Perinatal Mortality and Assisted Reproductive Technologies: A Meta-Analysis

Abstract & Commentary

Some European studies indicate that 2-3% of pregnancies occur through assisted reproductive techniques (ART) while US statistics suggest that about 0.9% of all pregnancies result from ART. Although there has been much written about the profusion of multiple gestations secondary to ART, little attention has been directed toward singleton pregnancies. However, very recently an article appeared by Jackson and colleagues that explored the relationship between ART and adverse pregnancy outcomes in singleton pregnancies.

The group searched the literature for studies dealing with ART in singleton pregnancies and out of 1400 studies found since 1978, only 15 satisfied Jackson et al’s rigid criteria for analysis. ART pregnancies consisted of ovulation induction, egg retrieval, and in vitro fertilization (IVF) with intrauterine transfer of fresh embryos. These pregnancies were compared with singletons that were conceived spontaneously and, most importantly, were matched according to parity and maternal age.

They found a statistically significant increase in the ART group with regard to perinatal mortality (OR, 2.2; 95% CI, 1.6-3.0), preterm delivery (OR, 2.0; 95% CI, 1.7-2.2), low birth weight (OR, 1.8; 95% CI, 1.4-2.2), and very low birth weight, defined as below 1500 grams, (OR, 2.7; 95% CI, 2.3-3.1). Last, they found an increase in SGA of 1.6 (95% CI, 1.3-2.0).

Comment by John C. Hobbins, MD

In previous OB/GYN Clinical Alerts, we have touched upon the incredible rise in multiple gestations from ART and its public health effect. For example, the rate of twins has risen from 1 in 80 to 1 in 40 over the last few years. According to the CDC, in 2001, the incidence of multiple births after ART was 42% for fresh donor eggs and 36% for insemination of the patient’s eggs. In some states more than 60% of live births from ART were multiple gestations. According to a 1995 NIH registry, multiple births contribute 22% of very low birth weight babies to neonatal intensive care units (NICU’s) and half of these result from ART. Also, as pointed out before in another OB/GYN Clinical Alert, twins are 6 times more expensive to manage than singletons from the beginning of pregnancy to neonatal discharge. Triplets are 11 times more expensive.

Now we find that singletons conceived through IVF have, on average, a 2-fold greater chance of dying, of being born preterm or very preterm, and of being small-for-gestational age (SGA).

So, what is going on here? Is the adverse pregnancy outcome related to the treatment itself or an inherent predisposition towards these problems in patients requiring specialized fertility help? One recent study showed that, when compared with spontaneously conceived singleton pregnancies, there was a 50% increase in preterm birth with "low tech" methods (intrauterine insemination) and a 2-fold increase in preterm birth with the "high tech" IVF. Others have found that seemingly infertile patients conceiving without treatment had a higher rate of perinatal loss and delivered very low birth weight singletons more frequently than those who had no fertility problems.

Putting this together, patients experiencing trouble conceiving without treatment have an increasingly higher rate of adverse pregnancy outcome to start with, and the more complicated the treatment to get these patients pregnant, the greater the risk of fetal mortality and morbidity.

Interestingly, the above meta-analysis from Jackson et al indicated more inductions of labor and Cesarean sections were done in the ART pregnancies. They felt that these "special" pregnancies might be more subject to maternal pressure and provider intervention, "thus leading to iatrogenic preterm delivery and low birth weight." However, this would not account for the increase in very low birth weight, perinatal mortality or SGA.

Women having trouble conceiving may not sail blithely through pregnancy without adversity, and it is unclear whether it is the environment into which these embryos alight, or the ends to which these patients will go to conceive, that are the responsible factors. Whatever the cause, each patient should be properly apprised of the results of this study, as well as of the data on twins, before entering infertility treatment.

Suggested Reading

  • Jackson RA, et al. Obstet Gynecol. 2004;103:551-563.
  • Wang JX, et al. Hum Reprod. 2002;17:945-949.
  • Draper ES, et al. Lancet. 1999;353:1746-1749.
  • McElrath TF, et al. Obstet Gynecol. 1997;90(4 Pt 1): 600-605.
  • Hashimoto LN, et al. Am J Obstet Gynecol. 2004;190: 401-406.
  • Lemons JA, et al. Pediatrics. 2001;107:E1.

John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.