Double Embryo Transfer for IVF Linked to Higher Risk of Neonatal Death

Patients who underwent a double embryo transfer (DET) during in vitro fertilization (IVF) had a slightly increased risk of adverse outcomes compared with those who had a single embryo transfer (SET), but the absolute risk remained low, a cohort study in Sweden showed.

Among over 1 million singleton births, a higher risk of neonatal death was found after DET versus SET (OR 2.67, 95% CI 1.28-5.55), reported Kenny Rodriguez-Wallberg, MD, PhD, of Karolinska University Hospital in Stockholm, and colleagues.

However, the absolute risk of neonatal death remained well under 1% in both cohorts, for an absolute risk difference of 0.2% (95% CI 0.0-0.4), they noted in JAMA Pediatrics.

"Although neonatal death is a serious detrimental outcome, the absolute risk after DET is still very low, especially in relation to the general risks of ART [assisted reproductive technology] and twin pregnancies," Rodriguez-Wallberg and colleagues wrote. "We conclude that although the results support the use of SET, the observed higher risk after DET should not in itself deter from the use of DET in women who are older or otherwise have a low reproductive potential."

Of note, the researchers found that the risk of adverse outcomes with DET was higher among patients who used frozen embryos or blastocysts. Among frozen embryo transfers, DET was linked to a higher risk of low birth weight (OR 1.64, 95% CI 1.19-2.25). And in blastocyst transfers, DET was associated with very preterm birth (relative risk ratio 2.64, 95% CI 1.50-4.63), as well as low birth weight (OR 1.83, 95% CI 1.29-2.60).

Alan Penzias, MD, of Harvard Medical School in Boston, who was not involved in this study, said that the findings were "reassuring," emphasizing that the incidence of adverse outcomes including neonatal mortality was low. As DET is typically more common among patients who are older or have a worse fertility prognosis, Penzias told MedPage Today that negative outcomes in this population could potentially be attributed to patient factors.

DET carries an increased risk of twin pregnancies, leading some countries to place restrictions on the number of transferred embryos a patient can receive, Rodriguez-Wallberg and colleagues noted.

In this study, Rodriguez-Wallberg and colleagues used data from women with singleton deliveries after SET or DET in Sweden from July 2007 through December 2017 as recorded in the National Quality Registry for Assisted Reproduction. Births from IVF that occurred after egg donation were not included in the analysis.

The researchers adjusted their analysis for covariates including maternal age, birth order, delivery year, maternal country of birth, previous spontaneous abortions, extrauterine pregnancies, and number of stimulation cycles.

Pregnancies that had two gestational sacs at ultrasound, evidence of a second fetus, or complications specific to multiple gestation were categorized as possible vanishing twin syndrome, which occurs when both transferred embryos implant but only one progresses during pregnancy.

Of 1,115,863 singleton births, 3% resulted from ART -- 30,713 were born after SET, and 5,123 were born after DET. Average maternal age was higher among patients who underwent DET compared with SET (36 vs 33, respectively). DET was also more common in the earlier years of the study cohort, from 2007 to 2010.

More women in the DET group underwent intracytoplasmic sperm injection, had embryo transfers during the cleavage stage, and more often underwent fresh transfers.

There were no significant differences in the risk of gestational hypertension, preeclampsia, gestational diabetes, placental abruption, bleeding during pregnancy, or pre-labor rupture of membranes between the SET and DET groups. There was also no difference in delivery mode or induction.

Multiple gestations made up 8% of singleton births after DET and 0.3% of singleton births after SET. In an analysis that eliminated these pregnancies, there was an increased risk of major congenital malformations in the DET group, but the absolute risk difference was not statistically significant.

Rodriguez-Wallberg and colleagues acknowledged that the data used in this study lacked information on embryo quality and type of infertility, which may limit the findings. Additionally, this analysis had limited power to detect differences in outcomes between frozen versus fresh transfers, as well as cleavage stage versus blastocyst transfers.

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