Effect of preconception antibiotics exposure on female reproductive health and pregnancy outcomes: a systematic review and meta-analysis

Abstract

Background: The preconception period is a window of opportunity to influence maternal and pregnancy outcomes. Inappropriate use of antibiotics results in gut dysbiosis and may affect host reproductive health through multiple dimensions. Animal studies demonstrate that antibiotic treatment profoundly affects ovarian functions and the estrous cycle, and it has a direct implication for infertility. Infertility was defined as the inability to conceive after 12 months of unprotected intercourse. However, whether antibiotic exposure in the preconception period influences female fertility, miscarriage, and congenital malformation remains obscure and controversial.

Methods: A systematic review and meta-analysis until April 20, 2024, was conducted by searching PubMed, Web of Science, Scopus, and Science Direct without restrictions to designs and language. The risk of bias was assessed by two independent reviewers using the Newcastle Ottawa Scale (NOS) and the Risk of Bias 2 (RoB-2) tools. The report followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relative risks (RR), odds ratios (OR), and fecundability ratios (FR) with a 95% confidence interval (CI) were effect size measures determined with a random effect model. Heterogeneity across included studies was assessed using I ² , T2, and H². The review protocol is registered in PROSPERO, CRD42024515680.

Findings: Fifteen studies with a total of 1,206,583 participants were included. Preconception exposure to macrolides reduced the FR by 35% (FR: 0.65, 95% CI: 0.48, 0.88, P < 0.001). Sulfonamide users were also at 2.35 times (OR:2.35, 95% CI: 1.86, 2.97; P < 0.001) more risk of developing infertility. Using beta-lactams other than penicillin G reduced the odds of infertility by 64% (OR: 0.36, 95% CI: 0.26,0.50; P < 0.001). The possibility of infertility among quinolone users was 13% lower (OR: 0.87, 95% CI: 0.77, 0.99; P = 0.03) than non-users. Preconception antibiotics exposure increased the risk of spontaneous miscarriage by 34% (RR: 1.34, 95% CI: 1.16, 1.53; P < 0.001). Moreover, trimethoprim intake also increased the odds of congenital malformations by 85% (OR:1.85, 95% CI: 1.54, 2.23; P < 0.001).

Interpretation: Preconception antibiotics exposure in females increases the risk of infertility, miscarriage, and congenital anomalies. Macrolides, sulfonamides, and trimethoprim increase the risk of infertility, spontaneous miscarriage, and congenital malformation while beta-lactams and quinolones reduce the risk. Clinicians, pregnancy planners, and health care policymakers should be warranted for pregnancy needs and success. Further clinical and mechanistic studies are required to illustrate their specific functions and cause effects.

Funding: Funded by Leading Discipline Development Fund (No. 403947), The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine; and The Hong Kong Obstetrical and Gynaecological Trust Fund.

Keywords: Congenital birth defect; Female reproduction; Gut microbiome; Infertility; Miscarriage; Preconception antibiotics.

Graphical abstract

Fig. 1

PRISMA flow diagram of study selection and inclusion.

Fig. 2

The ratio of the average per-cycle probability of conception (fecundability) among women who took A) Macrolides, B) Betalactams, C) Sulfonamides, and D) Other antibiotics in the preconception period; and E) the association of preconception antibiotics with clinical pregnancy rate.

Fig. 3

The relationship between preconception antibiotic exposure and A) Spontaneous miscarriage, and B) Congenital malformations.