Analgesia use during pregnancy and risk of cryptorchidism: a systematic review and meta-analysis

Study question: Are boys who are born to mothers who use analgesics during pregnancy at increased risk of cryptorchidism compared to those born to mothers who do not take analgesia?

Summary answer: In this systematic review and meta-analysis of 10 published studies, we observed only weak evidence of an association between analgesia use during pregnancy and risk of cryptorchidism in the son.

What is known already: Concentrations of analgesia relevant to human exposure have been implicated as causing endocrine disturbances in the developing foetal testis. However, when viewed collectively there appears to be conflicting evidence regarding an association between maternal use of analgesics and development of cryptorchidism.

Study design, size, duration: A systematic review and meta-analysis of studies on analgesia use during pregnancy and risk of cryptorchidism was performed. The search terms used were (analges* OR paracetamol OR acetaminophen) AND (cryptorchidism OR cryptorchism OR undescended test* OR non-descended test* OR non descended test*) for the databases Ovid Medline, Embase, Scopus and Web of Science. The search included all published articles up until 23 May 2016 and no limits were set in terms of language.

Participants/materials, setting, methods: Abstracts were screened by one reviewer to remove irrelevant studies, with a 10% random sample of these verified by a second reviewer. The full text of all remaining papers was assessed by two reviewers. Abstracts included in the final analysis were studies which reported associations between the exposure (analgesia) and the outcome (cryptorchidism). Studies were only included if data were provided from which summary associations (odds ratios (ORs) or relative risks) and their 95% CIs could be calculated, or if summary associations were provided by the authors themselves. For each included study, two reviewers independently extracted study meta-data in line with PRISMA recommendations. We assessed study quality and potential for bias using the criteria outlined in the Newcastle-Ottawa Quality Assessment Scale, but did not determine a quality score. Two reviewers independently assessed study quality against these criteria.

Main results and the role of chance: After screening 350 manuscripts, 10 were included in our review (5 case-control studies, 5 cohort studies). We observed weak evidence of an association between ever use of analgesia and risk of cryptorchidism (pooled crude OR: 1.11, 95% CI: 1.00-1.23), with case-control studies revealing a marginally stronger association (1.23, 95% CI: 0.85-1.78) than cohort studies (1.09, 95% CI: 0.97-1.22). We observed weak evidence of a dose-response relationship between increasing weeks of analgesia exposure and risk of cryptorchidism, as well as weak evidence of an effect of timing on analgesia exposure and risk of cryptorchidism. Assessment of study quality via the Newcastle-Ottawa criteria revealed little (if any) evidence of substantial bias that may have meaningfully affected a given study's results.

Limitations, reasons for caution: While confounding does not appear to be important, misclassification of the exposure is possibly an important source of measurement error in this context. The systematic review is open to reporting bias. Owing to scant data, no meta-analyses for two key questions (relating to dose-response and timing of exposure) could be performed. Medications were grouped based on their common effect and this offers little insight into the relation between specific types of analgesia and cryptorchidism. Finally, there are limitations in assuming that analgesia use reported by mothers is synonymous with actual intrauterine exposure.

Wider implications of the findings: The ubiquity of analgesia use during pregnancy makes this exposure particularly important from a population health perspective. About 9 of the 10 studies were conducted in Europe or USA, limiting generalizability of our observations. While the observations from our systematic review and meta-analysis suggest that analgesia use during pregnancy is not strongly associated with cryptorchidism development in the son, they also highlight the need for further detailed assessments of this relationship.

Study funding/competing interest(s): This study was funded by the Health Research Council of New Zealand (reference #: 14/052). The authors have no conflict of interest to declare.

Registration number: CRD42016041414.