In Vitro Fertilization
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 Problem
Infertility 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 thenumber 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.2 Several
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.
From the Division of Reproductive Endocrinology and
Infertility, University of Iowa School
of Medicine, Iowa
City. Address reprint requests to Dr. Van Voorhis at the Department
ofObstetrics and Gynecology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa
City, IA 52242,
or at brad-van-voorhis@uiowa.edu. N Engl J Med 2007 -86.
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 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 (Fig. 1) involves ovarian stimulation, egg retrieval (see
video in the Supplementary Appendix, 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 byculturing
eggs and sperm together or by means of the newer procedure of intracytoplasmic
sperm injection (Fig. 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
