Clinical Review

These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients. 

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.

 

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.

 

National standards for vaccination have been established by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). This yearly updated vaccination schedule is available at the CDC’s Web site (http://www.cdc.gov/vaccines/schedules/hcp/adult.html).⁷ Ideally, a woman’s immunization status should be evaluated and made complete prior to pregnancy. Some vaccines are safe and appropriate for administration during pregnancy, provided the benefits clearly outweigh the risks. The recommended vaccines during pregnancy include inactivated influenza (seasonal and H1N1) and the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).

Related Article: CDC urges flu vaccination for all, especially pregnant women (News for Your Practice, October 2013)

Many physicians avoid giving vaccinations during pregnancy because of the concern that a spontaneous abortion or congenital anomaly might be incorrectly attributed to vaccine administration, but few vaccines are contradicted during pregnancy. Those that are contraindicated are those containing live virus, including measles, mumps, and rubella (MMR); varicella; and herpes zoster. Concerns also have been raised regarding the safety of administering influenza vaccines containing the mercury-based preservative thimerosol. However, no scientific evidence has conclusively linked adverse effects on offspring with thimerosol-containing vaccines administered during pregnancy.

Immunizations recommended for women of reproductive age
Measles, mumps, rubella (MMR). This vaccine is recommended for all women lacking confirmed immunity to rubella. The vaccine contains live, attenuated virus and is given as a single dose. Women should avoid pregnancy for 1 month after vaccination.

Varicella. This vaccine is for all women lacking confirmed immunity to varicella. It also contains a live, attenuated virus. It is administered in two doses, 1 month apart, and women should avoid pregnancy for 1 month after vaccination.

Influenza. The flu vaccine is recommended annually for individuals 6 months of age and older. The injectable vaccine contains inactivated virus and may be administered during pregnancy—at any time but optimally in October or November because the flu season occurs January through March. (The intranasal influenza vaccine contains live, attenuated virus and should be avoided in pregnancy.) Either method is administered as a single dose. 

Thimerosal is a mercury-based preservative used in vaccines, including the influenza vaccine, and is appropriate for use in pregnant women; studies have not shown an association between vaccines containing thimerosal and adverse effects in pregnant women or their offspring.

Tetanus-diptheria-pertussis (Tdap) and tetanus-diphtheria (Td). Tdap or Td is recommended for adults aged 19 to 64 years who have or anticipate having close contact with an infant less than 12 months of age. Due to the recent increase in pertussis infection, Tdap should be given to all women who have not previously received the vaccine and who are pregnant or might become pregnant. It can be given anytime during pregnancy, but optimal administration is during the third trimester or late second trimester (after 20 weeks’ gestation) to confer the greatest amount of fetal protection.

If the vaccine is not being administered during pregnancy, it should be given in the immediate postpartum period to ensure pertussis immunity and to reduce transmission to the newborn. Tdap is administered as a single dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis. 

Non-routine vaccines include pneumococcus, hepatitis A, hepatitis B, and meningococcus (TABLE). These vaccines should be administered as indicated in high-risk patients.

Health-care providers caring for women with infertility are urged to assess patients’ immunization status prior to attempting pregnancy, to counsel patients about the importance of protecting them and their potential offspring from preventable disease, and to facilitate vaccination prior to conception attempts. 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Vaccination is a very important aspect of pre-pregnancy care but is especially important for infertile women who desire pregnancy. Planning of infertility treatment should include assessment of the patient’s vaccination status and completion of appropriate vaccinations before infertility treatment is initiated.

DO CURRENT OPTIONS EFFECTIVELY PREVENT POSTSURGICAL ADHESIONS?

Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: A committee opinion. Fertil Steril. 2013;99(6):1550–1555.

Postoperative adhesions are a natural consequence of surgery and a major problem in gynecology. They may cause postsurgical infertility, abdominal/pelvic pain, or bowel obstruction as well as complicate subsequent surgeries by increasing operative times and the risk of bowel injury. The American Society for Reproductive Medicine (ASRM) and the Society of Reproductive Surgeons (SRS) recently evaluated the epidemiology, pathogenesis, and clinical consequences of adhesion formation and the evidence behind strategies for reducing adhesion formation.

In their joint Committee Opinion, they noted that open and laparoscopic approaches to surgery carry comparable levels of risk for adhesion-related hospital readmission. Ovarian surgery has the highest risk for adhesion-related readmission, at 7.5 per 100 initial operations, and the incidence of small bowel obstruction after hysterectomy was found to be 1.6 per 100 procedures. Adhesion-related US health-care costs are estimated at approximately $1 billion annually.

 

The Societies noted that more severe adnexal adhesions are associated with lower pregnancy rates, and treatment of adnexal adhesions appears to improve pregnancy rates. Investigators found adhesions to cause about three-quarters of postoperative small bowel obstructions; however, the relationship between adhesions and pelvic pain remains unclear. It is thought that adhesions may cause visceral pain by impairing organ mobility, but there is no relationship between the extent of adhesions and the severity of pain. It appears that only dense adhesions ­involving the bowel are associated with chronic pelvic pain. Predicting the outcome of lysis of adnexal or bowel adhesions is difficult.

Reduction of adhesion formation
Theoretically, adhesions may be reduced by minimizing peritoneal injury during surgery, avoiding intraoperative reactive foreign bodies, reducing local inflammatory response, inhibiting the coagulation cascade and promoting fibrinolysis, or by placing barriers between damaged tissues.

Related Article: Update on Fertility G. David Adamson, MD (February 2008)

Careful surgical technique includes gentle tissue handling, meticulous hemostasis, excision of necrotic tissue, minimizing ischemia and desiccation, using fine and nonreactive suture, and preventing foreign-body reaction and infection, all “microsurgical principles.”

ASRM and SRS reported that the surgical approach (laparoscopy vs laparotomy) is much less important than the extent of tissue injury. However, laparoscopy may result in less tissue and organ handling and trauma, avoid contamination with foreign bodies, enable more precise tissue handling, and result in less postoperative infection. The pneumoperitoneum has a tamponade effect that facilitates hemostasis during laparoscopy, but the process also can be associated with peritoneal desiccation and reduced temperatures that can increase injury.

Laparoscopic myomectomy was found to have a 70% risk of postoperative adhesions, compared with a 90% risk after laparotomy. It is unclear whether peritoneal closure at laparotomy reduces or increases adhesions, but parietal peritoneal closure at primary cesarean delivery results in fewer dense and filmy adhesions.

Related Article: How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy Michael Baggish, MD (Second of a 2-part series on laparoscopic complications, October 2012)

Adjuncts to surgical technique
SRM and SRS reported on three adjuncts to surgical technique that have been proposed to reduce the risk of postoperative adhesions: anti-inflammatory agents, peritoneal instillates, and adhesion barriers.

Dexamethasone, promethazine, and other local and systemic anti-inflammatory drugs and adhesion-reducing substances have not been found effective for reducing postoperative adhesions.

Peritoneal instillates—which create “hydroflotation” and include antibiotic solutions, 32% dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids—have not been found effective.⁸ Icodextrin 4% (Adept Adhesion Reduction Solution, Baxter Healthcare) is FDA approved as an adjunct to good surgical technique for the reduction of postoperative adhesions in patients undergoing gynecologic laparoscopic adhesiolysis. However, a systematic review concluded that there is insufficient evidence for its use as an adhesion-preventing agent.⁸

Adhesion barriers may help reduce postoperative adhesions but cannot compensate for poor surgical technique. Although the bioresorbable membrane sodium hyaluronic acid and carboxymethyl cellulose (Seprafilm, Genzyme Corp) is FDA-approved, there is limited evidence that it prevents adhesions after myomectomy.⁹ Because it fragments easily, it is mostly used at laparotomy.

Oxidized regenerated cellulose (Interceed, Ethicon Women’s Health and Urology) is an FDA-approved absorbable adhesion barrier for use at laparotomy that requires no suturing and has been shown to reduce the incidence and extent of new and recurrent adhesions at both laparoscopy and laparotomy by 40% to 50%, although there is little evidence that this improves fertility.⁹ Complete hemostasis must be achieved to use Interceed, and the addition of heparin confers no benefit.

Another product is expanded polytetrafluoroethylene (ePTFE, Gore-Tex Surgical Membrane, WL Gore and Associates), a nonabsorbable adhesion barrier produced in thin sheets and approved by the FDA for peritoneal repair. ePTFE must be sutured to tissue and helps prevent adhesion formation and reformation regardless of the type of injury or whether complete hemostasis has been achieved. In a small trial, it decreased postmyomectomy adhesions.¹⁰ ePTFE also was more effective than oxidized regenerated cellulose in preventing adhesions after adnexal surgery.¹¹ Its use has been limited by the need for suturing and later reoperation for removal, although it probably does not have to be removed if it will not interfere with normal organ function since it has been used as a pericardial graft for many years.¹²

Hyaluronic acid (HA) solution (Sepracoat, Genzyme) is a natural bioabsorbable component of the extracellular matrix. Women undergoing laparotomy have fewer new adhesions with HA solution, but it is not approved for use in the United States.¹³ Polyethylene glycol (PEG; SprayGel, Confluent Surgical) was effective in early clinical trials but is not FDA-approved.¹² Fibrin sealant (Tisseel VH, Baxter Healthcare) has been reported to decrease the formation of adhesions after salpingostomy, salpingolysis, and ovariolysis. Because it is a biologic product derived from human blood donors, it poses a risk for transmission of infectious agents. It is FDA-approved for use in cardiothoracic surgery, splenic injuries, and colostomy closure for hemostasis.

 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adhesions are the most common complication following gynecologic surgery, and they pose potential longstanding consequences to patients. There is no evidence that anti-inflammatory agents reduce postoperative adhesions and insufficient evidence to recommend peritoneal instillates. FDA-approved surgical barriers reduce postoperative adhesions but there is not substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction. All gynecologists need to understand the importance of using microsurgical principles rather than relying on adhesion barriers to reduce postoperative adhesions.

 

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These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients. 

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.

 

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.

 

National standards for vaccination have been established by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). This yearly updated vaccination schedule is available at the CDC’s Web site (http://www.cdc.gov/vaccines/schedules/hcp/adult.html).⁷ Ideally, a woman’s immunization status should be evaluated and made complete prior to pregnancy. Some vaccines are safe and appropriate for administration during pregnancy, provided the benefits clearly outweigh the risks. The recommended vaccines during pregnancy include inactivated influenza (seasonal and H1N1) and the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).

Related Article: CDC urges flu vaccination for all, especially pregnant women (News for Your Practice, October 2013)

Many physicians avoid giving vaccinations during pregnancy because of the concern that a spontaneous abortion or congenital anomaly might be incorrectly attributed to vaccine administration, but few vaccines are contradicted during pregnancy. Those that are contraindicated are those containing live virus, including measles, mumps, and rubella (MMR); varicella; and herpes zoster. Concerns also have been raised regarding the safety of administering influenza vaccines containing the mercury-based preservative thimerosol. However, no scientific evidence has conclusively linked adverse effects on offspring with thimerosol-containing vaccines administered during pregnancy.

Immunizations recommended for women of reproductive age
Measles, mumps, rubella (MMR). This vaccine is recommended for all women lacking confirmed immunity to rubella. The vaccine contains live, attenuated virus and is given as a single dose. Women should avoid pregnancy for 1 month after vaccination.

Varicella. This vaccine is for all women lacking confirmed immunity to varicella. It also contains a live, attenuated virus. It is administered in two doses, 1 month apart, and women should avoid pregnancy for 1 month after vaccination.

Influenza. The flu vaccine is recommended annually for individuals 6 months of age and older. The injectable vaccine contains inactivated virus and may be administered during pregnancy—at any time but optimally in October or November because the flu season occurs January through March. (The intranasal influenza vaccine contains live, attenuated virus and should be avoided in pregnancy.) Either method is administered as a single dose. 

Thimerosal is a mercury-based preservative used in vaccines, including the influenza vaccine, and is appropriate for use in pregnant women; studies have not shown an association between vaccines containing thimerosal and adverse effects in pregnant women or their offspring.

Tetanus-diptheria-pertussis (Tdap) and tetanus-diphtheria (Td). Tdap or Td is recommended for adults aged 19 to 64 years who have or anticipate having close contact with an infant less than 12 months of age. Due to the recent increase in pertussis infection, Tdap should be given to all women who have not previously received the vaccine and who are pregnant or might become pregnant. It can be given anytime during pregnancy, but optimal administration is during the third trimester or late second trimester (after 20 weeks’ gestation) to confer the greatest amount of fetal protection.

If the vaccine is not being administered during pregnancy, it should be given in the immediate postpartum period to ensure pertussis immunity and to reduce transmission to the newborn. Tdap is administered as a single dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis. 

Non-routine vaccines include pneumococcus, hepatitis A, hepatitis B, and meningococcus (TABLE). These vaccines should be administered as indicated in high-risk patients.

Health-care providers caring for women with infertility are urged to assess patients’ immunization status prior to attempting pregnancy, to counsel patients about the importance of protecting them and their potential offspring from preventable disease, and to facilitate vaccination prior to conception attempts. 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Vaccination is a very important aspect of pre-pregnancy care but is especially important for infertile women who desire pregnancy. Planning of infertility treatment should include assessment of the patient’s vaccination status and completion of appropriate vaccinations before infertility treatment is initiated.

DO CURRENT OPTIONS EFFECTIVELY PREVENT POSTSURGICAL ADHESIONS?

Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: A committee opinion. Fertil Steril. 2013;99(6):1550–1555.

Postoperative adhesions are a natural consequence of surgery and a major problem in gynecology. They may cause postsurgical infertility, abdominal/pelvic pain, or bowel obstruction as well as complicate subsequent surgeries by increasing operative times and the risk of bowel injury. The American Society for Reproductive Medicine (ASRM) and the Society of Reproductive Surgeons (SRS) recently evaluated the epidemiology, pathogenesis, and clinical consequences of adhesion formation and the evidence behind strategies for reducing adhesion formation.

In their joint Committee Opinion, they noted that open and laparoscopic approaches to surgery carry comparable levels of risk for adhesion-related hospital readmission. Ovarian surgery has the highest risk for adhesion-related readmission, at 7.5 per 100 initial operations, and the incidence of small bowel obstruction after hysterectomy was found to be 1.6 per 100 procedures. Adhesion-related US health-care costs are estimated at approximately $1 billion annually.

 

The Societies noted that more severe adnexal adhesions are associated with lower pregnancy rates, and treatment of adnexal adhesions appears to improve pregnancy rates. Investigators found adhesions to cause about three-quarters of postoperative small bowel obstructions; however, the relationship between adhesions and pelvic pain remains unclear. It is thought that adhesions may cause visceral pain by impairing organ mobility, but there is no relationship between the extent of adhesions and the severity of pain. It appears that only dense adhesions ­involving the bowel are associated with chronic pelvic pain. Predicting the outcome of lysis of adnexal or bowel adhesions is difficult.

Reduction of adhesion formation
Theoretically, adhesions may be reduced by minimizing peritoneal injury during surgery, avoiding intraoperative reactive foreign bodies, reducing local inflammatory response, inhibiting the coagulation cascade and promoting fibrinolysis, or by placing barriers between damaged tissues.

Related Article: Update on Fertility G. David Adamson, MD (February 2008)

Careful surgical technique includes gentle tissue handling, meticulous hemostasis, excision of necrotic tissue, minimizing ischemia and desiccation, using fine and nonreactive suture, and preventing foreign-body reaction and infection, all “microsurgical principles.”

ASRM and SRS reported that the surgical approach (laparoscopy vs laparotomy) is much less important than the extent of tissue injury. However, laparoscopy may result in less tissue and organ handling and trauma, avoid contamination with foreign bodies, enable more precise tissue handling, and result in less postoperative infection. The pneumoperitoneum has a tamponade effect that facilitates hemostasis during laparoscopy, but the process also can be associated with peritoneal desiccation and reduced temperatures that can increase injury.

Laparoscopic myomectomy was found to have a 70% risk of postoperative adhesions, compared with a 90% risk after laparotomy. It is unclear whether peritoneal closure at laparotomy reduces or increases adhesions, but parietal peritoneal closure at primary cesarean delivery results in fewer dense and filmy adhesions.

Related Article: How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy Michael Baggish, MD (Second of a 2-part series on laparoscopic complications, October 2012)

Adjuncts to surgical technique
SRM and SRS reported on three adjuncts to surgical technique that have been proposed to reduce the risk of postoperative adhesions: anti-inflammatory agents, peritoneal instillates, and adhesion barriers.

Dexamethasone, promethazine, and other local and systemic anti-inflammatory drugs and adhesion-reducing substances have not been found effective for reducing postoperative adhesions.

Peritoneal instillates—which create “hydroflotation” and include antibiotic solutions, 32% dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids—have not been found effective.⁸ Icodextrin 4% (Adept Adhesion Reduction Solution, Baxter Healthcare) is FDA approved as an adjunct to good surgical technique for the reduction of postoperative adhesions in patients undergoing gynecologic laparoscopic adhesiolysis. However, a systematic review concluded that there is insufficient evidence for its use as an adhesion-preventing agent.⁸

Adhesion barriers may help reduce postoperative adhesions but cannot compensate for poor surgical technique. Although the bioresorbable membrane sodium hyaluronic acid and carboxymethyl cellulose (Seprafilm, Genzyme Corp) is FDA-approved, there is limited evidence that it prevents adhesions after myomectomy.⁹ Because it fragments easily, it is mostly used at laparotomy.

Oxidized regenerated cellulose (Interceed, Ethicon Women’s Health and Urology) is an FDA-approved absorbable adhesion barrier for use at laparotomy that requires no suturing and has been shown to reduce the incidence and extent of new and recurrent adhesions at both laparoscopy and laparotomy by 40% to 50%, although there is little evidence that this improves fertility.⁹ Complete hemostasis must be achieved to use Interceed, and the addition of heparin confers no benefit.

Another product is expanded polytetrafluoroethylene (ePTFE, Gore-Tex Surgical Membrane, WL Gore and Associates), a nonabsorbable adhesion barrier produced in thin sheets and approved by the FDA for peritoneal repair. ePTFE must be sutured to tissue and helps prevent adhesion formation and reformation regardless of the type of injury or whether complete hemostasis has been achieved. In a small trial, it decreased postmyomectomy adhesions.¹⁰ ePTFE also was more effective than oxidized regenerated cellulose in preventing adhesions after adnexal surgery.¹¹ Its use has been limited by the need for suturing and later reoperation for removal, although it probably does not have to be removed if it will not interfere with normal organ function since it has been used as a pericardial graft for many years.¹²

Hyaluronic acid (HA) solution (Sepracoat, Genzyme) is a natural bioabsorbable component of the extracellular matrix. Women undergoing laparotomy have fewer new adhesions with HA solution, but it is not approved for use in the United States.¹³ Polyethylene glycol (PEG; SprayGel, Confluent Surgical) was effective in early clinical trials but is not FDA-approved.¹² Fibrin sealant (Tisseel VH, Baxter Healthcare) has been reported to decrease the formation of adhesions after salpingostomy, salpingolysis, and ovariolysis. Because it is a biologic product derived from human blood donors, it poses a risk for transmission of infectious agents. It is FDA-approved for use in cardiothoracic surgery, splenic injuries, and colostomy closure for hemostasis.

 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adhesions are the most common complication following gynecologic surgery, and they pose potential longstanding consequences to patients. There is no evidence that anti-inflammatory agents reduce postoperative adhesions and insufficient evidence to recommend peritoneal instillates. FDA-approved surgical barriers reduce postoperative adhesions but there is not substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction. All gynecologists need to understand the importance of using microsurgical principles rather than relying on adhesion barriers to reduce postoperative adhesions.

 

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients. 

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.

 

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.

 

National standards for vaccination have been established by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). This yearly updated vaccination schedule is available at the CDC’s Web site (http://www.cdc.gov/vaccines/schedules/hcp/adult.html).⁷ Ideally, a woman’s immunization status should be evaluated and made complete prior to pregnancy. Some vaccines are safe and appropriate for administration during pregnancy, provided the benefits clearly outweigh the risks. The recommended vaccines during pregnancy include inactivated influenza (seasonal and H1N1) and the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).

Related Article: CDC urges flu vaccination for all, especially pregnant women (News for Your Practice, October 2013)

Many physicians avoid giving vaccinations during pregnancy because of the concern that a spontaneous abortion or congenital anomaly might be incorrectly attributed to vaccine administration, but few vaccines are contradicted during pregnancy. Those that are contraindicated are those containing live virus, including measles, mumps, and rubella (MMR); varicella; and herpes zoster. Concerns also have been raised regarding the safety of administering influenza vaccines containing the mercury-based preservative thimerosol. However, no scientific evidence has conclusively linked adverse effects on offspring with thimerosol-containing vaccines administered during pregnancy.

Immunizations recommended for women of reproductive age
Measles, mumps, rubella (MMR). This vaccine is recommended for all women lacking confirmed immunity to rubella. The vaccine contains live, attenuated virus and is given as a single dose. Women should avoid pregnancy for 1 month after vaccination.

Varicella. This vaccine is for all women lacking confirmed immunity to varicella. It also contains a live, attenuated virus. It is administered in two doses, 1 month apart, and women should avoid pregnancy for 1 month after vaccination.

Influenza. The flu vaccine is recommended annually for individuals 6 months of age and older. The injectable vaccine contains inactivated virus and may be administered during pregnancy—at any time but optimally in October or November because the flu season occurs January through March. (The intranasal influenza vaccine contains live, attenuated virus and should be avoided in pregnancy.) Either method is administered as a single dose. 

Thimerosal is a mercury-based preservative used in vaccines, including the influenza vaccine, and is appropriate for use in pregnant women; studies have not shown an association between vaccines containing thimerosal and adverse effects in pregnant women or their offspring.

Tetanus-diptheria-pertussis (Tdap) and tetanus-diphtheria (Td). Tdap or Td is recommended for adults aged 19 to 64 years who have or anticipate having close contact with an infant less than 12 months of age. Due to the recent increase in pertussis infection, Tdap should be given to all women who have not previously received the vaccine and who are pregnant or might become pregnant. It can be given anytime during pregnancy, but optimal administration is during the third trimester or late second trimester (after 20 weeks’ gestation) to confer the greatest amount of fetal protection.

If the vaccine is not being administered during pregnancy, it should be given in the immediate postpartum period to ensure pertussis immunity and to reduce transmission to the newborn. Tdap is administered as a single dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis. 

Non-routine vaccines include pneumococcus, hepatitis A, hepatitis B, and meningococcus (TABLE). These vaccines should be administered as indicated in high-risk patients.

Health-care providers caring for women with infertility are urged to assess patients’ immunization status prior to attempting pregnancy, to counsel patients about the importance of protecting them and their potential offspring from preventable disease, and to facilitate vaccination prior to conception attempts. 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Vaccination is a very important aspect of pre-pregnancy care but is especially important for infertile women who desire pregnancy. Planning of infertility treatment should include assessment of the patient’s vaccination status and completion of appropriate vaccinations before infertility treatment is initiated.

DO CURRENT OPTIONS EFFECTIVELY PREVENT POSTSURGICAL ADHESIONS?

Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: A committee opinion. Fertil Steril. 2013;99(6):1550–1555.

Postoperative adhesions are a natural consequence of surgery and a major problem in gynecology. They may cause postsurgical infertility, abdominal/pelvic pain, or bowel obstruction as well as complicate subsequent surgeries by increasing operative times and the risk of bowel injury. The American Society for Reproductive Medicine (ASRM) and the Society of Reproductive Surgeons (SRS) recently evaluated the epidemiology, pathogenesis, and clinical consequences of adhesion formation and the evidence behind strategies for reducing adhesion formation.

In their joint Committee Opinion, they noted that open and laparoscopic approaches to surgery carry comparable levels of risk for adhesion-related hospital readmission. Ovarian surgery has the highest risk for adhesion-related readmission, at 7.5 per 100 initial operations, and the incidence of small bowel obstruction after hysterectomy was found to be 1.6 per 100 procedures. Adhesion-related US health-care costs are estimated at approximately $1 billion annually.

 

The Societies noted that more severe adnexal adhesions are associated with lower pregnancy rates, and treatment of adnexal adhesions appears to improve pregnancy rates. Investigators found adhesions to cause about three-quarters of postoperative small bowel obstructions; however, the relationship between adhesions and pelvic pain remains unclear. It is thought that adhesions may cause visceral pain by impairing organ mobility, but there is no relationship between the extent of adhesions and the severity of pain. It appears that only dense adhesions ­involving the bowel are associated with chronic pelvic pain. Predicting the outcome of lysis of adnexal or bowel adhesions is difficult.

Reduction of adhesion formation
Theoretically, adhesions may be reduced by minimizing peritoneal injury during surgery, avoiding intraoperative reactive foreign bodies, reducing local inflammatory response, inhibiting the coagulation cascade and promoting fibrinolysis, or by placing barriers between damaged tissues.

Related Article: Update on Fertility G. David Adamson, MD (February 2008)

Careful surgical technique includes gentle tissue handling, meticulous hemostasis, excision of necrotic tissue, minimizing ischemia and desiccation, using fine and nonreactive suture, and preventing foreign-body reaction and infection, all “microsurgical principles.”

ASRM and SRS reported that the surgical approach (laparoscopy vs laparotomy) is much less important than the extent of tissue injury. However, laparoscopy may result in less tissue and organ handling and trauma, avoid contamination with foreign bodies, enable more precise tissue handling, and result in less postoperative infection. The pneumoperitoneum has a tamponade effect that facilitates hemostasis during laparoscopy, but the process also can be associated with peritoneal desiccation and reduced temperatures that can increase injury.

Laparoscopic myomectomy was found to have a 70% risk of postoperative adhesions, compared with a 90% risk after laparotomy. It is unclear whether peritoneal closure at laparotomy reduces or increases adhesions, but parietal peritoneal closure at primary cesarean delivery results in fewer dense and filmy adhesions.

Related Article: How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy Michael Baggish, MD (Second of a 2-part series on laparoscopic complications, October 2012)

Adjuncts to surgical technique
SRM and SRS reported on three adjuncts to surgical technique that have been proposed to reduce the risk of postoperative adhesions: anti-inflammatory agents, peritoneal instillates, and adhesion barriers.

Dexamethasone, promethazine, and other local and systemic anti-inflammatory drugs and adhesion-reducing substances have not been found effective for reducing postoperative adhesions.

Peritoneal instillates—which create “hydroflotation” and include antibiotic solutions, 32% dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids—have not been found effective.⁸ Icodextrin 4% (Adept Adhesion Reduction Solution, Baxter Healthcare) is FDA approved as an adjunct to good surgical technique for the reduction of postoperative adhesions in patients undergoing gynecologic laparoscopic adhesiolysis. However, a systematic review concluded that there is insufficient evidence for its use as an adhesion-preventing agent.⁸

Adhesion barriers may help reduce postoperative adhesions but cannot compensate for poor surgical technique. Although the bioresorbable membrane sodium hyaluronic acid and carboxymethyl cellulose (Seprafilm, Genzyme Corp) is FDA-approved, there is limited evidence that it prevents adhesions after myomectomy.⁹ Because it fragments easily, it is mostly used at laparotomy.

Oxidized regenerated cellulose (Interceed, Ethicon Women’s Health and Urology) is an FDA-approved absorbable adhesion barrier for use at laparotomy that requires no suturing and has been shown to reduce the incidence and extent of new and recurrent adhesions at both laparoscopy and laparotomy by 40% to 50%, although there is little evidence that this improves fertility.⁹ Complete hemostasis must be achieved to use Interceed, and the addition of heparin confers no benefit.

Another product is expanded polytetrafluoroethylene (ePTFE, Gore-Tex Surgical Membrane, WL Gore and Associates), a nonabsorbable adhesion barrier produced in thin sheets and approved by the FDA for peritoneal repair. ePTFE must be sutured to tissue and helps prevent adhesion formation and reformation regardless of the type of injury or whether complete hemostasis has been achieved. In a small trial, it decreased postmyomectomy adhesions.¹⁰ ePTFE also was more effective than oxidized regenerated cellulose in preventing adhesions after adnexal surgery.¹¹ Its use has been limited by the need for suturing and later reoperation for removal, although it probably does not have to be removed if it will not interfere with normal organ function since it has been used as a pericardial graft for many years.¹²

Hyaluronic acid (HA) solution (Sepracoat, Genzyme) is a natural bioabsorbable component of the extracellular matrix. Women undergoing laparotomy have fewer new adhesions with HA solution, but it is not approved for use in the United States.¹³ Polyethylene glycol (PEG; SprayGel, Confluent Surgical) was effective in early clinical trials but is not FDA-approved.¹² Fibrin sealant (Tisseel VH, Baxter Healthcare) has been reported to decrease the formation of adhesions after salpingostomy, salpingolysis, and ovariolysis. Because it is a biologic product derived from human blood donors, it poses a risk for transmission of infectious agents. It is FDA-approved for use in cardiothoracic surgery, splenic injuries, and colostomy closure for hemostasis.

 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adhesions are the most common complication following gynecologic surgery, and they pose potential longstanding consequences to patients. There is no evidence that anti-inflammatory agents reduce postoperative adhesions and insufficient evidence to recommend peritoneal instillates. FDA-approved surgical barriers reduce postoperative adhesions but there is not substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction. All gynecologists need to understand the importance of using microsurgical principles rather than relying on adhesion barriers to reduce postoperative adhesions.

 

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

Case

A 60-year-old man with stage IV hormoneindependent prostate cancer, with widely metastatic disease to the bone, presents to the ED with increased weakness and new onset of numbness in the lower extremities, which he states began earlier that day. After failing several lines of chemotherapy, he is currently being treated with hormonal therapy alone. Patient first noted weakness in the left lower extremity 5 days before presentation, which progressed to bilateral involvement, making ambulation difficult and requiring the use of a walker. He denies back pain or urinary or fecal incontinence. Regarding pain management, he had been recently treated at one of the pain clinics in the hospital and has continued on opioid medication at another institution. Until the past week, he states he had back pain without neurological deficits.

His vital signs are stable at presentation. Patient is obese but in no acute distress. His cardiopulmonary examination is unremarkable; abdominal examination is benign; and back examination is normal. On neurological examination, iliopsoas flexion is 4/5 bilaterally; the rest of the motor examination is normal, with toes downgoing bilaterally upon plantar stimulation. Diminished sensation to light touch is noted at the T4-T6 sensory level and below; patient also has diminished proprioception in his lower extremities.

Patient had undergone a whole body scan one month prior to presentation, which revealed increased tracer uptake of Technetium-99m in multiple areas in the thoracic and lumbar spine. The radiologist also reported bilateral involvement in the wrists, femurs, tibias, and humeri—all in concordance with multifocal bone disease noted in previous computed tomography scans.

How should you approach this case?

Overview of Metastatic Spinal Cord Compression
Malignant or metastatic spinal cord compression (MSCC) of the thecal sac is an ominous complication of advanced cancer and an oncologic emergency presenting clinically in approximately 3% to 10% of cancer-related deaths.1,2 Cancer patients have a median survival of 3 to 6 months from diagnosis of MSCC.1,3,4 This disease causes significant disability due to paralysis, sensory loss, protracted pain, and sphincter dysfunction.5 If left untreated, MSCC has the potential to cause paraplegia in almost all affected patients; therefore, prompt recognition and treatment are essential to maintain mobility and neurological function. Generally speaking, any cancer patient who presents with new or worsening back pain—even in the absence of neurological deficits—merits evaluation for spinal cord compression.6 Nevertheless, individual risk assessment is warranted.7

Epidemiology

In the United States, more than 20,000 cases of MSCC are reported each year.8 According to postmortem studies, this condition affects 5% to 36% of cancer patients.9,10 In a US nationwide study of 15,367 cases of MSCC,2 the mean age at hospitalization was 62 years, with 37% of cases occurring in women. In approximately 20% of cases, MSCC was the initial presentation of cancer4; this has been reflected in our experience at MD Anderson Cancer Center.

Cancers of the breast, lung, prostate, and multiple myeloma are the most frequent underlying conditions in MSCC.2,8 Its prevalence varies depending on tumor type, occurring in 0.2% of pancreatic cancers; however, MSCC may affect up to 7.9% to 15% of myelomas1,2 and 13% of lymphomas.2 Interestingly, 5.5% of patients with prostate cancer develop MSCC.2 According to a study by Lu et al,11 historical risk factors include known nonvertebral bony metastases and stage IV disease at the time of diagnosis.

The most common location of MSCC is the thoracic spine (69% of cases); 29% of cases occur at the lumbosacral level and 10% at the cervical area.12 Most likely this pattern follows the lymphatic drainage, as metastases from breast and lung cancers tend to be found in the thoracic spine. Pelvic and intra-abdominal malignancies most commonly migrate to the lumbar spine. Multiple spinal epidural metastases were noted in 31% of those who underwent complete imaging of the spine.12

Pathophysiology

Most cases of MSCC are epidural in origin, arising from the vertebral column in 85% of patients.8 Epidural spread is caused mainly by hematogenous mechanism through the Batson venous plexus,13 debilitating the bone and eventually causing vertebral collapse with compression of the spinal canal. Epidural spread is less likely caused by direct tumor extension (ie, erosion through the bone) or by direct deposition of tumor cells into the epidural space.14 Ultimate neuronal injury is thought to involve vasogenic edema,15 leading to ischemia13 through venous infarction, but there has been debate regarding this last phenomenon.16 In cases of paralysis, demyelination is striking.16

Clinical Presentation

Even though cancer accounts for less than 1% of episodes of low back pain, it is the most common systemic disease affecting the spine.17 An important clinical inquiry is to determine whether back pain in an established cancer patient can be ruled out without extensive imaging. Unfortunately, clinical examination alone cannot exclude MSCC. Because of the high specificity (0.98), any cancer patient with new back pain should be considered to have metastasis until proven otherwise.17

 

Symptoms in MSCC at presentation can be motor, sensory, and/or autonomic. Back pain varies depending on the site of metastasis, which can be referred, local, radicular, or a combination of all three.18 The primary complaint is pain in 83% to 96% of cases,19,20 though this is a nonspecific sign.

Back pain is typically experienced for a median of 62 days prior to treatment of MSCC, usually due to considerable delays in diagnosis and treatment21; patients presenting with radiculopathy are usually symptomatic an average of 9 weeks prior to diagnosis.22 Tenderness is often present over the affected area and, as with mechanical back pain, pain associated with MSCC may worsen with loads, which bear pressure on the vertebral column.23 In contrast to mechanical back pain, rest in a supine position frequently exacerbates pain in MSCC,17 often disrupting sleep. In addition, weakness follows pain with an estimated 35% to 85% of patients endorsing the symptom.24

Previous studies have shown 40% to 64% of patients were not ambulatory at the time of diagnosis.19,25 Recent case series, however, report an increased number of ambulatory patients—possibly due to increased clinician awareness.26 In other cases, only 9% of patients were able to walk independently without aid.27 Loss of sensation, dense paraplegia, and incontinence are late findings and likely signal some degree of permanent disability.19

Misdiagnosis is a common issue in the ED setting. In an interesting retrospective study of 63 patients with spinal cord compression28 (not necessarily malignant), 18 (29%) were misdiagnosed.28 Consequently, there was a significant delay in diagnosis despite obvious neurological deficits at presentation.

Evaluation and Imaging

A detailed physical examination is essential to diagnosing MSCC. A thorough neurological examination, including sensation, strength, and reflexes should be carefully documented. If spinal instability is suspected, range-of-motion testing is contraindicated. The modified Frankel classification,29 adapted from the traumatic spine cord injury work by Frankel, et al,30 may be used to assess the degree of disability (Table).

Lu et al11 noted hyperreflexia and upward going Babinski reflex as common findings. Moreover, risk factors of decreased rectal sphincter tone and bladder were determinant for poor outcomes.

Incidental discovery of MSCC on imaging in the absence of neurological findings is rare. Approximately 26% to 29% of total metastatic deposits are occult and not visible on X-ray.4,10 Prior to the 1990s, spinal cord compression was diagnosed by my elography.31 Fortunately, this uncomfortable procedure has been replaced by magnetic resonance imaging (MRI) (Figure 1).32 While gadolinium-enhanced MRI can help to determine intradural tumor or leptomeningeal disease, it is not required for cord compression studies. Unenhanced MRI is equal to myelography in detecting epidural disease and is more sensitive at detecting vertebral metastasis,33 justifying its use and reducing procedure time compared to gadolinium-enhanced studies.

MRI studies should include the entire spine—not just the perceived area of interest— as up to 38% of patients have multiple-site metastases12 (Figure 1). Sensory deficits and mechanical pain may be present two to four vertebral levels away from the actual lesion.11 If MRI suggests cord compression, severity can be graded using the MSCC scale34 (Figure 2). Several scoring systems have been developed to aid in decision making concerning surgical treatment.

Management and Outcomes

The goal of therapy is symptom control and preservation of function. This requires a multidisciplinary approach and may involve radiation therapy and surgery, as well as medical efforts. Upon diagnosis and initiation of therapy, serial neurological evaluation should be undertaken. Neurovital signs should be scheduled to coincide with other nursing efforts to ease the burden of care and minimize patient discomfort.

The mainstay of medical therapy is treatment with corticosteroids.35 Initial trials have demonstrated that corticosteroids improve functional status in MSCC, but controversy exists regarding the effective dose. In a randomized, controlled trial by Sorensen et al,36 which sought to evaluate functional outcomes of highdose corticosteroids as an adjunct to radiotherapy, 57 patients received either high-dose dexamethasone or no corticosteroid therapy. Fifty-nine percent of patients in the dexamethasone group were ambulatory 6 months after treatment compared to 39% in the group who did not receive steroids.36

The use of high-dose corticosteroids was once a common practice, but is no longer considered standard of care and should be avoided based on increased side effects with no improvement in outcome compared with low-dose corticosteroids. 37 At our institution, moderate doses of corticosteroids are recommended concomitantly with radiation therapy or/and surgery. Our patients generally receive 10 mg of dexamethasone as a loading dose, followed by 16 mg daily in divided doses. Gastrointestinal (GI) prophylaxis should be initiated to reduce GI tract toxicity, and special attention should be given to glucose control in patients with diabetes.

 

A patient without a biopsy-confirmed cancer diagnosis in need of corticosteroid treatment presents a dilemma. Plasmacytomas, thymomas, lymphomas, multiple myeloma, germ-cell tumors are very sensitive to corticosteroid therapy in patients with MSCC.38 However, corticosteroids given before tissue samples are obtained may hinder proper diagnosis and complicate future management.39,40 In the absence of neurological deficit, corticosteroids may be withheld and emergent consultation with neurosurgery and oncology should be obtained. If there is any question regarding the nature of the lesion, tissue diagnosis must be obtained without delay.

Strict bed rest (including logroll and bedpan use) should be instituted if there is suspicion of spinal cord instability. Patients with suspected involvement of the cervical spine should have a Philadelphia collar placed until spinal stability has been confirmed. In the United Kingdom, the National Institutes for Health Care Excellence guidelines recommend all patients with suspected cord compression be nursed in a flat position.22 Other institutions, however, do not believe that strict bed rest is necessary, as it is presumed that MSCC is inherently different from that caused by trauma. Authors supporting this position contend that the increased incidence of deep vein thrombosis, infection (particularly from the urinary tract), and decubitus ulcers outweighs the benefit of bed rest. Patient preference should be taken into consideration as those with good functional status may be quite resistant to bed rest. In cases where cord compression is strongly suspected, these patients should be educated on proper bed rest. The greatest predictors of outcome are ambulatory and functional status at the time of diagnosis (generally based on an Eastern Cooperative Oncology Group scale). Patients with a good functional status, limited disease, and a life expectancy of greater than 3 to 6 months may benefit from surgery.41 However, emergent surgical evaluation is required in patients not responding to radiotherapy or who received received only limited doses of radiotherapy, as well as those with spinal instability, direct cord compression due to a bony fragment, impending sphincter dysfunction, unknown primary tumor, or no paraplegia for >48 hours.15

Unfortunately, surgery is only indicated in 10% to 15% of MSCC cases.42 In the past two decades, significant improvements regarding new aggressive surgical techniques have been made, and include circumferential decompression of the spine and staged or single stage anterior posterior surgery with stabilization. 43 Additionally, the combination of surgery with radiotherapy has improved outcomes.44

Most patients benefit from short-course radiotherapy45 even when given palliatively. 46 Longer courses of radiotherapy are highly recommended for patients with a more favorable prognosis.47 Up to 10% of patients diagnosed with spinal cord compression will require treatment for disease recurrence.42 There is a limited role for chemotherapy, and in seminomas and lymphomas, results can be quite dramatic.38

The average lifespan after development of MSCC is usually less than 6 months.1,3,4 However, patients with limited disease and good functional status may survive for years.43 Patients with poor functional status or those in the late stages of disease may be referred to palliative care for the management of symptoms.48 Given the poor prognosis of MSCC in general, endof- life discussions are warranted. In a retrospective study of 88 patients with MSCC at MD Anderson Cancer Center,49 “do not resuscitate” orders were in place in only 9% of the patients during their hospital admission. Improved doctor-patient communication in the ED setting will facilitate the patient’s coping with future losses.

Prevention

Lu et al11 found that only 54% of patients were aware that back pain should be reported to their physician. Delays in diagnosis and treatment are common and well described in the literature.21 Patients should be instructed to call their physician within 24 hours from the development of any new or worsening back pain, and should be advised to seek immediate care if they develop any neurological symptoms. To facilitate appropriate and prompt management of MSCC, hospitals should develop diagnostic algorithms to minimize delays in referral to a comprehensive center for further treatment.

Case Conclusion

Based on this patient’s symptoms and status at presentation, the emergency team determined he was at high risk for MSCC. An initial dosage of 10 mg dexamethasone was administered intravenously (IV), followed by 4 mg IV every 6 hours prior to imaging. An MRI without contrast of the cervical, thoracic, and lumbar spine showed cord compression with mild cord edema at T4 level, along with diffused osseous metastasis.

Upon diagnosis, patient was referred to radiation oncology for radiotherapy of the T2-T6 vertebral bodies. Three days after initiation of radiation therapy, his neurological function deteriorated with paraplegia and incontinence, and he was emergently evaluated for neurosurgery. Although T4 laminectomy and decompression of the spinal cord were performed without complication, patient did not recover neurological function. His hospital course was complicated by Ogilvie syndrome and episodes of delirium, and he was discharged to a rehabilitation facility 23 days after admission; paraplegia and urinary and bowel incontinence remained unchanged.

Case

A 60-year-old man with stage IV hormoneindependent prostate cancer, with widely metastatic disease to the bone, presents to the ED with increased weakness and new onset of numbness in the lower extremities, which he states began earlier that day. After failing several lines of chemotherapy, he is currently being treated with hormonal therapy alone. Patient first noted weakness in the left lower extremity 5 days before presentation, which progressed to bilateral involvement, making ambulation difficult and requiring the use of a walker. He denies back pain or urinary or fecal incontinence. Regarding pain management, he had been recently treated at one of the pain clinics in the hospital and has continued on opioid medication at another institution. Until the past week, he states he had back pain without neurological deficits.

His vital signs are stable at presentation. Patient is obese but in no acute distress. His cardiopulmonary examination is unremarkable; abdominal examination is benign; and back examination is normal. On neurological examination, iliopsoas flexion is 4/5 bilaterally; the rest of the motor examination is normal, with toes downgoing bilaterally upon plantar stimulation. Diminished sensation to light touch is noted at the T4-T6 sensory level and below; patient also has diminished proprioception in his lower extremities.

Patient had undergone a whole body scan one month prior to presentation, which revealed increased tracer uptake of Technetium-99m in multiple areas in the thoracic and lumbar spine. The radiologist also reported bilateral involvement in the wrists, femurs, tibias, and humeri—all in concordance with multifocal bone disease noted in previous computed tomography scans.

How should you approach this case?

Overview of Metastatic Spinal Cord Compression
Malignant or metastatic spinal cord compression (MSCC) of the thecal sac is an ominous complication of advanced cancer and an oncologic emergency presenting clinically in approximately 3% to 10% of cancer-related deaths.1,2 Cancer patients have a median survival of 3 to 6 months from diagnosis of MSCC.1,3,4 This disease causes significant disability due to paralysis, sensory loss, protracted pain, and sphincter dysfunction.5 If left untreated, MSCC has the potential to cause paraplegia in almost all affected patients; therefore, prompt recognition and treatment are essential to maintain mobility and neurological function. Generally speaking, any cancer patient who presents with new or worsening back pain—even in the absence of neurological deficits—merits evaluation for spinal cord compression.6 Nevertheless, individual risk assessment is warranted.7

Epidemiology

In the United States, more than 20,000 cases of MSCC are reported each year.8 According to postmortem studies, this condition affects 5% to 36% of cancer patients.9,10 In a US nationwide study of 15,367 cases of MSCC,2 the mean age at hospitalization was 62 years, with 37% of cases occurring in women. In approximately 20% of cases, MSCC was the initial presentation of cancer4; this has been reflected in our experience at MD Anderson Cancer Center.

Cancers of the breast, lung, prostate, and multiple myeloma are the most frequent underlying conditions in MSCC.2,8 Its prevalence varies depending on tumor type, occurring in 0.2% of pancreatic cancers; however, MSCC may affect up to 7.9% to 15% of myelomas1,2 and 13% of lymphomas.2 Interestingly, 5.5% of patients with prostate cancer develop MSCC.2 According to a study by Lu et al,11 historical risk factors include known nonvertebral bony metastases and stage IV disease at the time of diagnosis.

The most common location of MSCC is the thoracic spine (69% of cases); 29% of cases occur at the lumbosacral level and 10% at the cervical area.12 Most likely this pattern follows the lymphatic drainage, as metastases from breast and lung cancers tend to be found in the thoracic spine. Pelvic and intra-abdominal malignancies most commonly migrate to the lumbar spine. Multiple spinal epidural metastases were noted in 31% of those who underwent complete imaging of the spine.12

Pathophysiology

Most cases of MSCC are epidural in origin, arising from the vertebral column in 85% of patients.8 Epidural spread is caused mainly by hematogenous mechanism through the Batson venous plexus,13 debilitating the bone and eventually causing vertebral collapse with compression of the spinal canal. Epidural spread is less likely caused by direct tumor extension (ie, erosion through the bone) or by direct deposition of tumor cells into the epidural space.14 Ultimate neuronal injury is thought to involve vasogenic edema,15 leading to ischemia13 through venous infarction, but there has been debate regarding this last phenomenon.16 In cases of paralysis, demyelination is striking.16

Clinical Presentation

Even though cancer accounts for less than 1% of episodes of low back pain, it is the most common systemic disease affecting the spine.17 An important clinical inquiry is to determine whether back pain in an established cancer patient can be ruled out without extensive imaging. Unfortunately, clinical examination alone cannot exclude MSCC. Because of the high specificity (0.98), any cancer patient with new back pain should be considered to have metastasis until proven otherwise.17

 

Symptoms in MSCC at presentation can be motor, sensory, and/or autonomic. Back pain varies depending on the site of metastasis, which can be referred, local, radicular, or a combination of all three.18 The primary complaint is pain in 83% to 96% of cases,19,20 though this is a nonspecific sign.

Back pain is typically experienced for a median of 62 days prior to treatment of MSCC, usually due to considerable delays in diagnosis and treatment21; patients presenting with radiculopathy are usually symptomatic an average of 9 weeks prior to diagnosis.22 Tenderness is often present over the affected area and, as with mechanical back pain, pain associated with MSCC may worsen with loads, which bear pressure on the vertebral column.23 In contrast to mechanical back pain, rest in a supine position frequently exacerbates pain in MSCC,17 often disrupting sleep. In addition, weakness follows pain with an estimated 35% to 85% of patients endorsing the symptom.24

Previous studies have shown 40% to 64% of patients were not ambulatory at the time of diagnosis.19,25 Recent case series, however, report an increased number of ambulatory patients—possibly due to increased clinician awareness.26 In other cases, only 9% of patients were able to walk independently without aid.27 Loss of sensation, dense paraplegia, and incontinence are late findings and likely signal some degree of permanent disability.19

Misdiagnosis is a common issue in the ED setting. In an interesting retrospective study of 63 patients with spinal cord compression28 (not necessarily malignant), 18 (29%) were misdiagnosed.28 Consequently, there was a significant delay in diagnosis despite obvious neurological deficits at presentation.

Evaluation and Imaging

A detailed physical examination is essential to diagnosing MSCC. A thorough neurological examination, including sensation, strength, and reflexes should be carefully documented. If spinal instability is suspected, range-of-motion testing is contraindicated. The modified Frankel classification,29 adapted from the traumatic spine cord injury work by Frankel, et al,30 may be used to assess the degree of disability (Table).

Lu et al11 noted hyperreflexia and upward going Babinski reflex as common findings. Moreover, risk factors of decreased rectal sphincter tone and bladder were determinant for poor outcomes.

Incidental discovery of MSCC on imaging in the absence of neurological findings is rare. Approximately 26% to 29% of total metastatic deposits are occult and not visible on X-ray.4,10 Prior to the 1990s, spinal cord compression was diagnosed by my elography.31 Fortunately, this uncomfortable procedure has been replaced by magnetic resonance imaging (MRI) (Figure 1).32 While gadolinium-enhanced MRI can help to determine intradural tumor or leptomeningeal disease, it is not required for cord compression studies. Unenhanced MRI is equal to myelography in detecting epidural disease and is more sensitive at detecting vertebral metastasis,33 justifying its use and reducing procedure time compared to gadolinium-enhanced studies.

MRI studies should include the entire spine—not just the perceived area of interest— as up to 38% of patients have multiple-site metastases12 (Figure 1). Sensory deficits and mechanical pain may be present two to four vertebral levels away from the actual lesion.11 If MRI suggests cord compression, severity can be graded using the MSCC scale34 (Figure 2). Several scoring systems have been developed to aid in decision making concerning surgical treatment.

Management and Outcomes

The goal of therapy is symptom control and preservation of function. This requires a multidisciplinary approach and may involve radiation therapy and surgery, as well as medical efforts. Upon diagnosis and initiation of therapy, serial neurological evaluation should be undertaken. Neurovital signs should be scheduled to coincide with other nursing efforts to ease the burden of care and minimize patient discomfort.

The mainstay of medical therapy is treatment with corticosteroids.35 Initial trials have demonstrated that corticosteroids improve functional status in MSCC, but controversy exists regarding the effective dose. In a randomized, controlled trial by Sorensen et al,36 which sought to evaluate functional outcomes of highdose corticosteroids as an adjunct to radiotherapy, 57 patients received either high-dose dexamethasone or no corticosteroid therapy. Fifty-nine percent of patients in the dexamethasone group were ambulatory 6 months after treatment compared to 39% in the group who did not receive steroids.36

The use of high-dose corticosteroids was once a common practice, but is no longer considered standard of care and should be avoided based on increased side effects with no improvement in outcome compared with low-dose corticosteroids. 37 At our institution, moderate doses of corticosteroids are recommended concomitantly with radiation therapy or/and surgery. Our patients generally receive 10 mg of dexamethasone as a loading dose, followed by 16 mg daily in divided doses. Gastrointestinal (GI) prophylaxis should be initiated to reduce GI tract toxicity, and special attention should be given to glucose control in patients with diabetes.

 

A patient without a biopsy-confirmed cancer diagnosis in need of corticosteroid treatment presents a dilemma. Plasmacytomas, thymomas, lymphomas, multiple myeloma, germ-cell tumors are very sensitive to corticosteroid therapy in patients with MSCC.38 However, corticosteroids given before tissue samples are obtained may hinder proper diagnosis and complicate future management.39,40 In the absence of neurological deficit, corticosteroids may be withheld and emergent consultation with neurosurgery and oncology should be obtained. If there is any question regarding the nature of the lesion, tissue diagnosis must be obtained without delay.

Strict bed rest (including logroll and bedpan use) should be instituted if there is suspicion of spinal cord instability. Patients with suspected involvement of the cervical spine should have a Philadelphia collar placed until spinal stability has been confirmed. In the United Kingdom, the National Institutes for Health Care Excellence guidelines recommend all patients with suspected cord compression be nursed in a flat position.22 Other institutions, however, do not believe that strict bed rest is necessary, as it is presumed that MSCC is inherently different from that caused by trauma. Authors supporting this position contend that the increased incidence of deep vein thrombosis, infection (particularly from the urinary tract), and decubitus ulcers outweighs the benefit of bed rest. Patient preference should be taken into consideration as those with good functional status may be quite resistant to bed rest. In cases where cord compression is strongly suspected, these patients should be educated on proper bed rest. The greatest predictors of outcome are ambulatory and functional status at the time of diagnosis (generally based on an Eastern Cooperative Oncology Group scale). Patients with a good functional status, limited disease, and a life expectancy of greater than 3 to 6 months may benefit from surgery.41 However, emergent surgical evaluation is required in patients not responding to radiotherapy or who received received only limited doses of radiotherapy, as well as those with spinal instability, direct cord compression due to a bony fragment, impending sphincter dysfunction, unknown primary tumor, or no paraplegia for >48 hours.15

Unfortunately, surgery is only indicated in 10% to 15% of MSCC cases.42 In the past two decades, significant improvements regarding new aggressive surgical techniques have been made, and include circumferential decompression of the spine and staged or single stage anterior posterior surgery with stabilization. 43 Additionally, the combination of surgery with radiotherapy has improved outcomes.44

Most patients benefit from short-course radiotherapy45 even when given palliatively. 46 Longer courses of radiotherapy are highly recommended for patients with a more favorable prognosis.47 Up to 10% of patients diagnosed with spinal cord compression will require treatment for disease recurrence.42 There is a limited role for chemotherapy, and in seminomas and lymphomas, results can be quite dramatic.38

The average lifespan after development of MSCC is usually less than 6 months.1,3,4 However, patients with limited disease and good functional status may survive for years.43 Patients with poor functional status or those in the late stages of disease may be referred to palliative care for the management of symptoms.48 Given the poor prognosis of MSCC in general, endof- life discussions are warranted. In a retrospective study of 88 patients with MSCC at MD Anderson Cancer Center,49 “do not resuscitate” orders were in place in only 9% of the patients during their hospital admission. Improved doctor-patient communication in the ED setting will facilitate the patient’s coping with future losses.

Prevention

Lu et al11 found that only 54% of patients were aware that back pain should be reported to their physician. Delays in diagnosis and treatment are common and well described in the literature.21 Patients should be instructed to call their physician within 24 hours from the development of any new or worsening back pain, and should be advised to seek immediate care if they develop any neurological symptoms. To facilitate appropriate and prompt management of MSCC, hospitals should develop diagnostic algorithms to minimize delays in referral to a comprehensive center for further treatment.

Case Conclusion

Based on this patient’s symptoms and status at presentation, the emergency team determined he was at high risk for MSCC. An initial dosage of 10 mg dexamethasone was administered intravenously (IV), followed by 4 mg IV every 6 hours prior to imaging. An MRI without contrast of the cervical, thoracic, and lumbar spine showed cord compression with mild cord edema at T4 level, along with diffused osseous metastasis.

Upon diagnosis, patient was referred to radiation oncology for radiotherapy of the T2-T6 vertebral bodies. Three days after initiation of radiation therapy, his neurological function deteriorated with paraplegia and incontinence, and he was emergently evaluated for neurosurgery. Although T4 laminectomy and decompression of the spinal cord were performed without complication, patient did not recover neurological function. His hospital course was complicated by Ogilvie syndrome and episodes of delirium, and he was discharged to a rehabilitation facility 23 days after admission; paraplegia and urinary and bowel incontinence remained unchanged.

Case

A 60-year-old man with stage IV hormoneindependent prostate cancer, with widely metastatic disease to the bone, presents to the ED with increased weakness and new onset of numbness in the lower extremities, which he states began earlier that day. After failing several lines of chemotherapy, he is currently being treated with hormonal therapy alone. Patient first noted weakness in the left lower extremity 5 days before presentation, which progressed to bilateral involvement, making ambulation difficult and requiring the use of a walker. He denies back pain or urinary or fecal incontinence. Regarding pain management, he had been recently treated at one of the pain clinics in the hospital and has continued on opioid medication at another institution. Until the past week, he states he had back pain without neurological deficits.

His vital signs are stable at presentation. Patient is obese but in no acute distress. His cardiopulmonary examination is unremarkable; abdominal examination is benign; and back examination is normal. On neurological examination, iliopsoas flexion is 4/5 bilaterally; the rest of the motor examination is normal, with toes downgoing bilaterally upon plantar stimulation. Diminished sensation to light touch is noted at the T4-T6 sensory level and below; patient also has diminished proprioception in his lower extremities.

Patient had undergone a whole body scan one month prior to presentation, which revealed increased tracer uptake of Technetium-99m in multiple areas in the thoracic and lumbar spine. The radiologist also reported bilateral involvement in the wrists, femurs, tibias, and humeri—all in concordance with multifocal bone disease noted in previous computed tomography scans.

How should you approach this case?

Overview of Metastatic Spinal Cord Compression
Malignant or metastatic spinal cord compression (MSCC) of the thecal sac is an ominous complication of advanced cancer and an oncologic emergency presenting clinically in approximately 3% to 10% of cancer-related deaths.1,2 Cancer patients have a median survival of 3 to 6 months from diagnosis of MSCC.1,3,4 This disease causes significant disability due to paralysis, sensory loss, protracted pain, and sphincter dysfunction.5 If left untreated, MSCC has the potential to cause paraplegia in almost all affected patients; therefore, prompt recognition and treatment are essential to maintain mobility and neurological function. Generally speaking, any cancer patient who presents with new or worsening back pain—even in the absence of neurological deficits—merits evaluation for spinal cord compression.6 Nevertheless, individual risk assessment is warranted.7

Epidemiology

In the United States, more than 20,000 cases of MSCC are reported each year.8 According to postmortem studies, this condition affects 5% to 36% of cancer patients.9,10 In a US nationwide study of 15,367 cases of MSCC,2 the mean age at hospitalization was 62 years, with 37% of cases occurring in women. In approximately 20% of cases, MSCC was the initial presentation of cancer4; this has been reflected in our experience at MD Anderson Cancer Center.

Cancers of the breast, lung, prostate, and multiple myeloma are the most frequent underlying conditions in MSCC.2,8 Its prevalence varies depending on tumor type, occurring in 0.2% of pancreatic cancers; however, MSCC may affect up to 7.9% to 15% of myelomas1,2 and 13% of lymphomas.2 Interestingly, 5.5% of patients with prostate cancer develop MSCC.2 According to a study by Lu et al,11 historical risk factors include known nonvertebral bony metastases and stage IV disease at the time of diagnosis.

The most common location of MSCC is the thoracic spine (69% of cases); 29% of cases occur at the lumbosacral level and 10% at the cervical area.12 Most likely this pattern follows the lymphatic drainage, as metastases from breast and lung cancers tend to be found in the thoracic spine. Pelvic and intra-abdominal malignancies most commonly migrate to the lumbar spine. Multiple spinal epidural metastases were noted in 31% of those who underwent complete imaging of the spine.12

Pathophysiology

Most cases of MSCC are epidural in origin, arising from the vertebral column in 85% of patients.8 Epidural spread is caused mainly by hematogenous mechanism through the Batson venous plexus,13 debilitating the bone and eventually causing vertebral collapse with compression of the spinal canal. Epidural spread is less likely caused by direct tumor extension (ie, erosion through the bone) or by direct deposition of tumor cells into the epidural space.14 Ultimate neuronal injury is thought to involve vasogenic edema,15 leading to ischemia13 through venous infarction, but there has been debate regarding this last phenomenon.16 In cases of paralysis, demyelination is striking.16

Clinical Presentation

Even though cancer accounts for less than 1% of episodes of low back pain, it is the most common systemic disease affecting the spine.17 An important clinical inquiry is to determine whether back pain in an established cancer patient can be ruled out without extensive imaging. Unfortunately, clinical examination alone cannot exclude MSCC. Because of the high specificity (0.98), any cancer patient with new back pain should be considered to have metastasis until proven otherwise.17

 

Symptoms in MSCC at presentation can be motor, sensory, and/or autonomic. Back pain varies depending on the site of metastasis, which can be referred, local, radicular, or a combination of all three.18 The primary complaint is pain in 83% to 96% of cases,19,20 though this is a nonspecific sign.

Back pain is typically experienced for a median of 62 days prior to treatment of MSCC, usually due to considerable delays in diagnosis and treatment21; patients presenting with radiculopathy are usually symptomatic an average of 9 weeks prior to diagnosis.22 Tenderness is often present over the affected area and, as with mechanical back pain, pain associated with MSCC may worsen with loads, which bear pressure on the vertebral column.23 In contrast to mechanical back pain, rest in a supine position frequently exacerbates pain in MSCC,17 often disrupting sleep. In addition, weakness follows pain with an estimated 35% to 85% of patients endorsing the symptom.24

Previous studies have shown 40% to 64% of patients were not ambulatory at the time of diagnosis.19,25 Recent case series, however, report an increased number of ambulatory patients—possibly due to increased clinician awareness.26 In other cases, only 9% of patients were able to walk independently without aid.27 Loss of sensation, dense paraplegia, and incontinence are late findings and likely signal some degree of permanent disability.19

Misdiagnosis is a common issue in the ED setting. In an interesting retrospective study of 63 patients with spinal cord compression28 (not necessarily malignant), 18 (29%) were misdiagnosed.28 Consequently, there was a significant delay in diagnosis despite obvious neurological deficits at presentation.

Evaluation and Imaging

A detailed physical examination is essential to diagnosing MSCC. A thorough neurological examination, including sensation, strength, and reflexes should be carefully documented. If spinal instability is suspected, range-of-motion testing is contraindicated. The modified Frankel classification,29 adapted from the traumatic spine cord injury work by Frankel, et al,30 may be used to assess the degree of disability (Table).

Lu et al11 noted hyperreflexia and upward going Babinski reflex as common findings. Moreover, risk factors of decreased rectal sphincter tone and bladder were determinant for poor outcomes.

Incidental discovery of MSCC on imaging in the absence of neurological findings is rare. Approximately 26% to 29% of total metastatic deposits are occult and not visible on X-ray.4,10 Prior to the 1990s, spinal cord compression was diagnosed by my elography.31 Fortunately, this uncomfortable procedure has been replaced by magnetic resonance imaging (MRI) (Figure 1).32 While gadolinium-enhanced MRI can help to determine intradural tumor or leptomeningeal disease, it is not required for cord compression studies. Unenhanced MRI is equal to myelography in detecting epidural disease and is more sensitive at detecting vertebral metastasis,33 justifying its use and reducing procedure time compared to gadolinium-enhanced studies.

MRI studies should include the entire spine—not just the perceived area of interest— as up to 38% of patients have multiple-site metastases12 (Figure 1). Sensory deficits and mechanical pain may be present two to four vertebral levels away from the actual lesion.11 If MRI suggests cord compression, severity can be graded using the MSCC scale34 (Figure 2). Several scoring systems have been developed to aid in decision making concerning surgical treatment.

Management and Outcomes

The goal of therapy is symptom control and preservation of function. This requires a multidisciplinary approach and may involve radiation therapy and surgery, as well as medical efforts. Upon diagnosis and initiation of therapy, serial neurological evaluation should be undertaken. Neurovital signs should be scheduled to coincide with other nursing efforts to ease the burden of care and minimize patient discomfort.

The mainstay of medical therapy is treatment with corticosteroids.35 Initial trials have demonstrated that corticosteroids improve functional status in MSCC, but controversy exists regarding the effective dose. In a randomized, controlled trial by Sorensen et al,36 which sought to evaluate functional outcomes of highdose corticosteroids as an adjunct to radiotherapy, 57 patients received either high-dose dexamethasone or no corticosteroid therapy. Fifty-nine percent of patients in the dexamethasone group were ambulatory 6 months after treatment compared to 39% in the group who did not receive steroids.36

The use of high-dose corticosteroids was once a common practice, but is no longer considered standard of care and should be avoided based on increased side effects with no improvement in outcome compared with low-dose corticosteroids. 37 At our institution, moderate doses of corticosteroids are recommended concomitantly with radiation therapy or/and surgery. Our patients generally receive 10 mg of dexamethasone as a loading dose, followed by 16 mg daily in divided doses. Gastrointestinal (GI) prophylaxis should be initiated to reduce GI tract toxicity, and special attention should be given to glucose control in patients with diabetes.

 

A patient without a biopsy-confirmed cancer diagnosis in need of corticosteroid treatment presents a dilemma. Plasmacytomas, thymomas, lymphomas, multiple myeloma, germ-cell tumors are very sensitive to corticosteroid therapy in patients with MSCC.38 However, corticosteroids given before tissue samples are obtained may hinder proper diagnosis and complicate future management.39,40 In the absence of neurological deficit, corticosteroids may be withheld and emergent consultation with neurosurgery and oncology should be obtained. If there is any question regarding the nature of the lesion, tissue diagnosis must be obtained without delay.

Strict bed rest (including logroll and bedpan use) should be instituted if there is suspicion of spinal cord instability. Patients with suspected involvement of the cervical spine should have a Philadelphia collar placed until spinal stability has been confirmed. In the United Kingdom, the National Institutes for Health Care Excellence guidelines recommend all patients with suspected cord compression be nursed in a flat position.22 Other institutions, however, do not believe that strict bed rest is necessary, as it is presumed that MSCC is inherently different from that caused by trauma. Authors supporting this position contend that the increased incidence of deep vein thrombosis, infection (particularly from the urinary tract), and decubitus ulcers outweighs the benefit of bed rest. Patient preference should be taken into consideration as those with good functional status may be quite resistant to bed rest. In cases where cord compression is strongly suspected, these patients should be educated on proper bed rest. The greatest predictors of outcome are ambulatory and functional status at the time of diagnosis (generally based on an Eastern Cooperative Oncology Group scale). Patients with a good functional status, limited disease, and a life expectancy of greater than 3 to 6 months may benefit from surgery.41 However, emergent surgical evaluation is required in patients not responding to radiotherapy or who received received only limited doses of radiotherapy, as well as those with spinal instability, direct cord compression due to a bony fragment, impending sphincter dysfunction, unknown primary tumor, or no paraplegia for >48 hours.15

Unfortunately, surgery is only indicated in 10% to 15% of MSCC cases.42 In the past two decades, significant improvements regarding new aggressive surgical techniques have been made, and include circumferential decompression of the spine and staged or single stage anterior posterior surgery with stabilization. 43 Additionally, the combination of surgery with radiotherapy has improved outcomes.44

Most patients benefit from short-course radiotherapy45 even when given palliatively. 46 Longer courses of radiotherapy are highly recommended for patients with a more favorable prognosis.47 Up to 10% of patients diagnosed with spinal cord compression will require treatment for disease recurrence.42 There is a limited role for chemotherapy, and in seminomas and lymphomas, results can be quite dramatic.38

The average lifespan after development of MSCC is usually less than 6 months.1,3,4 However, patients with limited disease and good functional status may survive for years.43 Patients with poor functional status or those in the late stages of disease may be referred to palliative care for the management of symptoms.48 Given the poor prognosis of MSCC in general, endof- life discussions are warranted. In a retrospective study of 88 patients with MSCC at MD Anderson Cancer Center,49 “do not resuscitate” orders were in place in only 9% of the patients during their hospital admission. Improved doctor-patient communication in the ED setting will facilitate the patient’s coping with future losses.

Prevention

Lu et al11 found that only 54% of patients were aware that back pain should be reported to their physician. Delays in diagnosis and treatment are common and well described in the literature.21 Patients should be instructed to call their physician within 24 hours from the development of any new or worsening back pain, and should be advised to seek immediate care if they develop any neurological symptoms. To facilitate appropriate and prompt management of MSCC, hospitals should develop diagnostic algorithms to minimize delays in referral to a comprehensive center for further treatment.

Case Conclusion

Based on this patient’s symptoms and status at presentation, the emergency team determined he was at high risk for MSCC. An initial dosage of 10 mg dexamethasone was administered intravenously (IV), followed by 4 mg IV every 6 hours prior to imaging. An MRI without contrast of the cervical, thoracic, and lumbar spine showed cord compression with mild cord edema at T4 level, along with diffused osseous metastasis.

Upon diagnosis, patient was referred to radiation oncology for radiotherapy of the T2-T6 vertebral bodies. Three days after initiation of radiation therapy, his neurological function deteriorated with paraplegia and incontinence, and he was emergently evaluated for neurosurgery. Although T4 laminectomy and decompression of the spinal cord were performed without complication, patient did not recover neurological function. His hospital course was complicated by Ogilvie syndrome and episodes of delirium, and he was discharged to a rehabilitation facility 23 days after admission; paraplegia and urinary and bowel incontinence remained unchanged.