Infertility, not its treatment, the likely cause of birth complications after IVF

Published 23 January 2019

Large registry study finds lighter birth weight and higher prematurity rates observed after IVF largely attributable to factors other than treatment.

A recent report in The Lancet has analysed data obtained from Finnish registries on 65,723 babies born between 1995 and 2000 aiming to investigate neonatal risks associated with assisted reproduction.(1) Their overall results from between-family and within family analyses found that the lighter birth weight and higher prematurity rates observed after ART were largely attributable to factors other than the treatments. These results are consistent with some - though not all - earlier findings but continue to support the safety of ART for the newborn.

The authors performed two separate analyses - to distinguish between risks attributable to underlying health problems associated with the need for fertility treatment, and risks directly related to fertility procedures, such as hormonal stimulation, in vitro embryo culture, or cryopreservation.

In between-family analyses, the neonatal outcomes of 62,947 babies born following natural conception were compared with those of 2776 babies conceived through ART (ovulation induction, IUI, IVF or ICSI). Children conceived with fertility treatments were on average 266 g lighter and had a 9.75% higher risk of being born prematurely. After adequate adjustments based on risk factors - such as maternal age at birth, smoking during pregnancy, and household income - babies born following fertility treatments still had a lighter birth weight by 60 g and were more likely to be born prematurely (2.15% difference) when compared to natural conceptions.

In within-family analyses, 620 siblings born following natural conception were compared with 625 siblings born after ART. The unadjusted associations were weaker and identified a 137 g difference in birth weight and 4.04 percentage points difference in preterm delivery. However, these differences completely lost relevance when analyses were adjusted for known risk factors of adverse neonatal outcomes.

The conclusion of this study suggests that higher risks of adverse birth outcomes following ART are likely to be attributable to factors other than the treatment itself. These findings complement the mixed evidence from two previous cohort studies of similar design conducted in Scandinavia.

The Norwegian cohort, reporting in 2008, compared the neonatal outcome of 8229 babies born following IVF/ICSI with those of 1,200,922 babies born after natural conception. IVF/ICSI was associated with lighter birth weight of 25 g, shorter duration of gestation by two days and increased risks of small-for-gestational age (OR 1.26) and perinatal death (OR 1.31) in its between-family analyses.(2) In addition, within-family analyses of 2546 women who conceived following IVF/ICSI or naturally revealed no difference in birth weight or gestational age between the modes of conception. Authors attributed the adverse outcomes after ART to the factors leading to infertility, rather than to factors related to the treatment.

The Danish cohort study of 2011 included 13,692 pairs of siblings conceived by IVF/ICSI or naturally. Babies born after IVF/ICSI were 65 g lighter, had shorter gestation by 1.4 days and a higher risk of low birth weight (OR 1.4) and preterm birth (OR 1.3) than their naturally conceived siblings. Additional analyses revealed heavier birth weight by 167 g after frozen embryo transfers than fresh. However, in contrast to both the Finnish and Norwegian studies, the Danish investigators did attribute the adverse outcomes following ART to the technology itself. 'When differentiating between order and mode of conception,' they wrote, 'it seems that assisted reproductive technology plays a role in mean birth weight and risk of low birth weight and preterm birth.'

In digesting the data, it's worth noting that assisted reproduction treatments differ between countries by important variables such as stimulation protocols, gonadotrophins used, fertilisation techniques, culture media and embryo storage. In addition, findings from IVF/ICSI cycles conducted over 20 years ago may not be totally applicable today because of changes in practice. Cycle outcomes should continue to be monitored strictly to provide ongoing safety data.

1. Goisis A, Remes H, Martikaenen P, et al. Medically assisted reproduction and birth outcomes: a within-family analysis using Finnish population registers. Lancet 2019.

2. Romundstad LB, Romunstad PR, Sunde A, et al. Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study. Lancet 2008; 372: 737-743.

3. Henningsen AK, Pinborg A, Lidegaard O, et al. Perinatal outcome of singleton siblings born after assisted reproductive technology and spontaneous conception: Danish national sibling-cohort study. Fertil Steril 2011; 95" 959-963.