Congenital Malformations and ART: Risks and Implications for Prenatal Diagnosis and Fetal Medicine

Abstract & Commentary

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

Dr. Hobbins reports no financial relationship to this field of study.

Synopsis: Incidence of some types of congenital anomalies after ART is increased to the point where heightened surveillance is indicated.

Source: Williams C, et al. Congenital malformations after assisted reproduction: Risks and implications for prenatal diagnosis and fetal medicine. Ultrasound Obstet Gynecol 2010;35:255-259.

Louise Brown, the first baby conceived through in-vitro fertilization (IVF), was born in England in 1978. Since then, there has been a steady rise in births conceived through various forms of assisted reproductive technology (ART), to a point where about 25% of live births now in the United Kingdom have been conceived through ART. In the United States, 1% of babies born in 2006 were through ART.

Unfortunately, pregnancies conceived through ART have been shown to be associated with higher rates of various complications, and very recently a group of British investigators summarized the data available on one facet — congenital anomalies.

In this review, two meta-analyses were cited, showing a 30% higher rate of major congenital anomalies in children born after ART than those conceived spontaneously. This is in sync with a very recent Swedish registry study,1 involving 16,000 ART children, which showed a 42% increase in congenital anomalies. The largest increase has been in cardiovascular anomalies (a 4-fold risk).2 Specifically, septal defects were the most common anomalies seen after ART (odds ratio, 2.6; 95% confidence interval, 2.2-3.1),1 but the greatest rise in ART-conceived pregnancies, first noted 20 years ago and reiterated by Williams et al, occurred with transposition of the great vessels (a 4-fold increase).

Other fetal abnormalities included neural tube defects (5-fold increase),1 oral facial defects (2.5-fold increase),1 and syndromes representative of defects in genetic imprinting such as Beckwith-Wiedemann syndrome.3 Interestingly, hypospadias in male infants was predominantly increased in those conceived through intracytoplasmic sperm injection (ICSI).4 The authors of the editorial point out that most of the studies in the review corrected for maternal age, parity, and multiple gestation (all of which can increase the risk of anomalies).

The nagging question of why this is happening is difficult to answer. Yes, women who are having difficulty getting pregnant are more prone to have offspring with anomalies, but adding ART to the mix seems to further accelerate this tendency.5 Multiple pregnancies are more often associated with anomalies, but when comparing apples to apples (ART multiples with spontaneously conceived multiples, and ART singletons with non-ART singletons), there still are significant differences. So the problem seems to be related more to the process, rather than the host.

Commentary

Many thousands of previously infertile couples have been helped by various forms of ART. However, this wonderful technology has come with a price (literally and figuratively). It is now clear that the women or insurance companies willing to shell out about $12,000 per try at IVF will also have to deal with the fallout, which involves a 48% chance of twins (2006 CDC statistics)6 — along with the accompanying increased rates of prematurity, low birth weight, fetal growth restriction, and cerebral palsy. Even in singletons, the rates of these complications after ART are higher than in spontaneously conceived singletons. Now it is clear that congenital anomalies are also part of this fallout.

The way to prevent complications from multiple gestations is to prevent multiple gestations from happening, and it is heartening that between 2004 and 2006 the rate of twins leveled off (32/1000 to 32.1/1000 live births).6However, a 48% rate of twins with ART is too high. Regarding fetal anomalies, since it is unclear what is responsible for their greater presence after ART, it will be difficult to prevent them. However, at least we should be able to identify them early in pregnancy or, better yet, to assure these already wired patients that their babies do not have any of the above anomalies. Since today's prenatal diagnostic motto is "the earlier the better," a very thorough first trimester scan should allow the provider to identify fetal number (and if twins, to determine chorionicity). Since there is a relationship between the size of the nuchal translucency (NT) and cardiac anomalies, an NT assessment at 11-14 weeks can be extremely helpful. A recent study shows that by adding a Doppler evaluation of the ductus venosus at that time, 50% of cardiac anomalies can be screened in.7 Today the ultimate diagnosis can often be made with a full fetal echocardiogram by transvaginal ultrasound by 15 weeks. Obviously, should this exam be incomplete, it can be accomplished later with excellent sensitivity. Open neural tube defects should be identified with virtually 100% accuracy by ultrasound by 16-18 weeks and Beckwith-Wiedemann syndrome can be suspected when an omphalocoele is seen after 12 weeks. Hypospadias can be detected effectively with 3-D ultrasound in the second trimester.

So, ART patients with singletons or multiple gestations can benefit from:

  • An early first trimester scan to assess the viability and number.
  • An NT evaluation with a Doppler assessment of the ductus, if possible.
  • An early attempt at 12-15 weeks at a transvaginal fetal echocardiogram, if either the NT or ductus is abnormal.
  • A detailed ultrasound survey of the fetal anatomy, with markers for Down syndrome if the patient is > age 34 with a singleton or 32 years old with di/di twins.
  • A full fetal echocardiogram at 20-24 weeks for all.

Note: Since the incidence of vasa previa is about 1 in 290 pregnancies conceived through IVF,8 an attempt should be made to identify the location of the placental cord insertion in one of the above exams.

If the results from these examinations are unremarkable, then these patients can be reassured that the likelihood of their fetuses having an anomaly is extremely small.

References

  1. Kallen B, et al. In vitro fertilization (IVF) in Sweden: Risk for congenital malformations after different IVF methods. Birth Defects Res A Clin Mol Teratol 2005;73:162-169.
  2. Koivurova S, et al. Neonatal outcome and congenital malformations in children born after in-vitro fertilization. Hum Reprod 2002;17:1391-1398.
  3. Lancaster PAL. Congenital malformations after in-vitro fertilization. Lancet 1987;2:1392-1393.
  4. Bonduelle M, et al. Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999). Hum Reprod 2002;17:671-694.
  5. Zhu JL, et al. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006;333:679-681.
  6. Martin JA, et al. Birth: Final data for 2006. Natl Vital Stat Rep 2009;57:1-102.
  7. Martinez JM, et al. Abnormal first trimester ductus venosus blood flow: A marker for cardiac defects normal karyotype and nuchal translucency. Ultrasound Obstet Gynecol 2010;35:267-272.
  8. Schachter M, et al. In vitro fertilization is a risk factor for vasa previa. Fertil Steril2002;78:642-643.