Correspondence

Low and Very Low Birth Weight after Use of Assisted Reproductive Technology

N Engl J Med 2002; 347:1451-1452October 31, 2002

Article

To the Editor:

Schieve et al. (March 7 issue)1 suggest that the observed increase in the risk of low birth weight among singleton infants conceived with assisted reproductive technology is more likely to be due to the treatment than to an underlying condition in infertile women. They report that a subgroup analysis of couples with male-factor infertility supports this contention. However, the use of this group to represent women who are free of infertility-related conditions may be inaccurate, since this diagnosis does not exclude the presence of other causal factors. Indeed, according to 1999 data from the Society for Assisted Reproductive Technology, 17.5 percent of couples had multiple factors that included both female and male factors.2 Moreover, the diagnosis of male-factor infertility has been used loosely and may be nonspecific, as demonstrated by Guzick et al., who showed that the traditional criteria used in the evaluation of semen are not diagnostic of male infertility.3 Analysis of the data with the use of more specific diagnoses of maternal conditions, such as tubal-factor infertility, could also help in the evaluation of the authors' conclusions.

George Kovalevsky, M.D.
Christos Coutifaris, M.D., Ph.D.
University of Pennsylvania Medical Center, Philadelphia, PA 19104
gkovalevsky@hotmail.com

3 References

1. 1

   Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731-737
   Full Text | Web of Science | Medline

2. 2

   1999 Assisted reproductive technology success rates: national summary and fertility clinic reports. Atlanta: CDC Division of Reproductive Health, December 2001:26.
   

3. 3

   Guzick DS, Overstreet JW, Factor-Litvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388-1393
   Full Text | Web of Science | Medline

To the Editor:

Schieve et al. observed an increased rate of multiple births in pregnancies that resulted from in vitro fertilization, attributable to the transfer of multiple embryos, but they did not find a greater risk of low birth weight in multiples conceived with in vitro fertilization than in multiples conceived spontaneously. In contrast, for singletons, in vitro fertilization was associated with a higher risk of low birth weight than was spontaneous conception. Hence, although it seems counterintuitive, twinning appeared to provide some relative protection from the effect of in vitro fertilization on the risk of low birth weight.

An alternative explanation, however, is that the transfer of multiple embryos during in vitro fertilization results in a high ratio of dizygotic twins to monozygotic twins.1 Hence, after controlling for the confounding effect of zygosity, we should expect to observe that the relative risk of low birth weight in twins conceived with in vitro fertilization is higher than that in twins conceived spontaneously — in accordance with the findings among singletons. Such a finding would be consistent with recent work showing that dizygotic twins conceived with in vitro fertilization had shorter gestations, lower birth weights, and lower Apgar scores than dizygotic twins conceived spontaneously.2 Thus, there is a continued need to identify and classify sources of risk associated with in vitro fertilization.

Michael J. Davies, M.P.H., Ph.D.
Adelaide University, Adelaide 5005, Australia
michael.davies@adelaide.edu.au

2 References

1. 1

   Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP, Willemsen WN, Visser GH. Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch university hospitals. Hum Reprod 2000;15:935-940
   CrossRef | Web of Science | Medline

2. 2

   Lambalk CB, van Hooff M. Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries. Fertil Steril 2001;75:731-736
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Kovalevsky and Coutifaris are concerned that a diagnosis of male-factor infertility does not exclude the presence of other causal factors. For the years covered in our study, infertility diagnoses were ascertained through the abstraction of clinic records. Each infertility clinic was asked to list the primary infertility diagnosis and was given the option of listing a secondary diagnosis. We agree that this system has limitations. Diagnostic protocols most likely varied among the more than 300 clinics included in the registry, and underreporting of additional diagnoses may have occurred. We limited our analyses of infants born to couples with male-factor infertility to those born to couples with a primary diagnosis of male-factor infertility and no reported secondary diagnosis (a total of 2759 couples, or 66.6 percent of the couples with a primary diagnosis of male-factor infertility). Thus, our findings for this subgroup suggest that the risk of low birth weight is higher than would be expected for infants conceived with assisted reproductive technology whose mothers were unlikely to have an underlying infertility-related disease.

In the interest of brevity, we did not present separate findings according to maternal diagnosis (such as tubal-factor infertility), but we have analyzed our data to examine this issue. The rate of low birth weight among singletons conceived by couples with tubal-factor infertility was 13.5 percent, as compared with 5.7 percent in the general population.

Dr. Davies suggests that our results for twins may have been biased toward the null hypothesis because we were unable to classify either the twins conceived with assisted reproductive technology or the twins in the general population according to zygosity. We agree. It is likely that a larger proportion of twins in the general population was monozygotic and that these twins may have been at higher risk for fetal growth restriction. For this reason, as well as for those outlined in our article, we do not believe that the lack of association between assisted reproductive technology and low birth weight in twins is inconsistent with a possible treatment effect.

In sum, our findings among singletons are suggestive of an effect of assisted reproduction technology on the risk of low birth weight. However, because our data were collected retrospectively from a large, population-based registry, we had only limited information on patients' medical conditions. A study that prospectively follows pregnancies that result from the use of assisted reproductive technology is needed in order to address this important issue more definitively.

Laura A. Schieve, Ph.D.
Susan F. Meikle, M.D.
Cynthia Ferre, M.S.
Centers for Disease Control and Prevention, Atlanta, GA 30341
ljs9@cdc.gov

Citing Articles (2)

Citing Articles

1. 1

   Gianpiero D Palermo, Queenie V Neri, Takumi Takeuchi, Jane Squires, Fred Moy, Zev Rosenwaks. (2008) Genetic and epigenetic characteristics of ICSI children. Reproductive BioMedicine Online 17:6, 820-833
   CrossRef

2. 2

   (2003) Current Awareness in prenatal diagnosis. Prenatal Diagnosis 23:2, 179-185
   CrossRef