Gurney Jason, Richiardi Lorenzo, McGlynn Katherine A, Signal Virginia, Sarfati Diana
Department of Public Health, University of Otago, 23a Mein St, Newtown, Wellington, New Zealand.
Cancer Epidemiology Unit, University of Turin, Turin, Italy.
Hum Reprod. 2017 May 1;32(5):1118-1129. doi: 10.1093/humrep/dex047.
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?
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.
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.
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.
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.
CRD42016041414.
与未使用镇痛药的母亲所生的男孩相比，孕期使用镇痛药的母亲所生的男孩患隐睾症的风险是否更高？
在这项对10项已发表研究的系统评价和荟萃分析中，我们仅观察到微弱证据表明孕期使用镇痛药与儿子患隐睾症风险之间存在关联。
与人类接触相关的镇痛药浓度被认为会导致发育中的胎儿睾丸出现内分泌紊乱。然而，总体来看，关于母亲使用镇痛药与隐睾症发生之间的关联，证据似乎相互矛盾。
研究设计、规模、持续时间：对孕期使用镇痛药与隐睾症风险的研究进行了系统评价和荟萃分析。在Ovid Medline、Embase、Scopus和Web of Science数据库中使用的检索词为（镇痛药或对乙酰氨基酚或醋氨酚）和（隐睾症或隐睾病或睾丸未降或非睾丸未降或未下降睾丸）。检索涵盖截至2016年5月23日的所有已发表文章，且未设置语言限制。
参与者/材料、环境、方法：由一名审阅者筛选摘要以排除无关研究，其中10%的随机样本由第二名审阅者进行核实。所有剩余论文的全文由两名审阅者评估。纳入最终分析的摘要为报告了暴露因素（镇痛药）与结局（隐睾症）之间关联的研究。只有当提供了可计算汇总关联（比值比（OR）或相对风险）及其95%置信区间的数据，或作者自己提供了汇总关联时，研究才会被纳入。对于每项纳入研究，两名审阅者根据PRISMA建议独立提取研究元数据。我们使用纽卡斯尔-渥太华质量评估量表中概述的标准评估研究质量和偏倚可能性，但未确定质量得分。两名审阅者根据这些标准独立评估研究质量。
在筛选了350篇手稿后，10篇被纳入我们的综述（5项病例对照研究，5项队列研究）。我们观察到曾使用镇痛药与隐睾症风险之间存在微弱关联证据（合并粗OR：1.11，95%CI：1.00 - 1.23），病例对照研究显示的关联（1.23，95%CI：0.85 - 1.78）略强于队列研究（1.09，95%CI：0.97 - 1.22）。我们观察到镇痛药暴露周数增加与隐睾症风险之间存在微弱的剂量反应关系证据，以及镇痛药暴露时间对隐睾症风险影响的微弱证据。通过纽卡斯尔-渥太华标准评估研究质量显示，几乎没有（如果有的话）实质性偏倚的证据可能对给定研究结果产生有意义的影响。
局限性、谨慎理由：虽然混杂因素似乎并不重要，但在这种情况下，暴露的错误分类可能是测量误差的一个重要来源。该系统评价存在报告偏倚的可能性。由于数据不足，无法对两个关键问题（与剂量反应和暴露时间有关）进行荟萃分析。药物是根据其共同作用进行分组的，这对特定类型镇痛药与隐睾症之间的关系提供的见解很少。最后，假设母亲报告的镇痛药使用等同于实际宫内暴露存在局限性。
孕期使用镇痛药的普遍性使得从人群健康角度来看这种暴露尤为重要。10项研究中有9项是在欧洲或美国进行的，限制了我们观察结果的普遍性。虽然我们的系统评价和荟萃分析的观察结果表明孕期使用镇痛药与儿子隐睾症的发生没有强烈关联，但它们也凸显了对这种关系进行进一步详细评估的必要性。
研究资金/利益冲突：本研究由新西兰健康研究委员会资助（参考编号：14/052）。作者声明无利益冲突。
CRD42016041414
