Reappraisal of adverse obstetric outcomes independently associated with contemporary fertility treatment practices: a US prospective cohort study.

backgroundObstetric complications linked to assisted reproductive technology could be confounded by underlying parental factors and were often derived from databases not designed to study these complications. With evolving assisted reproductive technology practices, it is unclear to what extent contemporary assisted reproductive technology independently contributes to obstetric risks.

objectiveWe aimed to prospectively evaluate obstetric risks associated with contemporary fertility practices, adjusting for parental and assisted reproductive technology parameters. STUDY

designProspective enrollment of patients with infertility who subsequently conceived unassisted, with non-in vitro fertilization fertility treatment, or assisted reproductive technology at a single US academic fertility center (September 2017-December 2021). Multiple gestations and surrogacy pregnancies were excluded from analysis. Parental characteristics, treatment parameters, and obstetric complications were assessed from medical records. The main outcome was physician-adjudicated obstetric complications (hypertensive disorders, abnormal placentation, fetal growth restriction, spontaneous preterm birth, and gestational diabetes). Maternal serum placental analyte level (pregnancy-associated plasma protein A) was also assessed by mode of conception. Cumulative incidences of obstetric complications by mode of conception were compared using chi-squared test. Univariable and multivariable log-binomial regression analyses were used to generate crude and adjusted risk ratios and their 95% confidence intervals to assess for associations between putative risk factors and abnormal placentation. Distributions of pregnancy-associated plasma protein A levels were compared using Kruskal-Wallis test, with correction for multiple pairwise comparisons with Dunn's test. All tests were 2-sided and conducted at the 0.05 level of significance.

resultsOf 2332 pregnancies approached for recruitment, 782 enrolled in the cohort, resulting in 656 singleton live births: 92 unassisted, 116 from non-in vitro fertilization fertility treatment, and 448 from assisted reproductive technology. The median (interquartile range) ages of the female patients were 37 (35-39), 36 (34-38), and 38 (35-41) years, respectively (P<.01). Abnormal placentation was the only assessed complication with a higher cumulative incidence in assisted reproductive technology vs nonassisted reproductive technology pregnancies (unassisted and non-in vitro fertilization fertility treatment combined). Thirty-nine patients had an abnormal placentation event in the assisted reproductive technology group, accounting for 8.7% (95% confidence interval, 6.3% to 11.7%) of assisted reproductive technology pregnancies, compared to 3, 1.4% (95% confidence interval, 0.3% to 4.1%), in non-assisted reproductive technology pregnancies (P<.01). Compared to non-assisted reproductive technology pregnancies, adjusting for parental factors, assisted reproductive technology was independently associated with a higher relative risk of abnormal placentation (adjusted relative risk, 6.19 [95% confidence interval, 1.84-20.82], P<.01). Within assisted reproductive technology pregnancies, fresh embryo transfer was the treatment parameter associated with abnormal placentation (adjusted relative risk, 2.07 [95% confidence interval, 1.10-3.92], P=.025). Pregnancy-associated plasma protein A level was particularly lower in fresh embryo transfer-conceived pregnancies (median multiple of the median value of 0.65 [interquartile range, 0.42-1.02 multiple of the median]), compared to non-assisted reproductive technology pregnancies (1.09 multiple of the median [interquartile range, 0.70-1.56 multiple of the median]) (P<.001).

conclusionAdjusting for underlying infertility, assisted reproductive technology remained independently associated with abnormal placentation. This risk should be considered during patient counseling and clinical management, particularly when assisted reproductive technology is pursued for elective reasons. The impact of fresh embryo transfer on placentation warrants further investigation.