Pre-eclampsia now associated with trophectoderm biopsy

Published 22 August 2019

Following a flurry of studies suggesting maternal and neonatal complications in ART, a new cohort analysis finds a higher incidence of pre-eclampsia in pregnancies following PGT than without PGT.

Maternal and neonatal complications in ART have been a theme of several studies this year. First, a large randomised trial from China found an apparently increased risk of pre-eclampsia and placenta praevia associated with frozen embryo transfers.(1) Then this same risk was further suggested in a large cohort study from Japan in which pregnancies following FET in hormonally prepared cycles had a significantly higher risk of pregnancy hypertension and placenta accreta than in those following natural cycle transfers.(2)

Meanwhile, at ESHRE's Annual Meeting in Vienna study results from the large cohort of the Committee of Nordic ART and Safety (CoNARTaS) appeared to confirm earlier concerns that blastocyst transfer is indeed associated with a higher risk of preterm (before 37 weeks) and large-for-gestational-age births.(3) The analysis showed that the singletons born after fresh blastocyst transfer had a 23% higher risk of being large for gestational age than after cleavage stage transfer. The authors explained that in everyday terms this higher risk would mean an overall increase in incidence from 3.7% following cleavage-stage transfers to 4.3% following blastocyst transfers. The authors described this increase as 'small', noting a similarly small increase in the risk of preterm birth following the transfer of frozen blastocysts (though none was found after the transfer of fresh blastocysts).

The results suggest that blastocyst transfer does indeed carry a small but higher risk of obstetric complications than day-three transfers, which in Vienna prompted the CoNARTaS investigators to urge caution in the widespread use of blastocyst transfer - despite its unquestioned improvement in outcome rates.

Now, a further cohort study from a single centre in the USA (Stanford) has found a three-fold higher risk of pre-eclampsia in pregnant patients following trophectoderm biopsy for PGT than in those having IVF without biopsy and PGT.(4) The incidence of pre-eclampsia was 10.5% in the IVF + PGT group, and 4.1% in the IVF without PGT group. Similar incidences of placenta praevia and gestational diabetes were recorded, although there were no differences in neonatal rates of preterm birth, low birth weight, neonatal intensive care unit admission, or birth defects. The three-fold increase in the odds of pre-eclampsia in the IVF + PGT cohort persisted even when analysis was confined to only singleton live births (to minimise confounding from multiples).

However, the study, which was described by the authors as ' the largest and most extensively controlled study examining maternal and neonatal outcomes after trophectoderm biopsy', did not adjust for frozen embryo transfers, which the recent evidence noted above suggests may be a strong independent risk factor for hypertensive disorders in pregnancy. This omission is considered in an editorial accompanying the report, alongside the broader vulnerabilities of a retrospective observational study like this, which could never prove causation.(5) However, the editorial - as hinted in earlier studies before it - does describe this latest study as 'important' for raising the ' the biologically plausible question of whether trophectoderm biopsy might lead to aberrant placentation, resulting in adverse obstetric outcomes'.

Meanwhile, at the practical end of this study the editorial speculatively estimates that '1 of 16 patients who get PGT will experience preeclampsia as a result of that decision', but with no difference in overall neonatal outcomes. These risks, the editorial adds, 'might be interpreted very differently based on the indication for PGT' (ie, PGT-M, PGT-SR or PGT-A).

1. Wei D, Liu J-Y, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet 2019; 393: 1310-1318.

2. Saito K, Kuwashara A, Ishikawa T, et al. Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Hum Reprod 2019; doi:10.1093/humrep/dez079.

3. Obstetric and perinatal risks in 8,368 singletons and 1,167 twins conceived after fresh and frozen blastocyst transfers in the Nordic countries – a CoNARTaS collaboration. ESHRE Annual Meeting 2019; Abstract 0-035.

4. Zhang WY, von Versen-Hoynck F, Kapphahn KI. et al. Maternal and neonatal outcomes associated with trophectoderm biopsy. Fertil Steril 2019;  112: 283-289.

5. Patounakis G. The preimplantation genetic testing debate continues: first the hype, then the tension, now the hypertension? Fertil Steril 2019; 112: 233-234.