibly MI⁴ during use of combined OCs, the WHO classifies it as category 2 in regard to this contraceptive method—advantages generally outweigh the theoretical or proven risks. This rating is based on the low number of major adverse events associated with use of low-dose combined OCs in obese women.¹

However, combined OCs appear to be less effective in obese women than in their normal-weight peers. A recent case-control study showed diminished efficacy for women with a BMI over 27, and an even higher rate of contraceptive failure for those with a BMI over 32.¹⁸ Nevertheless, it is important for clinicians and patients to recognize the benefits likely to accrue from this method—probably at a higher rate than is seen with most barrier methods.

Obese women who suffer from oligoovulation may also benefit from the progestin in combined OCs, which can mitigate the effects of unopposed estrogen.

Nevertheless, it may be wise, when counseling these women, to consider a more effective method that carries less risk, such as a progestin-releasing intrauterine contraceptive.

Stroke risk in migraine sufferers may render OC option unwise

Patients who experience migraine have a higher risk of stroke than their migraine-free peers. The risk is even higher when the migraine is preceded by an aura (a 5- to 10-minute episode of moving lights in a visual field, speech disturbance, paresthesias, or weakness that precedes the headache).^12,19 Risk is especially elevated when women who suffer migraines use a combined OC, with an odds ratio for stroke ranging from 6.6 to 8.7.

Because of these heightened risks, the WHO classifies migraine with aura as category 4 (contraindicated) for combined OCs. When no aura is present, the advisability of OC use depends on the woman’s age and whether her symptoms predate hormone use. Migraine without aura falls into category 4 for women over age 35 whose symptoms develop while on the contraceptive. It falls into category 2 if the woman is under age 35 and her symptoms predate contraceptive use. In other situations, migraine without aura falls into category 3.

Progestin-only options may be safer in women with cardiovascular risk

Women who face an unacceptable level of cardiovascular risk with combined OCs may still be candidates for progestin-only contraceptives. Although data are thin regarding the risks of progestins in the absence of estrogen, an international WHO study found no increased cardiovascular risk with the use of oral or injectable progestins.²⁰

Current breast cancer is the only medical condition in which progestin-only contraception is contraindicated (category 4). Significant or multiple cardiac risk factors are classified as category 3 in regard to depot medroxyprogesterone acetate, and as category 1 or 2 for progestin-only pills.

Current DVT or VTE is classified as category 3 in regard to progestin-only contraception. A history of DVT or VTE is category 2 (TABLE 4).

TABLE 4

Risks of progestin-only contraceptives may outweigh benefits in these conditions

Liver disease, cancer may rule out use of hormones

Estrogens and progestins are metabolized by the liver, and women with significant liver dysfunction may accumulate medication. Hormones are also contraindicated in the setting of hormone-sensitive tumors, such as liver adenomas and breast cancer.

In addition, hormones may interact with—and should be avoided during use of—drugs that affect metabolic enzymes, such as certain anticonvulsants, rifampin, and some antiretrovirals.¹

Intrauterine option is underused

Two types of intrauterine contraception (IUC) are available in the United States: the CuT-380A and the LNG-20. The former uses copper, whereas the latter delivers the progestin levonorgestrel directly to the endometrium. Both methods are extremely effective, with cumulative failure rates below 1% to 2% over 5 to 10 years.²¹ Unlike most hormonal contraceptives, IUCs do not require patient compliance, and the LNG-20 has the additional benefit of decreasing menstrual blood loss.²¹

Despite these advantages, fear of uterine infection has led to underuse of IUC in the United States.²² A worldwide review of prospective studies of IUC revealed that the risk of infection is limited to the first 20 days after insertion, when the risk of pelvic inflammatory disease (PID) is approximately 1%.²³ Thereafter, the risk of infection is significantly lower and can be linked to other PID risk factors, such as young age and multiple partners.^23,24 The risk may be even lower with the LNG-20 than with the copper system.²⁵ The IUC’s safety and high level of effectiveness make it an excellent choice for many women with chronic medical conditions.

Picture is murky in immunocompromised women

Infection caused by IUC may be unlikely in a healthy woman, but use of IUC in immunocompromised patients carries uncertain risk. Data from HIV-infected women in Africa have been reassuring, demonstrating an acceptably low risk of infection.²⁶ However, no studies have evaluated IUC among women on immunosuppressive drugs or those with otherwise impaired immune systems, and the WHO does not make formal recommendations for these patients. Two case reports of IUC failure in transplant patients led some to theorize that immune-mediated inflammation is necessary for IUC function, but this has not been proven.²⁷

When immunocompromised women do not qualify for other highly effective contraceptives, the benefit of IUC may outweigh any theoretical risks. In this case, the LNG-20 may be preferable for its possibly lower risk of infection and decreased reliance on an inflammatory mechanism of action.

Contraindications to IUC include breast cancer, pelvic infection

Although the LNG-20 contains a hormone, the amount of levonorgestrel entering the circulation is very low, so the method is not restricted in women with cardiovascular risk factors. The only contraindications to IUC are:

• pelvic infection or sepsis
• pregnancy
• undiagnosed abnormal uterine bleeding or gynecologic cancer
• distorted uterine cavity
• breast cancer (for the LNG-20)
• Wilson’s disease (for the CuT-380A).

Sterilization is a safe option

For women ready to forego future childbearing, surgical sterilization is an excellent option. It requires no compliance or follow-up on the part of the patient, and efficacy rates approach that of IUC—at 98% to 99% or higher.

Beyond regret and sterilization failure, the risks of sterilization are limited to those of the surgical procedure itself. These may be negligible if tubal ligation is performed at the time of another indicated surgery, such as cesarean section.

Interval sterilization with laparoscopic tubal ligation is usually performed with general anesthesia. The rate of major morbidity is approximately 0.9%, including major bleeding, need for laparotomy, organ injury, and major infection. Complications may be higher in women with diabetes, a history of major surgery, and obesity.²⁸

The WHO advises caution when using this method in the setting of severe diabetes, sickle cell disease, coagulopathy, severe renal disease, cardiovascular disease, or pulmonary disease.¹

Insertion of intratubal coils is less invasive than tubal ligation

Hysteroscopic tubal sterilization with placement of titanium–Dacron intratubal coils (sold by the name Essure) is another option gaining use (FIGURE). Although large-scale studies have yet to be published, data from the largest phase III trial are consistent with smaller studies.²⁹ In that multicenter trial, coil placement was successful in 92% of patients, and 99% of women completed the procedure without general anesthesia. Tubal perforation was identified in 1% of women, who went on to a laparoscopic procedure.

This less invasive method of permanent sterilization increases options for women who are poor laparoscopy candidates, although the 10% of women who experience technical failure will be forced to find an alternative method. Patient compliance is also an issue because the woman must use backup contraception for 3 months following the procedure, until tubal occlusion is confirmed by hysterosalpingography.

FIGURE Sterilization via insertion of intratubal coils

Delivery of the Essure device.
After 3 months, polyethylene (PET) fibers elicit ingrowth and proximal tubal occlusion.

Focusing on the patient’s partner may be the smartest approach

Male sterilization with vasectomy poses no medical risks to a woman with a complex medical history. However, long-term success requires that she keep the same sexual partner throughout her reproductive life or seek another form of contraception.

CASE RESOLVED Patient opts for progestin-only pills

Because of her sickle cell disease, D.M., the patient described at the beginning of this article, is not a good candidate for surgical sterilization, and neither is her boyfriend. According to WHO criteria, her sickle cell disease falls into category 2 in regard to combined OCs and category 1 for IUC—both effective methods. No guidance is available regarding concomitant use of steroids, which she is taking for lupus, with IUC, but her baseline risk for pelvic infection is thought to be relatively low. The noncontraceptive benefit of ovarian cyst suppression makes combined OCs even more attractive for this patient, but her history of stroke contraindicates this method (category 4). Depot medroxyprogesterone acetate may suppress ovarian function and is classified as category 3. She ultimately selects a combination of progestin-only pills and condoms and has successfully avoided pregnancy.

The authors report no financial relationships relevant to this article.

A pregnant woman whose thyroid gland isn’t doing its job presents a serious management problem for her obstetrician. If she has overt hypothyroidism, seen in between 0.3% and 2.5% of pregnancies, active intervention is required to prevent serious damage to the fetus.^1,2 Even if she has subclinical disease, seen in 2% to 3% of pregnancies, current research indicates that intervention may be indicated.

Fetal thyroxine requirements increase as early as 5 weeks of gestation, when the fetus is still dependent on maternal thyroxine. A deficiency of maternal thyroxine can have severe adverse outcomes, affecting the course of the pregnancy and the neurologic development of the fetus. To prevent such sequelae, patients who were on thyroid medication before pregnancy should increase the dosage by 30% once pregnancy is confirmed, and hypothyroidism that develops in pregnancy should be managed aggressively and meticulously.

Here, we’ll examine the published research to advise you on evidence-based approaches for diagnosis and management of this complex condition.

Maternal thyroid function

An elaborate negative-feedback loop prevails before pregnancy

In a nonpregnant woman, thyroid function is controlled by a negative-feedback loop that works like this:

• The hypothalamus releases thyroid-releasing hormone (TRH)
• TRH acts on the pituitary gland to release thyroid-stimulating hormone (TSH)
• TSH, in turn, acts on the thyroid gland to release the thyroid hormones iodothyronine (T₃) and thyroxine (T₄) that regulate metabolism
• TRH and TSH concentrations are inversely related to T₃ and T₄ concentrations. That is, the more TRH and TSH circulating in the blood stream, the less T₃ and T₄ will be produced by the thyroid gland³
• Almost all (approximately 99%) circulating T₃ and T₄ is bound to a protein called thyroxine-binding globulin (TBG). Only 1% of these hormones circulate in the free form, and only the free forms are biologically active.³

This relationship is illustrated in FIGURE 1.

FIGURE 1 Thyroid physiology and the impact of pregnancy

Pregnancy reduces free forms of T₃ and T₄, and increases TSH slightly

Pregnancy alters thyroid function in significant ways:

• Increases in circulating estrogen lead to the production of more TBG
• When TBG increases, more T₃ and T₄ are bound and fewer free forms of these hormones are available
• Because the total T₃ (TT₃) and total free T₄ (TT₄) are decreased in pregnancy, they are not good measures of thyroid function. Maternal thyroid function in pregnancy should be monitored using free T₄ (FT₄) and TSH levels
• Increased TBG also leads to a slight increase in TSH between the first trimester and term
• Human chorionic gonadotropin (hCG) concentrations also increase in pregnancy. Because hCG has thyrotropin-like activity, these higher levels cause a transient decrease in TSH by suppression of TSH production between approximately 8 and 14 weeks of gestation.

Fetal thyroid function

During early gestation, the fetus receives thyroid hormone from the mother.¹ Maternal T₄ crosses the placenta actively—the only hormone that does so.⁴ The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.⁵

Fetal thyroid development does not begin until 10 to 12 weeks of gestation, and then continues until term. The fetus relies on maternal T₄ exclusively before 12 weeks and partially thereafter for normal fetal neurologic development. It follows that maternal hypothyroidism could be detrimental to fetal development if not detected and corrected very early in gestation.

How (and whom) to screen for maternal hypothyroidism

Routine screening has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of deficient thyroid function.⁶ In recent years, some authors have recommended screening all pregnant women for thyroid dysfunction, but such recommendations remain controversial.^3,7,8 Routine screening is not endorsed by the American College of Obstetricians and Gynecologists.⁶

Symptoms overlap typical conditions of pregnancy

The difficulty here is that the characteristic signs and symptoms of hypothyroidism are very similar to physiologic conditions seen in most pregnancies. They include fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, brittle nails, weight gain, intellectual slowness, bradycardia, depression, insomnia, periorbital edema, myxedema, and myxedema coma.⁶ A side-by-side comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 1.

TABLE 1

Distinguishing hypothyroidism from a normal gestation can be challenging

Which laboratory tests are informative?

Because screening is controversial and symptomatology does not reliably distinguish hypothyroidism from normal pregnancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is diagnosed in a symptomatic patient by elevated TSH level and low levels of FT₄ and free T₃ (FT₃). Subclinical hypothyroidism is defined as elevated TSH with normal FT₄ and FT₃ in an asymptomatic patient. Level changes characteristic of normal pregnancy, overt hypothyroidism, and subclinical hypothyroidism are given in TABLE 2.⁶

TABLE 2

Laboratory diagnosis of hypothyroidism

What causes hypothyroidism?

The most common cause of hypothyroidism in most of the world is iodine deficiency. In developed countries, however, where lack of iodine in the diet is not a problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause. Hashimoto’s thyroiditis is characterized by the presence of antithyroid antibodies, including both thyroid antimicrosomial and antithyroglobulin antibodies. Both iodine deficiency and Hashimoto’s thyroiditis are associated with goiter.⁵ Other causes of hypothyroidism include radioactive iodine therapy for Graves’ disease, a condition we will discuss in Part 2 of this series in February; thyroidectomy; viral thyroiditis; pituitary tumors; Sheehan’s syndrome; and a number of medications.

Causes of hypothyroidism are summarized in TABLE 3.³

TABLE 3

Causes of hypothyroidism

Effects vary by medication

Medications alter thyroid function in different ways. Iodine and lithium inhibit thyroid function and, along with dopamine antagonists, increase TSH levels. Conversely, thioamides, glucocorticoids, dopamine agonists, and somatostatins decrease TSH levels. Finally, ferrous sulfate, sucrafate, cholestyramine, and aluminum hydroxide antacids all inhibit gastrointestinal absorption of thyroid hormone and therefore should not be taken within 4 hours of thyroid medication.⁶

Maternal hypothyroidism: Effects on fetus, newborn

The impact of maternal hypothyroidism on the fetus depends on the severity of the condition.

• Uncontrolled hypothyroidism. The consequences of this condition can be dire. The possibilities include intrauterine fetal demise and stillbirth, preterm delivery, low birth weight, preeclampsia, and developmental anomalies including reduced intelligence quotient (IQ).^1,2,4,6 Blazer and colleagues correlated intrauterine growth with maternal TSH and fetal FT₄ and concluded that impaired intrauterine growth is related to abnormal thyroid function and might reflect an insufficient level of hormone production by hypothyroid mothers during pregnancy.⁹ Maternal and congenital hypothyroidism resulting from severe iodine deficiency are associated with profound neurologic impairment and mental retardation.^1,3,10 If the condition is left untreated, cretinism can occur. Congenital cretinism is associated with growth failure, mental retardation, and other neuropsychologic deficits including deaf-mutism.^3,4 However, if cretinism is identified and treated in the first 3 months of life, near-normal growth and intelligence can be expected.⁶ For this reason, all 50 states and the District of Columbia require newborn screening for congenital hypothyroidism.⁶
• Asymptomatic overt hypothyroidism. Several studies have evaluated neonatal outcomes in pregnancy complicated by asymptomatic overt hypothyroidism—that is, women who had previously been diagnosed with hypothyroidism, who have abnormal TSH and FT₄ levels, but who do not have symptoms. Pop and colleagues have shown impaired psychomotor development at 10 months in infants born to mothers who had low T₄ during the first 12 weeks of gestation.⁷ Haddow and colleagues correlated elevated maternal TSH levels at less than 17 weeks’ gestation with low IQ scores in the offspring at 7 to 9 years of age.⁸ Klein and colleagues demonstrated an inverse correlation between a woman’s TSH level during pregnancy and the IQ of her offspring.¹¹ Kooistra and colleagues confirmed that maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities that can be identified as early as 3 weeks of age.¹² Studies of this relationship are summarized in TABLE 4.
• Subclinical hypothyroidism. During the past decade, researchers have focused attention on neonatal neurologic function in infants born to mothers who had subclinical disease. Mitchell and Klein evaluated the prevalence of subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children with those of controls.⁴ They found the mean and standard-deviation IQs of the children in the control and treated groups to be significantly higher than those of the children whose mothers were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclinical hypothyroidism.¹⁰ They found that such pregnancies were more likely to be complicated by placental abruption and preterm birth, and speculated that the reduced IQ demonstrated in the Mitchell and Klein study might have been related to the effects of prematurity.

TABLE 4

Fetal and neonatal effects of asymptomatic overt hypothyroidism

Managing hypothyroidism in pregnancy

The treatment of choice for correction of hypothyroidism is synthetic T₄, or levothyroxine (Levothyroid, Levoxyl, Synthroid, and Unithroid). Initial treatment in the nonpregnant patient is 1.7 μg/kg/day or 12.5 to 25 μg/day adjusted by 25 μg/day every 2 to 4 weeks until a euthyroid state is achieved.¹³

Patients who were on thyroxine therapy before pregnancy should increase the dose by 30% once pregnancy is confirmed.^1,5 Serum thyrotropin levels should be monitored every 4 weeks to maintain a TSH level between 1 and 2 mU/L and FT₄ in upper third of normal.¹ Once a euthyroid state has been achieved, thyrotropin levels should be monitored every trimester until delivery. FIGURE 2 provides an algorithm for management of hypothyroidism in pregnancy.

FIGURE 2 During pregnancy, thyroid function merits regular monitoring, fine-tuning of treatment

Postpartum thyroiditis

About 5% of all obstetrical patients develop postpartum thyroiditis. Approximately 45% of these women present with hypothyroidism, with the rest evenly divided between thyrotoxicosis (hyperthyroidism) and thyrotoxicosis followed by hypothyroidism. Unfortunately, the signs and symptoms of hypo- and hyperthyroidism are similar to the postpartum state. Many of these patients are not diagnosed. A high index of suspicion warrants thyroid function testing. Women who have a history of type 1 diabetes mellitus have a 25% chance of developing postpartum thyroid dysfunction.

The diagnosis is made by documenting abnormal levels of TSH and FT₄. Postpartum hyperthyroidism may be diagnosed by the presence of antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies. Goiter may be present in up to 50% of patients.

Postpartum thyroiditis has two phases

The first phase, also known as the thyrotoxic phase, occurs 1 to 4 months after delivery when transient thyrotoxicosis develops from excessive release of thyroid hormones. The most common symptoms with early postpartum thyroiditis are fatigue and palpitations. Approximately 67% of these women will return to a euthyroid state, and thioamide therapy is generally considered ineffective. Hypothyroidism can develop within 1 month of the onset of thyroiditis.

The second phase occurs between 4 and 8 months postpartum, and these women present with hypothyroidism. Thyromegaly and associated symptoms are common. Unlike the first (thyrotoxic) phase, medical treatment is recommended. Thyroxine treatment should be initiated and maintained for 6 to 12 months. Postpartum thyroiditis carries a 30% risk of recurrence.¹⁴

Postpartum thyroiditis may be associated with depression or aggravate symptoms of depression, although the data on this association are conflicting. The largest study addressing this issue concluded that there was no difference in the clinical and psychiatric signs and symptoms between postpartum thyroiditis and controls.¹⁵ Nevertheless, it would seem prudent to evaluate thyroid function in postpartum depression if other signs of thyroid dysfunction are present.

The authors report no financial relationships relevant to this article.

A pregnant woman whose thyroid gland isn’t doing its job presents a serious management problem for her obstetrician. If she has overt hypothyroidism, seen in between 0.3% and 2.5% of pregnancies, active intervention is required to prevent serious damage to the fetus.^1,2 Even if she has subclinical disease, seen in 2% to 3% of pregnancies, current research indicates that intervention may be indicated.

Fetal thyroxine requirements increase as early as 5 weeks of gestation, when the fetus is still dependent on maternal thyroxine. A deficiency of maternal thyroxine can have severe adverse outcomes, affecting the course of the pregnancy and the neurologic development of the fetus. To prevent such sequelae, patients who were on thyroid medication before pregnancy should increase the dosage by 30% once pregnancy is confirmed, and hypothyroidism that develops in pregnancy should be managed aggressively and meticulously.

Here, we’ll examine the published research to advise you on evidence-based approaches for diagnosis and management of this complex condition.

Maternal thyroid function

An elaborate negative-feedback loop prevails before pregnancy

In a nonpregnant woman, thyroid function is controlled by a negative-feedback loop that works like this:

• The hypothalamus releases thyroid-releasing hormone (TRH)
• TRH acts on the pituitary gland to release thyroid-stimulating hormone (TSH)
• TSH, in turn, acts on the thyroid gland to release the thyroid hormones iodothyronine (T₃) and thyroxine (T₄) that regulate metabolism
• TRH and TSH concentrations are inversely related to T₃ and T₄ concentrations. That is, the more TRH and TSH circulating in the blood stream, the less T₃ and T₄ will be produced by the thyroid gland³
• Almost all (approximately 99%) circulating T₃ and T₄ is bound to a protein called thyroxine-binding globulin (TBG). Only 1% of these hormones circulate in the free form, and only the free forms are biologically active.³

This relationship is illustrated in FIGURE 1.

FIGURE 1 Thyroid physiology and the impact of pregnancy

Pregnancy reduces free forms of T₃ and T₄, and increases TSH slightly

Pregnancy alters thyroid function in significant ways:

• Increases in circulating estrogen lead to the production of more TBG
• When TBG increases, more T₃ and T₄ are bound and fewer free forms of these hormones are available
• Because the total T₃ (TT₃) and total free T₄ (TT₄) are decreased in pregnancy, they are not good measures of thyroid function. Maternal thyroid function in pregnancy should be monitored using free T₄ (FT₄) and TSH levels
• Increased TBG also leads to a slight increase in TSH between the first trimester and term
• Human chorionic gonadotropin (hCG) concentrations also increase in pregnancy. Because hCG has thyrotropin-like activity, these higher levels cause a transient decrease in TSH by suppression of TSH production between approximately 8 and 14 weeks of gestation.

Fetal thyroid function

During early gestation, the fetus receives thyroid hormone from the mother.¹ Maternal T₄ crosses the placenta actively—the only hormone that does so.⁴ The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.⁵

Fetal thyroid development does not begin until 10 to 12 weeks of gestation, and then continues until term. The fetus relies on maternal T₄ exclusively before 12 weeks and partially thereafter for normal fetal neurologic development. It follows that maternal hypothyroidism could be detrimental to fetal development if not detected and corrected very early in gestation.

How (and whom) to screen for maternal hypothyroidism

Routine screening has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of deficient thyroid function.⁶ In recent years, some authors have recommended screening all pregnant women for thyroid dysfunction, but such recommendations remain controversial.^3,7,8 Routine screening is not endorsed by the American College of Obstetricians and Gynecologists.⁶

Symptoms overlap typical conditions of pregnancy

The difficulty here is that the characteristic signs and symptoms of hypothyroidism are very similar to physiologic conditions seen in most pregnancies. They include fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, brittle nails, weight gain, intellectual slowness, bradycardia, depression, insomnia, periorbital edema, myxedema, and myxedema coma.⁶ A side-by-side comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 1.

TABLE 1

Distinguishing hypothyroidism from a normal gestation can be challenging

Which laboratory tests are informative?

Because screening is controversial and symptomatology does not reliably distinguish hypothyroidism from normal pregnancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is diagnosed in a symptomatic patient by elevated TSH level and low levels of FT₄ and free T₃ (FT₃). Subclinical hypothyroidism is defined as elevated TSH with normal FT₄ and FT₃ in an asymptomatic patient. Level changes characteristic of normal pregnancy, overt hypothyroidism, and subclinical hypothyroidism are given in TABLE 2.⁶

TABLE 2

Laboratory diagnosis of hypothyroidism

What causes hypothyroidism?

The most common cause of hypothyroidism in most of the world is iodine deficiency. In developed countries, however, where lack of iodine in the diet is not a problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause. Hashimoto’s thyroiditis is characterized by the presence of antithyroid antibodies, including both thyroid antimicrosomial and antithyroglobulin antibodies. Both iodine deficiency and Hashimoto’s thyroiditis are associated with goiter.⁵ Other causes of hypothyroidism include radioactive iodine therapy for Graves’ disease, a condition we will discuss in Part 2 of this series in February; thyroidectomy; viral thyroiditis; pituitary tumors; Sheehan’s syndrome; and a number of medications.

Causes of hypothyroidism are summarized in TABLE 3.³

TABLE 3

Causes of hypothyroidism

Effects vary by medication

Medications alter thyroid function in different ways. Iodine and lithium inhibit thyroid function and, along with dopamine antagonists, increase TSH levels. Conversely, thioamides, glucocorticoids, dopamine agonists, and somatostatins decrease TSH levels. Finally, ferrous sulfate, sucrafate, cholestyramine, and aluminum hydroxide antacids all inhibit gastrointestinal absorption of thyroid hormone and therefore should not be taken within 4 hours of thyroid medication.⁶

Maternal hypothyroidism: Effects on fetus, newborn

The impact of maternal hypothyroidism on the fetus depends on the severity of the condition.

• Uncontrolled hypothyroidism. The consequences of this condition can be dire. The possibilities include intrauterine fetal demise and stillbirth, preterm delivery, low birth weight, preeclampsia, and developmental anomalies including reduced intelligence quotient (IQ).^1,2,4,6 Blazer and colleagues correlated intrauterine growth with maternal TSH and fetal FT₄ and concluded that impaired intrauterine growth is related to abnormal thyroid function and might reflect an insufficient level of hormone production by hypothyroid mothers during pregnancy.⁹ Maternal and congenital hypothyroidism resulting from severe iodine deficiency are associated with profound neurologic impairment and mental retardation.^1,3,10 If the condition is left untreated, cretinism can occur. Congenital cretinism is associated with growth failure, mental retardation, and other neuropsychologic deficits including deaf-mutism.^3,4 However, if cretinism is identified and treated in the first 3 months of life, near-normal growth and intelligence can be expected.⁶ For this reason, all 50 states and the District of Columbia require newborn screening for congenital hypothyroidism.⁶
• Asymptomatic overt hypothyroidism. Several studies have evaluated neonatal outcomes in pregnancy complicated by asymptomatic overt hypothyroidism—that is, women who had previously been diagnosed with hypothyroidism, who have abnormal TSH and FT₄ levels, but who do not have symptoms. Pop and colleagues have shown impaired psychomotor development at 10 months in infants born to mothers who had low T₄ during the first 12 weeks of gestation.⁷ Haddow and colleagues correlated elevated maternal TSH levels at less than 17 weeks’ gestation with low IQ scores in the offspring at 7 to 9 years of age.⁸ Klein and colleagues demonstrated an inverse correlation between a woman’s TSH level during pregnancy and the IQ of her offspring.¹¹ Kooistra and colleagues confirmed that maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities that can be identified as early as 3 weeks of age.¹² Studies of this relationship are summarized in TABLE 4.
• Subclinical hypothyroidism. During the past decade, researchers have focused attention on neonatal neurologic function in infants born to mothers who had subclinical disease. Mitchell and Klein evaluated the prevalence of subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children with those of controls.⁴ They found the mean and standard-deviation IQs of the children in the control and treated groups to be significantly higher than those of the children whose mothers were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclinical hypothyroidism.¹⁰ They found that such pregnancies were more likely to be complicated by placental abruption and preterm birth, and speculated that the reduced IQ demonstrated in the Mitchell and Klein study might have been related to the effects of prematurity.

TABLE 4

Fetal and neonatal effects of asymptomatic overt hypothyroidism

Managing hypothyroidism in pregnancy

The treatment of choice for correction of hypothyroidism is synthetic T₄, or levothyroxine (Levothyroid, Levoxyl, Synthroid, and Unithroid). Initial treatment in the nonpregnant patient is 1.7 μg/kg/day or 12.5 to 25 μg/day adjusted by 25 μg/day every 2 to 4 weeks until a euthyroid state is achieved.¹³

Patients who were on thyroxine therapy before pregnancy should increase the dose by 30% once pregnancy is confirmed.^1,5 Serum thyrotropin levels should be monitored every 4 weeks to maintain a TSH level between 1 and 2 mU/L and FT₄ in upper third of normal.¹ Once a euthyroid state has been achieved, thyrotropin levels should be monitored every trimester until delivery. FIGURE 2 provides an algorithm for management of hypothyroidism in pregnancy.

FIGURE 2 During pregnancy, thyroid function merits regular monitoring, fine-tuning of treatment

Postpartum thyroiditis

About 5% of all obstetrical patients develop postpartum thyroiditis. Approximately 45% of these women present with hypothyroidism, with the rest evenly divided between thyrotoxicosis (hyperthyroidism) and thyrotoxicosis followed by hypothyroidism. Unfortunately, the signs and symptoms of hypo- and hyperthyroidism are similar to the postpartum state. Many of these patients are not diagnosed. A high index of suspicion warrants thyroid function testing. Women who have a history of type 1 diabetes mellitus have a 25% chance of developing postpartum thyroid dysfunction.

The diagnosis is made by documenting abnormal levels of TSH and FT₄. Postpartum hyperthyroidism may be diagnosed by the presence of antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies. Goiter may be present in up to 50% of patients.

Postpartum thyroiditis has two phases

The first phase, also known as the thyrotoxic phase, occurs 1 to 4 months after delivery when transient thyrotoxicosis develops from excessive release of thyroid hormones. The most common symptoms with early postpartum thyroiditis are fatigue and palpitations. Approximately 67% of these women will return to a euthyroid state, and thioamide therapy is generally considered ineffective. Hypothyroidism can develop within 1 month of the onset of thyroiditis.

The second phase occurs between 4 and 8 months postpartum, and these women present with hypothyroidism. Thyromegaly and associated symptoms are common. Unlike the first (thyrotoxic) phase, medical treatment is recommended. Thyroxine treatment should be initiated and maintained for 6 to 12 months. Postpartum thyroiditis carries a 30% risk of recurrence.¹⁴

Postpartum thyroiditis may be associated with depression or aggravate symptoms of depression, although the data on this association are conflicting. The largest study addressing this issue concluded that there was no difference in the clinical and psychiatric signs and symptoms between postpartum thyroiditis and controls.¹⁵ Nevertheless, it would seem prudent to evaluate thyroid function in postpartum depression if other signs of thyroid dysfunction are present.

The authors report no financial relationships relevant to this article.

A pregnant woman whose thyroid gland isn’t doing its job presents a serious management problem for her obstetrician. If she has overt hypothyroidism, seen in between 0.3% and 2.5% of pregnancies, active intervention is required to prevent serious damage to the fetus.^1,2 Even if she has subclinical disease, seen in 2% to 3% of pregnancies, current research indicates that intervention may be indicated.

Fetal thyroxine requirements increase as early as 5 weeks of gestation, when the fetus is still dependent on maternal thyroxine. A deficiency of maternal thyroxine can have severe adverse outcomes, affecting the course of the pregnancy and the neurologic development of the fetus. To prevent such sequelae, patients who were on thyroid medication before pregnancy should increase the dosage by 30% once pregnancy is confirmed, and hypothyroidism that develops in pregnancy should be managed aggressively and meticulously.

Here, we’ll examine the published research to advise you on evidence-based approaches for diagnosis and management of this complex condition.

Maternal thyroid function

An elaborate negative-feedback loop prevails before pregnancy

In a nonpregnant woman, thyroid function is controlled by a negative-feedback loop that works like this:

• The hypothalamus releases thyroid-releasing hormone (TRH)
• TRH acts on the pituitary gland to release thyroid-stimulating hormone (TSH)
• TSH, in turn, acts on the thyroid gland to release the thyroid hormones iodothyronine (T₃) and thyroxine (T₄) that regulate metabolism
• TRH and TSH concentrations are inversely related to T₃ and T₄ concentrations. That is, the more TRH and TSH circulating in the blood stream, the less T₃ and T₄ will be produced by the thyroid gland³
• Almost all (approximately 99%) circulating T₃ and T₄ is bound to a protein called thyroxine-binding globulin (TBG). Only 1% of these hormones circulate in the free form, and only the free forms are biologically active.³

This relationship is illustrated in FIGURE 1.

FIGURE 1 Thyroid physiology and the impact of pregnancy

Pregnancy reduces free forms of T₃ and T₄, and increases TSH slightly

Pregnancy alters thyroid function in significant ways:

• Increases in circulating estrogen lead to the production of more TBG
• When TBG increases, more T₃ and T₄ are bound and fewer free forms of these hormones are available
• Because the total T₃ (TT₃) and total free T₄ (TT₄) are decreased in pregnancy, they are not good measures of thyroid function. Maternal thyroid function in pregnancy should be monitored using free T₄ (FT₄) and TSH levels
• Increased TBG also leads to a slight increase in TSH between the first trimester and term
• Human chorionic gonadotropin (hCG) concentrations also increase in pregnancy. Because hCG has thyrotropin-like activity, these higher levels cause a transient decrease in TSH by suppression of TSH production between approximately 8 and 14 weeks of gestation.

Fetal thyroid function

During early gestation, the fetus receives thyroid hormone from the mother.¹ Maternal T₄ crosses the placenta actively—the only hormone that does so.⁴ The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.⁵

Fetal thyroid development does not begin until 10 to 12 weeks of gestation, and then continues until term. The fetus relies on maternal T₄ exclusively before 12 weeks and partially thereafter for normal fetal neurologic development. It follows that maternal hypothyroidism could be detrimental to fetal development if not detected and corrected very early in gestation.

How (and whom) to screen for maternal hypothyroidism

Routine screening has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of deficient thyroid function.⁶ In recent years, some authors have recommended screening all pregnant women for thyroid dysfunction, but such recommendations remain controversial.^3,7,8 Routine screening is not endorsed by the American College of Obstetricians and Gynecologists.⁶

Symptoms overlap typical conditions of pregnancy

The difficulty here is that the characteristic signs and symptoms of hypothyroidism are very similar to physiologic conditions seen in most pregnancies. They include fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, brittle nails, weight gain, intellectual slowness, bradycardia, depression, insomnia, periorbital edema, myxedema, and myxedema coma.⁶ A side-by-side comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 1.

TABLE 1

Distinguishing hypothyroidism from a normal gestation can be challenging

Which laboratory tests are informative?

Because screening is controversial and symptomatology does not reliably distinguish hypothyroidism from normal pregnancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is diagnosed in a symptomatic patient by elevated TSH level and low levels of FT₄ and free T₃ (FT₃). Subclinical hypothyroidism is defined as elevated TSH with normal FT₄ and FT₃ in an asymptomatic patient. Level changes characteristic of normal pregnancy, overt hypothyroidism, and subclinical hypothyroidism are given in TABLE 2.⁶

TABLE 2

Laboratory diagnosis of hypothyroidism

What causes hypothyroidism?

The most common cause of hypothyroidism in most of the world is iodine deficiency. In developed countries, however, where lack of iodine in the diet is not a problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause. Hashimoto’s thyroiditis is characterized by the presence of antithyroid antibodies, including both thyroid antimicrosomial and antithyroglobulin antibodies. Both iodine deficiency and Hashimoto’s thyroiditis are associated with goiter.⁵ Other causes of hypothyroidism include radioactive iodine therapy for Graves’ disease, a condition we will discuss in Part 2 of this series in February; thyroidectomy; viral thyroiditis; pituitary tumors; Sheehan’s syndrome; and a number of medications.

Causes of hypothyroidism are summarized in TABLE 3.³

TABLE 3

Causes of hypothyroidism

Effects vary by medication

Medications alter thyroid function in different ways. Iodine and lithium inhibit thyroid function and, along with dopamine antagonists, increase TSH levels. Conversely, thioamides, glucocorticoids, dopamine agonists, and somatostatins decrease TSH levels. Finally, ferrous sulfate, sucrafate, cholestyramine, and aluminum hydroxide antacids all inhibit gastrointestinal absorption of thyroid hormone and therefore should not be taken within 4 hours of thyroid medication.⁶

Maternal hypothyroidism: Effects on fetus, newborn

The impact of maternal hypothyroidism on the fetus depends on the severity of the condition.

• Uncontrolled hypothyroidism. The consequences of this condition can be dire. The possibilities include intrauterine fetal demise and stillbirth, preterm delivery, low birth weight, preeclampsia, and developmental anomalies including reduced intelligence quotient (IQ).^1,2,4,6 Blazer and colleagues correlated intrauterine growth with maternal TSH and fetal FT₄ and concluded that impaired intrauterine growth is related to abnormal thyroid function and might reflect an insufficient level of hormone production by hypothyroid mothers during pregnancy.⁹ Maternal and congenital hypothyroidism resulting from severe iodine deficiency are associated with profound neurologic impairment and mental retardation.^1,3,10 If the condition is left untreated, cretinism can occur. Congenital cretinism is associated with growth failure, mental retardation, and other neuropsychologic deficits including deaf-mutism.^3,4 However, if cretinism is identified and treated in the first 3 months of life, near-normal growth and intelligence can be expected.⁶ For this reason, all 50 states and the District of Columbia require newborn screening for congenital hypothyroidism.⁶
• Asymptomatic overt hypothyroidism. Several studies have evaluated neonatal outcomes in pregnancy complicated by asymptomatic overt hypothyroidism—that is, women who had previously been diagnosed with hypothyroidism, who have abnormal TSH and FT₄ levels, but who do not have symptoms. Pop and colleagues have shown impaired psychomotor development at 10 months in infants born to mothers who had low T₄ during the first 12 weeks of gestation.⁷ Haddow and colleagues correlated elevated maternal TSH levels at less than 17 weeks’ gestation with low IQ scores in the offspring at 7 to 9 years of age.⁸ Klein and colleagues demonstrated an inverse correlation between a woman’s TSH level during pregnancy and the IQ of her offspring.¹¹ Kooistra and colleagues confirmed that maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities that can be identified as early as 3 weeks of age.¹² Studies of this relationship are summarized in TABLE 4.
• Subclinical hypothyroidism. During the past decade, researchers have focused attention on neonatal neurologic function in infants born to mothers who had subclinical disease. Mitchell and Klein evaluated the prevalence of subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children with those of controls.⁴ They found the mean and standard-deviation IQs of the children in the control and treated groups to be significantly higher than those of the children whose mothers were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclinical hypothyroidism.¹⁰ They found that such pregnancies were more likely to be complicated by placental abruption and preterm birth, and speculated that the reduced IQ demonstrated in the Mitchell and Klein study might have been related to the effects of prematurity.

TABLE 4

Fetal and neonatal effects of asymptomatic overt hypothyroidism

Managing hypothyroidism in pregnancy

The treatment of choice for correction of hypothyroidism is synthetic T₄, or levothyroxine (Levothyroid, Levoxyl, Synthroid, and Unithroid). Initial treatment in the nonpregnant patient is 1.7 μg/kg/day or 12.5 to 25 μg/day adjusted by 25 μg/day every 2 to 4 weeks until a euthyroid state is achieved.¹³

Patients who were on thyroxine therapy before pregnancy should increase the dose by 30% once pregnancy is confirmed.^1,5 Serum thyrotropin levels should be monitored every 4 weeks to maintain a TSH level between 1 and 2 mU/L and FT₄ in upper third of normal.¹ Once a euthyroid state has been achieved, thyrotropin levels should be monitored every trimester until delivery. FIGURE 2 provides an algorithm for management of hypothyroidism in pregnancy.

FIGURE 2 During pregnancy, thyroid function merits regular monitoring, fine-tuning of treatment

Postpartum thyroiditis

About 5% of all obstetrical patients develop postpartum thyroiditis. Approximately 45% of these women present with hypothyroidism, with the rest evenly divided between thyrotoxicosis (hyperthyroidism) and thyrotoxicosis followed by hypothyroidism. Unfortunately, the signs and symptoms of hypo- and hyperthyroidism are similar to the postpartum state. Many of these patients are not diagnosed. A high index of suspicion warrants thyroid function testing. Women who have a history of type 1 diabetes mellitus have a 25% chance of developing postpartum thyroid dysfunction.

The diagnosis is made by documenting abnormal levels of TSH and FT₄. Postpartum hyperthyroidism may be diagnosed by the presence of antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies. Goiter may be present in up to 50% of patients.

Postpartum thyroiditis has two phases

The first phase, also known as the thyrotoxic phase, occurs 1 to 4 months after delivery when transient thyrotoxicosis develops from excessive release of thyroid hormones. The most common symptoms with early postpartum thyroiditis are fatigue and palpitations. Approximately 67% of these women will return to a euthyroid state, and thioamide therapy is generally considered ineffective. Hypothyroidism can develop within 1 month of the onset of thyroiditis.

The second phase occurs between 4 and 8 months postpartum, and these women present with hypothyroidism. Thyromegaly and associated symptoms are common. Unlike the first (thyrotoxic) phase, medical treatment is recommended. Thyroxine treatment should be initiated and maintained for 6 to 12 months. Postpartum thyroiditis carries a 30% risk of recurrence.¹⁴

Postpartum thyroiditis may be associated with depression or aggravate symptoms of depression, although the data on this association are conflicting. The largest study addressing this issue concluded that there was no difference in the clinical and psychiatric signs and symptoms between postpartum thyroiditis and controls.¹⁵ Nevertheless, it would seem prudent to evaluate thyroid function in postpartum depression if other signs of thyroid dysfunction are present.

Investigations of maternal alcohol consumption have consistently produced the same finding: Even a low level of alcohol—especially in the first trimester—has a harmful effect on fetal development. The American College of Obstetricians and Gynecologists (ACOG), American Academy of Pediatricians, and the US Surgeon General now support the tenet that no lower limit of alcohol consumption is safe during pregnancy.

Although a specific fetal alcohol syndrome (FAS) was not identified until 1968, the adverse effects of alcohol during pregnancy have been observed for centuries. FAS is the most severe manifestation of maternal alcohol consumption and is estimated to affect 0.2 to 1.5 of every 1,000 births. The term refers to a “constellation of physical abnormalities” and “problems of behavior and cognition in children born to mothers who drank heavily during pregnancy.”¹ The syndrome is also “completely preventable.”¹

The US Surgeon General recommends that health professionals:

• routinely inquire about alcohol consumption in women of childbearing age
  
• inform them of the risks of alcohol consumption during pregnancy
  
• advise them not to drink during pregnancy.²
  

New drinking pattern emerges

Of special concern is binge drinking, initially defined as the consumption of five or more drinks during one session, even among women who do not chronically consume alcohol. Like lower levels of alcohol consumption during pregnancy, binge drinking increases the risk of developmental and growth delays in the child. The higher peak levels of alcohol associated with binge drinking appear particularly deleterious to fetal neurodevelopment. And because a woman may engage in binge drinking before she is aware that she is pregnant, the issue merits particular attention.

Hallmarks of FAS

FAS causes facial dysmorphia, including short palpebral fissures, flattened midfacies, epicanthal folds, and micrognathia. Defects of the central nervous system and cardiac, renal, and skeletal systems also can occur, along with prenatal and postnatal growth delay. In addition, developmental delay is present.

FAS can be present even if history of alcohol exposure is uncertain

In 1996, the Institute of Medicine broadened the classification of FAS to include:

• Category 1 – FAS with a confirmed history of maternal alcohol exposure
  
• Category 2 – FAS with no confirmed history of maternal alcohol exposure
  
• Category 3 – partial FAS with a history of maternal alcohol exposure
  
• Category 4 – alcohol-related birth defects (physical anomalies only)
  
• Category 5 – alcohol-related neurodevelopmental disorders.¹
  

Alcohol exposure linked to a spectrum of effects

In 2005, the term “fetal alcohol spectrum disorder” (FASD) entered the lexicon. FASD is not intended to be used as a clinical diagnosis but to describe a spectrum of conditions that may result from prenatal alcohol exposure.

The prevalence of FASD is uncertain, although alcohol-related neurobehavioral abnormalities that affect learning and behavior may occur in three additional children for every one child who is given a diagnosis of classic FAS.

In this Update, I highlight recent studies or publications that:

• describe drinking patterns among women of reproductive age
  
• offer screening strategies or
  
• suggest a framework for counseling the patient to reduce or eliminate alcohol consumption.
  

Which women are most likely to drink during pregnancy?

Tsai J, Floyd RL, Green PP, Bouyle CA. Patterns and average volume of alcohol use among women of childbearing age. Matern Child Health J. 2007;11:437–445.

Tsai J, Floyd RL, Bertrand J. Tracking binge drinking among childbearing-age women. Prev Med. 2007; 44:298–302.

Caetano R, Ramisetty-Mikler S, Floyd L, McGrath C. The epidemiology of drinking among women of childbearing age. Alcohol Clin Exp Res. 2006;30:1023–1030.

Studies that led to the phenotypic description of FASD focused on women who had recognized alcohol dependency and who drank heavily. Additional research has identified another subset of women who are likely to continue alcohol consumption during pregnancy: binge drinkers. Many women who report binge drinking do not consider their alcohol consumption to be chronic or excessive.

Binge drinking is on the rise among women of childbearing age…

Binge drinking has increased steadily over the past 10 years despite public health initiatives and other programs developed to educate consumers. Tsai and colleagues used data from the Centers for Disease Control and Prevention (CDC) Behavior Risk Factor Surveillance System from 2001 to 2003 to calculate the magnitude of alcohol consumption among women of childbearing age. The rate of binge drinking increased from 10.3% to 13% between 1991 and 2003. In 2003, the highest prevalence of binge drinking was observed in the 18- to 24-year-old age group (20.5%), and among non-Hispanic white (15.5%), employed (14%), college-educated (13.3%), and unmarried women (18.7%). The highest number of binge sessions in the preceding month followed the same pattern.

In 2004, as it became clear that the adverse effects of binge alcohol consumption were more significant in women than men, at-risk binge drinking was redefined as more than three drinks in a single session.

…and also on the rise among pregnant women

In a separate study by Tsai and colleagues using the same data, one in 50 gravidas reported alcohol consumption in a binge fashion during the current pregnancy, with a background rate of 9% to 12% of pregnant women who reported any use of alcohol. More than 50% of the pregnant women who reported binge drinking said they had engaged in binge drinking at least twice during the preceding month.

Binge drinking and unplanned pregnancy—a risky combination

Binge drinking among women of reproductive age is especially risky because roughly half of all pregnancies in the United States are unplanned, so a woman may unwittingly engage in binge drinking during pregnancy. The rate of unintended pregnancy is highest among adolescents (82%) and 20- to 24-year-olds (61%), the groups with the highest rate of binge drinking (20%) and the most episodes in the preceding month (3.5). These figures suggest that efforts to prevent FAS should encompass the concept of binge drinking as an at-risk behavior and focus on all women of reproductive age, not just those known to be pregnant.

The typical binge drinker? She’s young, white, single, and employed

Utilizing the 2002 National Epidemiologic Survey on Alcohol and Related Conditions, Caetano and colleagues explored alcohol consumption among women of reproductive age before they recognized they were pregnant. Women of childbearing age who are social drinkers but develop a pattern of binge drinking represent a larger percentage of the female population than do women who consume alcohol daily, but both groups face an increased risk of bearing a child with alcohol-related neurodevelopmental difficulties.

Unplanned pregnancies were associated with a higher rate of preconception binge drinking than were planned gestations, and unmarried Caucasian women who smoked were most likely to engage in preconception binge drinking.

When the year preceding the study was assessed for both alcohol use and pregnancy, Caetano and associates found that 20% of women met the criteria for binge drinking or alcohol dependence. The high prevalence probably reflects the longer time span for acknowledgment of alcohol consumption (an entire year) and the lower drink limit for the redefined term “binge drinking” (in this study, it was defined as four drinks or more rather than five or more drinks on one occasion). The highest-risk women were young, single, and Caucasian, and had a higher income (>$40,000). White women had higher rates of binge drinking than black or Hispanic women at comparable ages, marital status, and income levels.

What’s the best way to screen for “at-risk” alcohol consumption?

Drinking and Reproductive Health: A Fetal Alcohol Spectrum Disorders Prevention Tool Kit. Washington, DC: American College of Obstetricians and Gynecologists; 2006. Available at: cdc.gov/ncbddd/fas/acog_toolkit.htm

In 2006, in collaboration with the CDC, ACOG developed a comprehensive educational tool kit for physicians. The kit, which can be downloaded from the CDC Web site, outlines office-based screening for at-risk drinking patterns in pregnant and nonpregnant women. It includes a screening tool—T-ACE—that has proved to be effective and can be incorporated into practice fairly efficiently. T-ACE and a similar tool—TWEAK—are presented in the TABLE.

ACOG recommends, and research supports, routine screening of all women of childbearing age. Studies assessing the prevalence of at-risk drinking and the efficacy of various interventions suggest that screening for alcohol use should be a routine part of prenatal care—as well as annual gynecologic care among women of childbearing age. One applicable approach is incorporation of a screening tool into the health-and-habits questionnaire administered to the patient.

Available as companion pieces to the tool kit are patient education sheets covering the risks of alcohol exposure and emphasizing basic concepts such as:

• alcohol equivalency (12 oz of beer=5 oz of wine=1 oz of liquor)
  
• risks of alcohol exposure before pregnancy is recognized
  
• goals for reducing or eliminating alcohol consumption.
  

Use these tools to screen for excessive alcohol consumption

Are efforts to reduce alcohol use among gravidas successful?

Floyd RL, Sobell M, Velasquez M, et al; Project CHOICES Efficacy Study Group. Preventing alcohol-exposed pregnancies. A randomized controlled trial. Am J Prev Med. 2007;32:1–10.

Brief intervention has been a successful tool for changing the behavior of nonpregnant adults. It also appears to be effective and efficient in the pregnant population. A brief intervention typically consists of a time-limited motivational counseling session that aims to educate, recommend a change in habits, and help the patient set goals. Brief intervention has had special success among nondependent women and has been used effectively in obstetric clinics and among women of various racial, ethnic, and socioeconomic backgrounds.

This randomized, controlled trial by Floyd and colleagues focused on the pregnant population. Like three other brief intervention trials conducted between 2000 and 2006, it found that brief intervention reduced alcohol consumption, increased positive newborn outcomes, and decreased alcohol consumption in subsequent pregnancies.^3-5

FRAMES model: 6 manageable steps

One successful brief intervention is the FRAMES model, which is included in the ACOG tool kit for physicians. It is based on concepts of:

• feedback (F) – compare the patient’s level of drinking with drinking patterns that are not risky
  
• responsibility (R) – emphasize that it is up to her to change her habits
  
• advice (A) – counsel her to change her behavior
  
• menu (M) – identify risky drinking situations and offer tactics for coping
  
• empathy (E) – be understanding
  
• self-efficacy (S) – encourage the patient to set goals and commit to change.
  

Use an individualized approach to change behavior

Despite widespread, population-based educational efforts throughout the 1990s, the prevalence of alcohol consumption among nonpregnant and pregnant women remains largely unchanged or even increased, particularly binge drinking. Other approaches are needed to avert the largest preventable contributor to birth defects and childhood neurodevelopmental disability.

With improved and validated office-based methods for identifying alcohol consumption, along with referrals when appropriate, it is possible to reduce maternal alcohol consumption during pregnancy. These simple methods are also easy to incorporate into an office routine. Equally important is incorporation of these methods into the office visit for the nonpregnant woman of reproductive age, with the aim of reducing alcohol consumption and increasing use of effective contraception.

Investigations of maternal alcohol consumption have consistently produced the same finding: Even a low level of alcohol—especially in the first trimester—has a harmful effect on fetal development. The American College of Obstetricians and Gynecologists (ACOG), American Academy of Pediatricians, and the US Surgeon General now support the tenet that no lower limit of alcohol consumption is safe during pregnancy.

Although a specific fetal alcohol syndrome (FAS) was not identified until 1968, the adverse effects of alcohol during pregnancy have been observed for centuries. FAS is the most severe manifestation of maternal alcohol consumption and is estimated to affect 0.2 to 1.5 of every 1,000 births. The term refers to a “constellation of physical abnormalities” and “problems of behavior and cognition in children born to mothers who drank heavily during pregnancy.”¹ The syndrome is also “completely preventable.”¹

The US Surgeon General recommends that health professionals:

• routinely inquire about alcohol consumption in women of childbearing age
  
• inform them of the risks of alcohol consumption during pregnancy
  
• advise them not to drink during pregnancy.²
  

New drinking pattern emerges

Of special concern is binge drinking, initially defined as the consumption of five or more drinks during one session, even among women who do not chronically consume alcohol. Like lower levels of alcohol consumption during pregnancy, binge drinking increases the risk of developmental and growth delays in the child. The higher peak levels of alcohol associated with binge drinking appear particularly deleterious to fetal neurodevelopment. And because a woman may engage in binge drinking before she is aware that she is pregnant, the issue merits particular attention.

Hallmarks of FAS

FAS causes facial dysmorphia, including short palpebral fissures, flattened midfacies, epicanthal folds, and micrognathia. Defects of the central nervous system and cardiac, renal, and skeletal systems also can occur, along with prenatal and postnatal growth delay. In addition, developmental delay is present.

FAS can be present even if history of alcohol exposure is uncertain

In 1996, the Institute of Medicine broadened the classification of FAS to include:

• Category 1 – FAS with a confirmed history of maternal alcohol exposure
  
• Category 2 – FAS with no confirmed history of maternal alcohol exposure
  
• Category 3 – partial FAS with a history of maternal alcohol exposure
  
• Category 4 – alcohol-related birth defects (physical anomalies only)
  
• Category 5 – alcohol-related neurodevelopmental disorders.¹
  

Alcohol exposure linked to a spectrum of effects

In 2005, the term “fetal alcohol spectrum disorder” (FASD) entered the lexicon. FASD is not intended to be used as a clinical diagnosis but to describe a spectrum of conditions that may result from prenatal alcohol exposure.

The prevalence of FASD is uncertain, although alcohol-related neurobehavioral abnormalities that affect learning and behavior may occur in three additional children for every one child who is given a diagnosis of classic FAS.

In this Update, I highlight recent studies or publications that:

• describe drinking patterns among women of reproductive age
  
• offer screening strategies or
  
• suggest a framework for counseling the patient to reduce or eliminate alcohol consumption.
  

Which women are most likely to drink during pregnancy?

Tsai J, Floyd RL, Green PP, Bouyle CA. Patterns and average volume of alcohol use among women of childbearing age. Matern Child Health J. 2007;11:437–445.

Tsai J, Floyd RL, Bertrand J. Tracking binge drinking among childbearing-age women. Prev Med. 2007; 44:298–302.

Caetano R, Ramisetty-Mikler S, Floyd L, McGrath C. The epidemiology of drinking among women of childbearing age. Alcohol Clin Exp Res. 2006;30:1023–1030.

Studies that led to the phenotypic description of FASD focused on women who had recognized alcohol dependency and who drank heavily. Additional research has identified another subset of women who are likely to continue alcohol consumption during pregnancy: binge drinkers. Many women who report binge drinking do not consider their alcohol consumption to be chronic or excessive.

Binge drinking is on the rise among women of childbearing age…

Binge drinking has increased steadily over the past 10 years despite public health initiatives and other programs developed to educate consumers. Tsai and colleagues used data from the Centers for Disease Control and Prevention (CDC) Behavior Risk Factor Surveillance System from 2001 to 2003 to calculate the magnitude of alcohol consumption among women of childbearing age. The rate of binge drinking increased from 10.3% to 13% between 1991 and 2003. In 2003, the highest prevalence of binge drinking was observed in the 18- to 24-year-old age group (20.5%), and among non-Hispanic white (15.5%), employed (14%), college-educated (13.3%), and unmarried women (18.7%). The highest number of binge sessions in the preceding month followed the same pattern.

In 2004, as it became clear that the adverse effects of binge alcohol consumption were more significant in women than men, at-risk binge drinking was redefined as more than three drinks in a single session.

…and also on the rise among pregnant women

In a separate study by Tsai and colleagues using the same data, one in 50 gravidas reported alcohol consumption in a binge fashion during the current pregnancy, with a background rate of 9% to 12% of pregnant women who reported any use of alcohol. More than 50% of the pregnant women who reported binge drinking said they had engaged in binge drinking at least twice during the preceding month.

Binge drinking and unplanned pregnancy—a risky combination

Binge drinking among women of reproductive age is especially risky because roughly half of all pregnancies in the United States are unplanned, so a woman may unwittingly engage in binge drinking during pregnancy. The rate of unintended pregnancy is highest among adolescents (82%) and 20- to 24-year-olds (61%), the groups with the highest rate of binge drinking (20%) and the most episodes in the preceding month (3.5). These figures suggest that efforts to prevent FAS should encompass the concept of binge drinking as an at-risk behavior and focus on all women of reproductive age, not just those known to be pregnant.

The typical binge drinker? She’s young, white, single, and employed

Utilizing the 2002 National Epidemiologic Survey on Alcohol and Related Conditions, Caetano and colleagues explored alcohol consumption among women of reproductive age before they recognized they were pregnant. Women of childbearing age who are social drinkers but develop a pattern of binge drinking represent a larger percentage of the female population than do women who consume alcohol daily, but both groups face an increased risk of bearing a child with alcohol-related neurodevelopmental difficulties.

Unplanned pregnancies were associated with a higher rate of preconception binge drinking than were planned gestations, and unmarried Caucasian women who smoked were most likely to engage in preconception binge drinking.

When the year preceding the study was assessed for both alcohol use and pregnancy, Caetano and associates found that 20% of women met the criteria for binge drinking or alcohol dependence. The high prevalence probably reflects the longer time span for acknowledgment of alcohol consumption (an entire year) and the lower drink limit for the redefined term “binge drinking” (in this study, it was defined as four drinks or more rather than five or more drinks on one occasion). The highest-risk women were young, single, and Caucasian, and had a higher income (>$40,000). White women had higher rates of binge drinking than black or Hispanic women at comparable ages, marital status, and income levels.

What’s the best way to screen for “at-risk” alcohol consumption?

Drinking and Reproductive Health: A Fetal Alcohol Spectrum Disorders Prevention Tool Kit. Washington, DC: American College of Obstetricians and Gynecologists; 2006. Available at: cdc.gov/ncbddd/fas/acog_toolkit.htm

In 2006, in collaboration with the CDC, ACOG developed a comprehensive educational tool kit for physicians. The kit, which can be downloaded from the CDC Web site, outlines office-based screening for at-risk drinking patterns in pregnant and nonpregnant women. It includes a screening tool—T-ACE—that has proved to be effective and can be incorporated into practice fairly efficiently. T-ACE and a similar tool—TWEAK—are presented in the TABLE.

ACOG recommends, and research supports, routine screening of all women of childbearing age. Studies assessing the prevalence of at-risk drinking and the efficacy of various interventions suggest that screening for alcohol use should be a routine part of prenatal care—as well as annual gynecologic care among women of childbearing age. One applicable approach is incorporation of a screening tool into the health-and-habits questionnaire administered to the patient.

Available as companion pieces to the tool kit are patient education sheets covering the risks of alcohol exposure and emphasizing basic concepts such as:

• alcohol equivalency (12 oz of beer=5 oz of wine=1 oz of liquor)
  
• risks of alcohol exposure before pregnancy is recognized
  
• goals for reducing or eliminating alcohol consumption.
  

Use these tools to screen for excessive alcohol consumption

Are efforts to reduce alcohol use among gravidas successful?

Floyd RL, Sobell M, Velasquez M, et al; Project CHOICES Efficacy Study Group. Preventing alcohol-exposed pregnancies. A randomized controlled trial. Am J Prev Med. 2007;32:1–10.

Brief intervention has been a successful tool for changing the behavior of nonpregnant adults. It also appears to be effective and efficient in the pregnant population. A brief intervention typically consists of a time-limited motivational counseling session that aims to educate, recommend a change in habits, and help the patient set goals. Brief intervention has had special success among nondependent women and has been used effectively in obstetric clinics and among women of various racial, ethnic, and socioeconomic backgrounds.

This randomized, controlled trial by Floyd and colleagues focused on the pregnant population. Like three other brief intervention trials conducted between 2000 and 2006, it found that brief intervention reduced alcohol consumption, increased positive newborn outcomes, and decreased alcohol consumption in subsequent pregnancies.^3-5

FRAMES model: 6 manageable steps

One successful brief intervention is the FRAMES model, which is included in the ACOG tool kit for physicians. It is based on concepts of:

• feedback (F) – compare the patient’s level of drinking with drinking patterns that are not risky
  
• responsibility (R) – emphasize that it is up to her to change her habits
  
• advice (A) – counsel her to change her behavior
  
• menu (M) – identify risky drinking situations and offer tactics for coping
  
• empathy (E) – be understanding
  
• self-efficacy (S) – encourage the patient to set goals and commit to change.
  

Use an individualized approach to change behavior

Despite widespread, population-based educational efforts throughout the 1990s, the prevalence of alcohol consumption among nonpregnant and pregnant women remains largely unchanged or even increased, particularly binge drinking. Other approaches are needed to avert the largest preventable contributor to birth defects and childhood neurodevelopmental disability.

With improved and validated office-based methods for identifying alcohol consumption, along with referrals when appropriate, it is possible to reduce maternal alcohol consumption during pregnancy. These simple methods are also easy to incorporate into an office routine. Equally important is incorporation of these methods into the office visit for the nonpregnant woman of reproductive age, with the aim of reducing alcohol consumption and increasing use of effective contraception.

Investigations of maternal alcohol consumption have consistently produced the same finding: Even a low level of alcohol—especially in the first trimester—has a harmful effect on fetal development. The American College of Obstetricians and Gynecologists (ACOG), American Academy of Pediatricians, and the US Surgeon General now support the tenet that no lower limit of alcohol consumption is safe during pregnancy.

Although a specific fetal alcohol syndrome (FAS) was not identified until 1968, the adverse effects of alcohol during pregnancy have been observed for centuries. FAS is the most severe manifestation of maternal alcohol consumption and is estimated to affect 0.2 to 1.5 of every 1,000 births. The term refers to a “constellation of physical abnormalities” and “problems of behavior and cognition in children born to mothers who drank heavily during pregnancy.”¹ The syndrome is also “completely preventable.”¹

The US Surgeon General recommends that health professionals:

• routinely inquire about alcohol consumption in women of childbearing age
  
• inform them of the risks of alcohol consumption during pregnancy
  
• advise them not to drink during pregnancy.²
  

New drinking pattern emerges

Of special concern is binge drinking, initially defined as the consumption of five or more drinks during one session, even among women who do not chronically consume alcohol. Like lower levels of alcohol consumption during pregnancy, binge drinking increases the risk of developmental and growth delays in the child. The higher peak levels of alcohol associated with binge drinking appear particularly deleterious to fetal neurodevelopment. And because a woman may engage in binge drinking before she is aware that she is pregnant, the issue merits particular attention.

Hallmarks of FAS

FAS causes facial dysmorphia, including short palpebral fissures, flattened midfacies, epicanthal folds, and micrognathia. Defects of the central nervous system and cardiac, renal, and skeletal systems also can occur, along with prenatal and postnatal growth delay. In addition, developmental delay is present.

FAS can be present even if history of alcohol exposure is uncertain

In 1996, the Institute of Medicine broadened the classification of FAS to include:

• Category 1 – FAS with a confirmed history of maternal alcohol exposure
  
• Category 2 – FAS with no confirmed history of maternal alcohol exposure
  
• Category 3 – partial FAS with a history of maternal alcohol exposure
  
• Category 4 – alcohol-related birth defects (physical anomalies only)
  
• Category 5 – alcohol-related neurodevelopmental disorders.¹
  

Alcohol exposure linked to a spectrum of effects

In 2005, the term “fetal alcohol spectrum disorder” (FASD) entered the lexicon. FASD is not intended to be used as a clinical diagnosis but to describe a spectrum of conditions that may result from prenatal alcohol exposure.

The prevalence of FASD is uncertain, although alcohol-related neurobehavioral abnormalities that affect learning and behavior may occur in three additional children for every one child who is given a diagnosis of classic FAS.

In this Update, I highlight recent studies or publications that:

• describe drinking patterns among women of reproductive age
  
• offer screening strategies or
  
• suggest a framework for counseling the patient to reduce or eliminate alcohol consumption.
  

Which women are most likely to drink during pregnancy?

Tsai J, Floyd RL, Green PP, Bouyle CA. Patterns and average volume of alcohol use among women of childbearing age. Matern Child Health J. 2007;11:437–445.

Tsai J, Floyd RL, Bertrand J. Tracking binge drinking among childbearing-age women. Prev Med. 2007; 44:298–302.

Caetano R, Ramisetty-Mikler S, Floyd L, McGrath C. The epidemiology of drinking among women of childbearing age. Alcohol Clin Exp Res. 2006;30:1023–1030.

Studies that led to the phenotypic description of FASD focused on women who had recognized alcohol dependency and who drank heavily. Additional research has identified another subset of women who are likely to continue alcohol consumption during pregnancy: binge drinkers. Many women who report binge drinking do not consider their alcohol consumption to be chronic or excessive.

Binge drinking is on the rise among women of childbearing age…

Binge drinking has increased steadily over the past 10 years despite public health initiatives and other programs developed to educate consumers. Tsai and colleagues used data from the Centers for Disease Control and Prevention (CDC) Behavior Risk Factor Surveillance System from 2001 to 2003 to calculate the magnitude of alcohol consumption among women of childbearing age. The rate of binge drinking increased from 10.3% to 13% between 1991 and 2003. In 2003, the highest prevalence of binge drinking was observed in the 18- to 24-year-old age group (20.5%), and among non-Hispanic white (15.5%), employed (14%), college-educated (13.3%), and unmarried women (18.7%). The highest number of binge sessions in the preceding month followed the same pattern.

In 2004, as it became clear that the adverse effects of binge alcohol consumption were more significant in women than men, at-risk binge drinking was redefined as more than three drinks in a single session.

…and also on the rise among pregnant women

In a separate study by Tsai and colleagues using the same data, one in 50 gravidas reported alcohol consumption in a binge fashion during the current pregnancy, with a background rate of 9% to 12% of pregnant women who reported any use of alcohol. More than 50% of the pregnant women who reported binge drinking said they had engaged in binge drinking at least twice during the preceding month.

Binge drinking and unplanned pregnancy—a risky combination

Binge drinking among women of reproductive age is especially risky because roughly half of all pregnancies in the United States are unplanned, so a woman may unwittingly engage in binge drinking during pregnancy. The rate of unintended pregnancy is highest among adolescents (82%) and 20- to 24-year-olds (61%), the groups with the highest rate of binge drinking (20%) and the most episodes in the preceding month (3.5). These figures suggest that efforts to prevent FAS should encompass the concept of binge drinking as an at-risk behavior and focus on all women of reproductive age, not just those known to be pregnant.

The typical binge drinker? She’s young, white, single, and employed

Utilizing the 2002 National Epidemiologic Survey on Alcohol and Related Conditions, Caetano and colleagues explored alcohol consumption among women of reproductive age before they recognized they were pregnant. Women of childbearing age who are social drinkers but develop a pattern of binge drinking represent a larger percentage of the female population than do women who consume alcohol daily, but both groups face an increased risk of bearing a child with alcohol-related neurodevelopmental difficulties.

Unplanned pregnancies were associated with a higher rate of preconception binge drinking than were planned gestations, and unmarried Caucasian women who smoked were most likely to engage in preconception binge drinking.

When the year preceding the study was assessed for both alcohol use and pregnancy, Caetano and associates found that 20% of women met the criteria for binge drinking or alcohol dependence. The high prevalence probably reflects the longer time span for acknowledgment of alcohol consumption (an entire year) and the lower drink limit for the redefined term “binge drinking” (in this study, it was defined as four drinks or more rather than five or more drinks on one occasion). The highest-risk women were young, single, and Caucasian, and had a higher income (>$40,000). White women had higher rates of binge drinking than black or Hispanic women at comparable ages, marital status, and income levels.

What’s the best way to screen for “at-risk” alcohol consumption?

Drinking and Reproductive Health: A Fetal Alcohol Spectrum Disorders Prevention Tool Kit. Washington, DC: American College of Obstetricians and Gynecologists; 2006. Available at: cdc.gov/ncbddd/fas/acog_toolkit.htm

In 2006, in collaboration with the CDC, ACOG developed a comprehensive educational tool kit for physicians. The kit, which can be downloaded from the CDC Web site, outlines office-based screening for at-risk drinking patterns in pregnant and nonpregnant women. It includes a screening tool—T-ACE—that has proved to be effective and can be incorporated into practice fairly efficiently. T-ACE and a similar tool—TWEAK—are presented in the TABLE.

ACOG recommends, and research supports, routine screening of all women of childbearing age. Studies assessing the prevalence of at-risk drinking and the efficacy of various interventions suggest that screening for alcohol use should be a routine part of prenatal care—as well as annual gynecologic care among women of childbearing age. One applicable approach is incorporation of a screening tool into the health-and-habits questionnaire administered to the patient.

Available as companion pieces to the tool kit are patient education sheets covering the risks of alcohol exposure and emphasizing basic concepts such as:

• alcohol equivalency (12 oz of beer=5 oz of wine=1 oz of liquor)
  
• risks of alcohol exposure before pregnancy is recognized
  
• goals for reducing or eliminating alcohol consumption.
  

Use these tools to screen for excessive alcohol consumption

Are efforts to reduce alcohol use among gravidas successful?

Floyd RL, Sobell M, Velasquez M, et al; Project CHOICES Efficacy Study Group. Preventing alcohol-exposed pregnancies. A randomized controlled trial. Am J Prev Med. 2007;32:1–10.

Brief intervention has been a successful tool for changing the behavior of nonpregnant adults. It also appears to be effective and efficient in the pregnant population. A brief intervention typically consists of a time-limited motivational counseling session that aims to educate, recommend a change in habits, and help the patient set goals. Brief intervention has had special success among nondependent women and has been used effectively in obstetric clinics and among women of various racial, ethnic, and socioeconomic backgrounds.

This randomized, controlled trial by Floyd and colleagues focused on the pregnant population. Like three other brief intervention trials conducted between 2000 and 2006, it found that brief intervention reduced alcohol consumption, increased positive newborn outcomes, and decreased alcohol consumption in subsequent pregnancies.^3-5

FRAMES model: 6 manageable steps

One successful brief intervention is the FRAMES model, which is included in the ACOG tool kit for physicians. It is based on concepts of:

• feedback (F) – compare the patient’s level of drinking with drinking patterns that are not risky
  
• responsibility (R) – emphasize that it is up to her to change her habits
  
• advice (A) – counsel her to change her behavior
  
• menu (M) – identify risky drinking situations and offer tactics for coping
  
• empathy (E) – be understanding
  
• self-efficacy (S) – encourage the patient to set goals and commit to change.
  

Use an individualized approach to change behavior

Despite widespread, population-based educational efforts throughout the 1990s, the prevalence of alcohol consumption among nonpregnant and pregnant women remains largely unchanged or even increased, particularly binge drinking. Other approaches are needed to avert the largest preventable contributor to birth defects and childhood neurodevelopmental disability.

With improved and validated office-based methods for identifying alcohol consumption, along with referrals when appropriate, it is possible to reduce maternal alcohol consumption during pregnancy. These simple methods are also easy to incorporate into an office routine. Equally important is incorporation of these methods into the office visit for the nonpregnant woman of reproductive age, with the aim of reducing alcohol consumption and increasing use of effective contraception.