Risk of stillbirth in singleton gestations following in vitro methods of conception: a systematic review and meta‐analysis

Abstract

Background In vitro methods of conception are associated with adverse perinatal outcomes. It is unclear if the risk of stillbirth is increased also. Objective This systematic review and meta‐analysis aimed to estimate the risk of stillbirth in singleton gestations following in vitro methods of conception compared to non‐in vitro conceptions. Search strategy A comprehensive search in PubMed, Embase, CINAHL, and Cochrane Library was undertaken from database inception to February 2021, with backward citation tracking. Selection criteria Eligible studies included randomized controlled trials, cohort studies, or case‐control studies that assessed stillbirth following in vitro fertilisation and/or intracytoplasmic sperm injection in comparison to non‐in vitro methods of conception, including spontaneous conceptions, intrauterine insemination, and ovarian stimulation. Data collection and analysis The Newcastle‐Ottawa Scale was used to assess risk of bias. A summary odds ratio (OR) for stillbirth following in vitro methods of conception compared to non‐in vitro methods was calculated using a random‐effects model for meta‐analysis. Main results Thirty‐three cohort studies met inclusion criteria. There was an increased risk of stillbirth with in vitro methods: OR 1.41 (95% CI 1.20–1.65); however, the crude baseline risk of stillbirth was low (4.44/1000 total births). Subgroup analysis did not demonstrate an increased risk when in vitro methods were compared to conception without in vitro methods in the context of subfertility. Conclusions Compared to non‐in vitro conceptions, in vitro conceptions have an increased risk of stillbirth. However, there is insufficient evidence to demonstrate whether this risk is associated with in vitro techniques or underlying subfertility. Tweetable abstract This meta‐analysis found an increased risk of stillbirth in singletons from in vitro methods of conception.

Risk of stillbirth and neonatal death in singletons born after fresh and frozen embryo transfer: cohort study from the Committee of Nordic Assisted Reproduction Technology and Safety

“…( 15 ) A meta-analysis comparing 68,274 ART-conceived and 3,570,990 conceived without medical assistance, mainly from cohort studies, also found higher odds of stillbirth after ART (OR 1.41, 95%CI 1.20-1.65). ( 14 ) Previous observations from the Nordic countries, overlapping our study population with births from 1988 to 2007, indicated similar risk of stillbirth for both frozen-ET (n=6,647) and fresh-ET (n= 42,242) compared to conceptions without medical assistance (n=288,542). ( 23 )…”

“…The lack of association between conception method and risk of stillbirth in our study is in contrast to the results from a population-based study from the Netherlands, where a nearly doubled risk of stillbirth was found for any ART (n ¼ 19,896) compared with pregnancies conceived without medical assistance (n ¼ 999,050; OR, 1.94; 95% CI 1.54-2.44) (15). A metaanalysis comparing 68,274 ART-conceived and 3,570,990 conceived without medical assistance, mainly from cohort studies, also found higher odds of stillbirth after ART (OR, 1.41; 95% CI, 1.20-1.65) (14). Previous observations from the Nordic countries, overlapping our study population with births from 1988 to 2007, indicated similar risk of stillbirth for both frozen-ET (n ¼ 6,647) and fresh-ET (n ¼ 42,242) compared with conceptions without medical assistance (n ¼ 288,542) (23).…”

“…Perinatal loss, whether stillbirth or neonatal death, is a traumatic outcome for expecting couples and often associated with preterm birth, congenital malformations, and placental complications (7)(8)(9)(10)(11). Studies show an overall high risk of perinatal death and of stillbirth after any ART compared with singletons conceived without medical assistance (12)(13)(14). Only one previous cohort study has separated perinatal mortality into stillbirth and neonatal death, and found high risk of both stillbirth and neonatal death after any ART vs. conceptions without medical assistance (15).…”

Additional Adverse Perinatal Outcomes With No Effect on Neonatal Mortality and Birth Defects in Pregnancies Conceived by Assisted Reproductive Technology

“…Birth defects are closely related to the perinatal period and infant mortality ( 30 ). However, there is still no consensus on whether ART increases the incidence of neonatal birth defects.…”

Reproductive outcomes in women and men conceived by assisted reproductive technologies in Norway: prospective registry based study

“…Pregnancies conceived by ART have increased risks of complications, including hypertensive disorders of pregnancy, preterm birth, and low birth weight, with some variation by ART method. [2][3][4][5][6][7][8] A high proportion of early cohorts of people conceived by ART were part of a multiple birth, which explains some of the obstetric and perinatal outcomes, but not all. [2][3][4] Whether these risks are increased by causes of subfertility or by the ART treatments is still an ongoing debate.…”