Infertility is defined by the failure to conceive after 12 months of unprotected
intercourse, and it affects an estimated 10 percent of the population of reproductive age
in the United States.1 Medical approaches to overcoming infertility include artificial
insemination and stimulation of ovulation with medication. More invasive techniques
requiring the use of assisted reproductive technology involve the external manipulation of
both egg and sperm and include in vitro fertilization and intracytoplasmic sperm
injection. When successful, the use of assisted reproductive technology dramatically
increases the risk of multiple births2 and, in so doing, increases the risk of low birth
weight (a birth weight of less than 2500 g). It is unclear, however, whether the use of
assisted reproductive technology also increases the risk of low birth weight among
singleton infants or increases the risk of birth defects.
Two studies in this issue of the Journal3,4 bear directly on these questions. In one
study, Schieve et al.3 compared the rate of low birth weight among liveborn infants
conceived with procedures involving assisted reproductive technology in the United States
in 1996 and 1997 with the rate in the general population. A total of 23 percent of 137,000
procedures resulted in live births. In the 57 percent of deliveries that involved multiple
births, low birth weight was predictably common, but it was no more common among multiples
conceived with assisted reproductive technology than among those in the general
population.
The situation was different among singletons. Although there was a slight increase in
the risk of low birth weight among preterm singletons, the risk of low birth weight among
term singletons conceived with assisted reproductive technology was 2.6 times that in the
general population (6.5 percent vs. 2.5 percent). The risk did not vary substantially
according to the cause of infertility. Because the risk was elevated among infants who had
been carried by apparently healthy women, the authors suggest that the excess rate of low
birth weight may be attributable to the use of these forms of technology.
Information on birth defects is not as simply or systematically obtained as data on
birth weight. Past studies of birth defects have been limited by potential overreporting
or underreporting of defects among infants conceived with assisted reproductive technology
and by the lack of similarly screened comparison groups.5,6,7,8 In a second study in this
issue, Hansen et al.4 combined data from three comprehensive registries in Western
Australia: one of procedures involving assisted reproductive technology, one of
deliveries, and one of birth defects. By one year of age, one or more major birth defects
had been identified in 9.0 percent of babies conceived with assisted reproductive
technology, as compared with 4.2 percent of those who were conceived naturally. Rates were
similar for in vitro fertilization and intracytoplasmic sperm injection. Excess defects
were observed among multiple, singleton, and term singleton births. Increases in risk with
the use of assisted reproductive technology were found in most categories of defects, and
the differences were significant for musculoskeletal and cardiovascular defects.
Both studies benefited from laws requiring reporting of procedures involving assisted
reproductive technology, so problems of incomplete or selective reporting were minimized.
Schieve et al. distinguished true singleton pregnancies from those that had originated as
multiple gestations and also controlled for other factors, such as age and parity. Hansen
et al. used a common scheme for the classification of birth defects in all infants. By
having an independent pediatrician identify defects that might have been detected only
because of increased surveillance, the authors demonstrated that enhanced detection did
not explain the excess rate of defects associated with assisted reproductive technology.
These findings will help infertile couples to evaluate the risks they and their
offspring might face if they choose to use assisted reproductive technology. However, an
important consideration is the absolute risk of these complications, rather than the
relative risk. The use of assisted reproductive technology appears roughly to double the
risk of having a term singleton with low birth weight or a child with a major birth
defect. However, the majority of couples who require assistance with reproduction will not
be affected, since according to these studies, the likelihood of having a term singleton
infant of normal birth weight is about 94 percent, and the likelihood of having an infant
who is free of major defects is about 91 percent.
Neither these nor previous studies7,8,9 identify the reason for these excess risks of
low birth weight and birth defects. In particular, they do not allow us to distinguish
whether these risks are due to the underlying infertility or to the drugs and procedures
used to overcome it. To infertile couples who desire pregnancy and require assisted
reproductive technology to achieve it, the distinction may be irrelevant.
But what determines the need for assisted reproductive technology? Although there is a
standard definition of infertility, other factors (such as a woman's age) influence the
decision to use such technology. Unfortunately, studies of assisted reproductive
technology rarely describe the eligibility criteria for the use of these procedures. This
limitation is complicated by the rapid growth in the use of assisted reproductive
technology. A recent news report noted that the number of in vitro fertilization
procedures in the United States increased by 37 percent between 1995 and 1998.10 The
growing numbers of fertility specialists and clinics have increased the competition for
clients, which has led to aggressive marketing of fertility services to referring doctors
and directly to consumers, as well as to reductions in costs, with some clinics offering
attractive financing programs.10
The studies in this week's issue focus on the outcomes of procedures performed in the
mid-1990s. Since neither report provided eligibility criteria for the use of assisted
reproductive technology, we must assume that their findings reflect the risks for couples
who met the criteria for the use of these procedures during those years. A real concern is
that the increased marketing of these services will lead to their use by couples who, in
previous years, would have waited longer before seeking help. We can expect that such
marketing will attract at least some couples who would have conceived without assisted
reproductive technology had they tried to conceive naturally for a few months longer.
Here is where questions of causality become critical. If infertility itself causes the
increased risks of low birth weight and birth defects, providing assisted reproductive
technology to couples who are not really infertile will involve stress, time, and money,
but the costs will not include an excess rate of low birth weight or birth defects. On the
other hand, if it is the drugs or procedures involved that lead to these complications,
then the use of assisted reproductive technology for couples who are not infertile would
result in unfortunate — and avoidable — excess risks of low birth weight and
birth defects.
For couples who are currently concerned about fertility, the messages seem clear. For
those in whom pregnancy could not otherwise occur, assisted reproductive technology offers
great hope, with risks of adverse outcomes that many would consider acceptable. However,
the risks demonstrated by Schieve et al. and Hansen et al. may not be acceptable for all
couples and must be considered as assisted reproductive technology is increasingly
marketed to health care providers and the public.
Allen A. Mitchell, M.D.
Boston University School of Public Health
Boston, MA 02118
References
1.Frequently asked questions about infertility. Birmingham, Ala.: American Society of
Reproductive Medicine, 2000-2001. (Accessed February 13, 2002, at
http://www.asrm.org/Patients/faqs.html.)
2.1999 Assisted reproductive technology success rates: section 2: ART cycles using
fresh, nondonor eggs or embryos. Atlanta: National Center for Chronic Disease Prevention
and Health Promotion. (Accessed February 13, 2002, at
http://www.cdc.gov/nccdphp/drh/art99/section2.htm.)
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birth weight in infants conceived with use of assisted reproductive technology. N Engl J
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born after intracytoplasmic sperm injection. Hum Reprod 1996;11:1558-1564.[Abstract]
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10.Kolata G. Fertility Inc.: clinics race to lure clients. New York Times. January 1,
2002:F1.