This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.A 37-year-old woman who has never been pregnant and her 40-year-old husband have been attempting to conceive a child for the past 3 years. An infertility evaluation has shown no cause for the difficulty. She is ovulating regularly, and a hysterosalpingogram shows that her reproductive tract is anatomically normal. He has a normal sperm count; he has not fathered any children. They are frustrated and want to proceed with in vitro fertilization. What should you advise?THE CLINICAL PROBLEMInfertility is common — approximately 10% of couples have difficulty conceiving a child. In young, healthy couples, the probability of conception in one reproductive cycle is typically 20 to 25%, and in 1 year it is approximately 90%.1 An evaluation is commonly recommended after 1 year of unprotected intercourse without conception, the standard clinical definition of infertility.Many infertility specialists are surprised by the number of otherwise highly educated older couples with unrealistic expectations of fertility. The negative effect of a woman's age on fertility cannot be overemphasized. As women age, fertility declines and the rate of miscarriages increases. In addition, the rate of pregnancy after treatment for infertility drops more rapidly in women who are over the age of 35 years than in younger women. Thus, some clinicians argue that an infertility evaluation should begin after six cycles of unprotected intercourse in women older than 35 years.2Several societal factors may contribute to infertility related to aging in women. In the United States, there have been increases over time in the mean maternal age at first birth (25.1 years in 2002 vs. 21.4 years in 1968) and in the mean age of women delivering a child (27.3 years in 2002 vs. 24.9 years in 1968).3 This trend toward delayed childbearing in part reflects an increasing emphasis on career and educational goals as well as a later mean age at first marriage.4 In addition, the increased availability of effective methods of birth control makes it more likely that earlier unplanned pregnancies will be avoided.
STRATEGIES AND EVIDENCE
Regardless of the cause of infertility, the treatment that leads to the highest pregnancy rate per cycle is in vitro fertilization (IVF). Since its inception in 1978,5 there has been a remarkable increase in the numbers of IVF cycles worldwide. Approximately 1 in 50 births in Sweden, 1 in 60 births in Australia, and 1 in 80 to 100 births in the United States now result from IVF. In 2003, more than 100,000 IVF cycles were reported from 399 clinics in the United States, resulting in the birth of more than 48,000 babies.
The process of IVF (Figure 1FIGURE 1
The Process of IVF.
) involves ovarian stimulation, egg retrieval (see video, available with the full text of this article at www.nejm.org), fertilization, embryo culture, and the transfer of embryos to the uterus. The fertilization of eggs can be achieved by culturing eggs and sperm together or by means of the newer procedure of intracytoplasmic sperm injection (Figure 1). As compared with the rate of pregnancy associated with routine IVF, this procedure has been proved to increase the rate of pregnancy only for couples with severe male-factor infertility, but it is now used in the majority of IVF cycles.
Screening before IVF
Before IVF, most couples will have had a standard infertility evaluation, including a semen analysis; assessment of the female reproductive tract by means of hysterosalpingography, transvaginal ultrasonography, or both; and tests to detect ovulation. Because there is great variation in ovarian responsiveness and fertility at a given chronologic age, additional testing of ovarian reserve is commonly performed in women before they undergo IVF. A reduced ovarian reserve is manifested by a diminished ovarian response to medications for ovulation stimulation, resulting in fewer eggs retrieved, fewer embryos, and a lower pregnancy rate. Many women with unexplained infertility are found to have a reduced ovarian reserve when tested.
A reduced ovarian reserve is commonly diagnosed on the basis of either an elevated serum follicle-stimulating hormone level (e.g., >12 mIU per milliliter) on cycle day 3 or transvaginal ultrasonographic findings of a low ovarian volume (e.g., <3 ml per ovary) or few antral follicles (e.g., <10 antral follicles between 2 and 10 mm in diameter). These tests have less than ideal characteristics.6,7 The positive predictive value of abnormal test results is lower among women younger than 35 years of age than among older women, and women older than 40 years of age have a poor chance of achieving pregnancy even with normal test results. All tests are better at predicting ovarian responsiveness to gonadotropins than at predicting pregnancy. Nevertheless, tests of ovarian reserve provide some prognostic information, and the results are sometimes used to select the ovarian-stimulation protocol.
Benefits of IVF
By law, all IVF clinics in the United States report outcomes to the Centers for Disease Control and Prevention (CDC), and national and clinic-specific outcomes are available on the CDC Web site (www.cdc.gov/ART/ART2003/index.htm). In 2003, the clinical pregnancy rate per cycle for IVF cycles with fresh, nondonor eggs was 34% in the United States. Because of subsequent miscarriages, the actual live-birth rate per cycle was 28%. Thus, although IVF is considered to be highly effective in relation to other treatments and outcomes have steadily improved over time, the majority of IVF cycles still do not result in pregnancy.
The effect of a woman's age on the outcomes of IVF with her own eggs is striking (Figure 2FIGURE 2
Effect of a Woman's Age on the Rate of Live Births per IVF Embryo Transfer.
).8 The rate of live births per embryo transfer in women who are 34 years of age or younger is between 40 and 49%. Thereafter, the live-birth rate drops by 2 to 6% for each 1-year increase in chronologic age. By the time a woman is 43 years of age, the live-birth rate is only 5%. Concomitantly, the miscarriage rate increases dramatically, and by 43 years of age, 50% of pregnancies conceived with IVF result in miscarriage.
In contrast, IVF with the use of donor eggs from young women is highly successful, and the rate of pregnancy appears to vary little according to the age of the recipient (Figure 2). The average live-birth rate per embryo transfer for donor-egg cycles is approximately 50%, indicating that the reduced rate of pregnancy associated with aging is a direct result of diminished ovarian function and egg quality and is not due to a reduction in endometrial receptivity.
The use of cryopreserved embryos may be cost-effective, since ovarian stimulation is not needed.9 In general, however, the rate of live births per embryo transfer is lower with cryopreserved embryos than with fresh embryos, indicating some detrimental effect of the cryopreservation and thawing process. In addition to their highly publicized use as a source of stem cells, residual cryopreserved embryos can be donated to other infertile couples.10
Risks of IVF
Multiple Gestations
In general, the transfer of more than one embryo results in a higher rate of pregnancy than single-embryo transfer, but it is also associated with a high risk of multiple gestations. Multiple births are the most frequent complication of IVF, contributing to a virtual epidemic of multiple gestations in the United States.11 Of pregnancies conceived by means of IVF in 2003, 31% were twin gestations and 3% were triplet or higher-order gestations, as compared with a 1% rate of spontaneous multiple gestations.12,13
Multiple gestations account for 3% of all live births nationally but are linked to 23% of early preterm births (<32 weeks of gestation) and 26% of very-low-birth-weight infants (<1500 g).14 Premature birth, in turn, is associated with long-term pulmonary and neurologic consequences.15 Although children from triplet and higher-order multiple gestations are at greatest risk, one study showed that IVF twins were more likely than IVF singletons to be admitted to a neonatal intensive care unit, to require surgical intervention, and to have special needs and poor speech development.16 The mothers of these IVF twins gave lower ratings for their children's general health than did the mothers of the IVF singletons, and twin births were associated with more marital stress.
As compared with women who carry one fetus, women who carry multiple fetuses have a greater need for bed rest and higher risks of premature labor, hypertension, postpartum hemorrhage, cesarean delivery, and, although rare, death. Excess hospital costs for multiple births resulting from IVF cycles have been estimated at $640 million per year in the United States.17
To reduce the incidence of multiple gestations associated with IVF, the number of embryos transferred is limited by law or by insurance plans in many countries, but it remains largely unregulated in the United States. The American Society of Reproductive Medicine has issued voluntary guidelines that have resulted in the transfer of fewer embryos in the United States. This reduction, in turn, has led to a lower rate of triplet and higher-order gestations; however, the rate of twin gestations remains high. The rate of monozygotic twinning (the spontaneous splitting of an embryo) is also increased with IVF (3.2%, vs. 0.4% among women in the general population).18
One obvious way to reduce multiple gestations is to transfer a single embryo. The transfer of a single, fresh, cleavage-stage embryo (2 or 3 days old), followed by the transfer of a single cryopreserved embryo in women who do not conceive initially, can be nearly
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