Abstract

BACKGROUND

The aromatase inhibitor letrozole is increasingly recommended for ovulation induction, as it is more effective with fewer side-effects than other agents. But many clinicians are reluctant to use the drug for fertility treatment due to a strong-label warning against its use, which warns about congenital malformation risk to the foetus in women seeking pregnancy.

OBJECTIVE AND RATIONALE

The aim of this study was to determine the risks of congenital malformations and pregnancy loss with letrozole compared with clomiphene primarily, and with other fertility drugs and natural conception.

SEARCH METHODS

A systematic review and meta-analysis using PRISMA harms guidelines. We searched MEDLINE, EMBASE and other sources from inception until January 2020, with the MeSH words for ‘letrozole’ and pregnancy OR foetal/neonatal outcome. We included studies reported on congenital malformations in foetuses born to mothers conceived after fertility treatment, with letrozole versus clomiphene, placebo, gonadotrophins, metformin, natural conception or other agents, from randomised trials, comparative cohort studies and non-comparative observational cohorts. Quality of the studies was assessed using Cochrane risk of bias tool and Newcastle Ottawa Scale. The McMaster tool was used to assess the quality of reported harm for foetal congenital malformations in the studies. We compared the absolute risk of events using risk difference measures and pooled the findings using a fixed-effect model. We evaluated the statistical heterogeneity using forest plots and the I² statistic and funnel plot to assess publication bias. We assessed the strength of evidence for congenital malformation and pregnancy loss as per the GRADE recommendations and with the Fragility index.

OUTCOMES

We included 46 studies (18 randomised trials; 21 comparative cohorts; 7 non-comparative cohorts). Overall 2.15% (101/4697; 95% CI 1.7 to 2.5) of babies conceived on letrozole for fertility treatment had congenital foetal malformations. We did not observe a significant increase in congenital malformations with letrozole versus clomiphene in the randomised trials (risk difference (RD) 0.01, 95% CI −0.02, 0.03; I² = 0%; 14 studies) and found a significant reduction in the cohort studies (RD −0.02, 95% CI −0.04, −0.01; I² = 0%, 11 studies). The fragility index was 44% (7/16) (either an increase in the intervention arm or a decrease in control arm was needed to alter the results). The risks of pregnancy loss were not increased with letrozole versus clomiphene in the 14 randomised trials (RD −0.01, 95% CI −0.06, 0.04; I² = 0%), and the risks were reduced in the six cohort studies (RD −0.09, 95% CI −0.17, −0.00; I² = 68%). The GRADE quality of evidence was low to moderate for congenital malformations and pregnancy loss. We did not find any increased congenital malformation risk with letrozole versus gonadotrophins, natural conception or natural cycle ART, but the number of studies was small.

WIDER IMPLICATIONS

There is no evidence that letrozole increases the risk of congenital foetal malformation or pregnancy loss compared with clomiphene, natural conception or other fertility agents, to warrant warning against its use. Given its therapeutic benefits and lack of evidence of harm to the foetus, clinicians should consider letrozole as first-line agent for ovulation induction.

中文翻译：

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来曲唑用于生育治疗的胎儿伤害风险：系统评价和荟萃分析

摘要

背景

芳香酶抑制剂来曲唑越来越多地被推荐用于促排卵，因为它比其他药物更有效，副作用更少。但是许多临床医生不愿意使用这种药物进行生育治疗，因为强烈的标签警告不要使用这种药物，警告寻求怀孕的女性胎儿有先天性畸形风险。

目标和理由

本研究的目的是确定来曲唑与主要的克罗米芬相比，以及与其他生育药物和自然受孕相比，先天性畸形和流产的风险。

搜索方法

使用 PRISMA 危害指南的系统评价和荟萃分析。我们搜索了从开始到 2020 年 1 月的 MEDLINE、EMBASE 和其他来源，使用 MeSH 词表示“来曲唑”和妊娠或胎儿/新生儿结局。我们纳入了来自随机试验、比较队列研究和非比较观察队列的研究报告，这些研究报告了在生育治疗后怀孕的母亲所生胎儿的先天性畸形，使用来曲唑与克罗米芬、安慰剂、促性腺激素、二甲双胍、自然受孕或其他药物。使用 Cochrane 偏倚风险工具和纽卡斯尔渥太华量表评估研究质量。McMaster 工具用于评估研究中报告的胎儿先天性畸形危害的质量。我们使用风险差异测量比较了事件的绝对风险，并使用固定效应模型汇总了研究结果。我们使用森林图和I ²统计量和漏斗图评估发表偏倚。我们根据 GRADE 建议和脆弱性指数评估了先天性畸形和流产的证据强度。

结果

我们纳入了 46 项研究（18 项随机试验；21 个比较队列；7 个非比较队列）。总体而言，2.15% (101/4697; 95% CI 1.7 至 2.5) 接受来曲唑治疗生育的婴儿有先天性胎儿畸形。在随机试验中，我们没有观察到来曲唑与克罗米芬的先天性畸形显着增加（风险差异 (RD) 0.01, 95% CI -0.02, 0.03；I ² = 0%；14 项研究），并发现队列研究（RD -0.02, 95% CI -0.04, -0.01；I ²= 0%，11 项研究）。脆弱性指数为 44% (7/16)（需要增加干预组或减少控制组来改变结果）。在 14 项随机试验（RD -0.01, 95% CI -0.06, 0.04； I ² = 0%）中，来曲唑与克罗米芬相比未增加妊娠丢失的风险，并且在 6 项队列研究（RD - 0.09, 95% CI -0.17, -0.00；I ² = 68%)。先天性畸形和流产的 GRADE 证据质量为低到中等。我们没有发现来曲唑与促性腺激素、自然受孕或自然周期 ART 相比有任何增加的先天性畸形风险，但研究数量很少。

更广泛的影响

与克罗米芬、自然受孕或其他生育药物相比，没有证据表明来曲唑会增加先天性胎儿畸形或流产的风险，因此需要对其使用提出警告。鉴于其治疗益处和缺乏对胎儿有害的证据，临床医生应考虑来曲唑作为促排卵的一线药物。