Clinical Review

FERTILITY

OBG Manag. 2007 February;19(2):37-76

References

1. Practice Committee. American Society for Reproductive Medicine. Definition of “infertility.” Fertil Steril. 2006;86(Suppl 4):S228.-

2. Practice Committee, American Society for Reproductive Medicine. Aging and infertility in women. Fertil Steril. 2006;86(Suppl 4):S248-252.

3. Practice Committee, American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril. 2006;86(Suppl 4):S264-267.

4. Practice Committee, American Society for Reproductive Medicine. Smoking and infertility. Fertil Steril. 2006;86(Suppl 4):S172-177.

5. Practice committee, American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2006;86(Suppl 4):S187-193.

6. Male Infertility Best Practice Committee, American Urological Association, and Practice Committee, American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril. 2006;86(Suppl 4):S202-209.

7. Christiansen OB, Andersen A-MN, Bosch E, et al. Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril. 2005;83:821-839.

8. Jauniauz E, Farquharson RG, Christiansen OB, et al. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod. 2006;21:2216-2222.

9. Practice Committee, American Society for Reproductive Medicine. Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss. Fertil Steril. 2006;86(Suppl 4):S226-227.

10. Practice committee, American Society for Reproductive Medicine. Multiple pregnancy associated with infertility therapy. Fertil Steril. 2006;86(Suppl 4):S106-110.

11. Practice Committee, Society for Assisted Reproductive Technology and the Practice Committee of the American Society for Reproductive Medicine. Guidelines on number of embryos transferred. Fertil Steril. 2006;86(Suppl 4):S51-52.

12. Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive Technology. Preimplantation genetic diagnosis. Fertil Steril. 2006;86(Suppl 4):S257-258.

13. Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive Technology. Ovarian tissue and oocyte cryopreservation. Fertil Steril. 2006;86(Suppl 4):S142-147.

14. Ethics Committee of the American Society for Reproductive Medicine. Fertility preservation and reproduction in cancer patients. Fertil Steril. 2005;83:1622-1628.

Dr. Adamson reports no financial relationships with any company whose products are mentioned in this article. He receives grant/research support from IBSA, Serono, and ViaCell and is a consultant to ViaCell.

Genetic component likely. The risk of recurrent pregnancy loss in first-degree relatives of women with unexplained repeated pregnancy loss who have normal chromosomes is approximately 6 times higher than the risk in the background population, suggesting a polygenic mode of inheritance.^7,8

Other possible causes include low plasma folate levels, which have been associated with an increased risk of first-trimester pregnancy loss. Environmental toxins such as ionizing radiation, organic solvents, alcohol, mercury, and lead are confirmed causes of recurrent pregnancy loss; hyperthermia is a suspected cause.⁸

Recommended evaluation

Investigations that have been proven in many studies include:

HSG, hysteroscopy, and sonohysterography
karyotyping of the couple
measurement of thyroid hormone
hemoglobin A1C and serum glucose assessment
activated partial thromboplastin time, dilute Russell viper venom time, and lupus anticoagulant assessment
measurement of immunoglobulin G and immunoglobulin M anticardiolipin antibodies
test for factor V Leiden mutation

Tests that are possibly useful include assessment of androgens and FSH in women with irregular periods.⁷

Examine products of conception?

Although it is routine practice to send products of conception for histologic examination, mainly to exclude a gestational trophoblastic disorder, the usefulness of this practice is unclear.⁸ In couples with recurrent pregnancy loss, chromosomal analysis of the products of conception indicates that a normal conceptus karyotype in a previous pregnancy is a predictor of a higher rate of miscarriage in a subsequent pregnancy.⁸ When stratified by maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with recurrent pregnancy loss, compared with controls.⁸ The cost-effectiveness of karyotyping is therefore unclear.

High levels of homocysteine (ie, hyperhomocysteinemia) can be associated with recurrent pregnancy loss. Among genetic causes is polymorphism at position 677 in the methylene tetrahydrofolate reductase (MTHFR) gene, which is often evaluated to rule out this condition.

Infections with bacteria, viruses, or parasites can all interfere with early pregnancy development, but none seem to be a significant cause of recurrent pregnancy loss.⁸ Testing is most useful in the context of an acute infectious episode.

Can recurrent loss be treated?

The hallmark of treatment is empathetic care, along with counseling emphasizing the complexity of this condition. Any endocrinologic, anatomic, or other abnormality that is identified during evaluation should be treated, if possible.

Progesterone supplementation is not proven treatment. This therapy is commonly prescribed but has not been proved to improve live birth rates.

Prednisone, aspirin, and NSAIDs have no benefits but potential risks and should not be used.

Current immunologic therapies for recurrent pregnancy loss have no sound scientific basis, except for the use of heparin and aspirin in patients with well-documented antiphospholipid antibodies.⁷ Specifically, intravenous immunoglobulin remains unproven, is experimental, and should be provided only in approved research settings.⁹ Paternal leukocyte immunization does not work, has been proscribed by the US Food and Drug Administration, and should be avoided.

Careful counseling and education of the patient about the history, pathophysiology, testing, test results, and treatment of recurrent pregnancy loss are necessary. Women with subfertility who have taken a long time to conceive should be treated empirically with ovarian stimulation in an attempt to shorten the time to conception.

Singleton births can be encouraged without jeopardizing IVF, ART

Multiple gestations have increased over the past 15 years, largely because of:

ovulation induction for management of oligo-ovulation
superovulation to produce more than 1 ovulated egg for fertility treatments
assisted reproductive technologies (ART), in which more than 1 embryo is replaced to increase the pregnancy rate

Approximately 40% of triplet and higher-order pregnancies have resulted from ovulation induction and superovulation; 40% result from ART; and 20% occur spontaneously.¹⁰ Variables that increase the risk of higher-order pregnancies include the infertile couple’s sense of urgency, competitive pressures among IVF clinics, and inadequate or absent health-care insurance.

Multiple gestations are a bad idea

Risks include a higher complication rate for gravidas and fetuses, as well as higher short- and long-term costs to patients and society. It is therefore important to reduce the incidence of multiple gestation associated with fertility treatments.¹⁰

How to reduce the likelihood of multiple fetuses

Closely monitor cycles involving ovulation induction and superovulation for efficacy and safety, to avoid ovarian hyperstimulation and reduce the risk of multiple gestation. Although attempts to limit multiple gestation during ovulation induction or superovulation using ultrasonographic criteria and serum estradiol limits have been ineffective,¹⁰ it is my opinion that we should err on the side of conservatism, even though the optimal parameters for doing so have not been determined by high-quality trials. I recommend that hCG or IUI be avoided if more than 4 mature follicles (>15 mm) or 6 large follicles (>12 mm) are present on a sonogram, and the couple should be instructed to refrain from intercourse.
Focus on the objective of a single healthy baby as the optimal outcome. Data published by the Society for Assisted Reproductive Technology (SART) clearly demonstrate the clinical impact of a reduction in the number of embryos transferred, which reduced triplet pregnancy rates in 2005 to less than half the rate in the late 1990s. Fewer embryos are transferred today than just a few years ago, and the trend is continuing. This will help reduce the triplet rate further and also reduce twin pregnancies. In the past 6 months, guidelines have recommended replacement of only 1 blastocyst at day 5 or 1 to 2 embryos at day 3 in women under age 35 with a favorable prognosis.