Association between prolactin levels and pregnancy outcomes: evidence from multi-center cohort study and Mendelian randomization analysis

Objective To investigate whether moderately elevated serum prolactin levels are associated with pregnancy outcomes. Design Multi-center retrospective cohort study and Mendelian randomization (MR) analysis. Setting Three reproductive centers in Ningbo, Wenzhou, and Xiamen, China. Population 11,004 women undergoing their first in vitro fertilization (IVF) fresh embryo transfer cycle. Individuals with prolactin levels ≥100 ng/mL, missing follow-up outcomes, and relevant diseases were excluded, resulting in 8,073 participants. MR analysis utilized genome-wide association study data from individuals of European ancestry. Methods Multivariable-adjusted logistic regression and combining cohort-specific estimates with meta-analysis were used to examine cohort associations. MR analyses were performed to assess the effect of genetically predicted prolactin levels on pregnancy outcomes and complications. Main Outcome Measures The primary outcome was live birth rate. Secondary outcomes included clinical pregnancy, biochemical pregnancy, miscarriage, preterm birth, and birthweight. Results A total of 8073 individuals were included, with mean age of 32 years, mean body mass index of 22 kg/m 2 , and mean serum prolactin levels of 14.6 ng/mL. Each 5 ng/mL increase in serum prolactin levels were significant associated with increased rate of live birth (odds ratio [OR]= 1.05, 95% confidence interval [CI] = 1.04 – 1.08; P < 0.001), clinical pregnancy (OR = 1.03, 95% CI =1.00–1.06; P = 0.03), biochemical pregnancy (OR = 1.04, 95% CI =1.00–1.07; P = 0.03), and decreased risk of miscarriage (OR =0.92, 95% CI = 0.88–0.97; P = 0.002). However, after adjusting for multiple confounders, the association between prolactin levels and live birth attenuated and became no longer statistically significant (adjusted OR [aOR] 1.03 per 5 ng/mL increase, 95% CI = 0.99–1.06; P = 0.10). Similarly, associations with clinical pregnancy (aOR = 1.02, 95% CI = 0.99–1.05; P = 0.26) and miscarriage (aOR = 0.96, 95% CI = 0.90–1.02; P = 0.14) also became non-significant after adjustment. Consistently, MR analysis indicated that genetically predicted prolactin levels were not significantly associated with live birth, miscarriage, preterm birth, birth weight, gestational diabetes mellitus, maternal hypertensive disorder, preeclampsia ( P > 0.05 for all). Conclusions Moderate increase in serum prolactin levels may not adversely affect pregnancy outcomes. The necessity of treatments for lowering prolactin before conception needs to be re-evaluated. Funding Source: National Natural Science Foundation of China (No. 82401908), Natural Science Foundation of Fujian Province of China (No. 2024J08309) Keywords: Prolactin, Pregnancy outcomes, Cohort study, Multi-centers, Mendelian randomization