Chaabane Sonia, Sheehy Odile, Monnier Patricia, Fraser William, Bissonnette François, Trasler Jaquetta M, Muanda Flory T, Boukhris Takoua, Karam Fatiha, Santos Fabiano, Blais Lucie, Bérard Anick
Sainte-Justine Hospital, Research Center, 3175, chemin de la Côte-Ste-Catherine, Montreal (Quebec) H3T 1C5.
Curr Drug Saf. 2016;11(3):222-61. doi: 10.2174/1574886311666160627094051.
Multiple pregnancies are a recognized adverse effect of assisted reproductive technologies; nevertheless, there is no consensus on the incremental risk associated with the ovarian stimulation (OS) used alone and intrauterine insemination (IUI). The relationship between OS and IUI and the risk of major congenital malformations (MCM) is unclear.
To summarise the literature and evaluate the risk of multiple pregnancy and MCM associated with OS used alone and IUI used with or without OS compared to natural conception (spontaneously conceived infants without any type of fertility treatments).
We carried out a systematic review to identify published papers between 1966 and 2014 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We included observational studies and randomized clinical trials related to the risk of multiple pregnancies and MCM conceived following OS alone or IUI compared to natural conception (spontaneously conceived infants without any fertility treatments). The quality of the included studies was evaluated using The Cochrane Collaboration's tool for assessing risk of bias for RCTs and the Newcastle-Ottawa Scale for observational studies.
There were 63 studies included in this review. Our systematic review suggests that the use of any OS alone was associated with an increased risk of multiple pregnancy compared to natural conception (pooled RR 8.80, 95% CI 5.09- 15.20; p= 0.000; 9 studies). Similar increases in the risk of multiple pregnancies were observed following clomiphene citrate used without assisted reproductive technologies. Compared to natural conception, the use of IUI with or without OS was associated with an increased risk of multiple pregnancy (pooled RR 9.73, 95% CI 7.52 -12.60; p= 0.000; 6 studies). Compared to natural conception, the use of any OS alone was associated with an increased risk of any MCM (RR pooled 1.18, 95%CI 1.03-1.36; 11 studies), major musculoskeletal malformations (pooled RR 1.48, 95%CI 1.21-1.81; 7 studies), and malformations of the nervous system (pooled RR 1.73, 95%CI 1.15-2.61; 6 studies). Compared to natural conception, the use of IUI was associated with an increased risk of any MCM (pooled RR 1.23, 95%CI 1.10-1.37; 10 studies), major urogenital (pooled RR 1.52, 95%CI 1.04-2.22; 7 studies), and musculoskeletal malformations (pooled RR 1.54, 95%CI 1.20-1.98; 7 studies). The overall quality of the included studies was acceptable.
The increased risk of multiple pregnancy and certain types of MCM associated with the use of less invasive fertility treatments, such as OS and IUI, found in this review, highlights the importance of the practice framing. Heterogeneity in OS protocols, the combination with other fertility agents, the limited number of studies and the methodological quality differences reduce our ability to draw conclusions on specific treatment. More observational studies, assessing the risk of multiple pregnancy or MCM, as a primary outcome, using standardized methodologies, in larger and better clinically defined populations are needed.
多胎妊娠是辅助生殖技术公认的不良后果；然而，对于单独使用卵巢刺激（OS）和宫内人工授精（IUI）所带来的额外风险，目前尚无共识。OS与IUI之间的关系以及与严重先天性畸形（MCM）风险之间的关系尚不清楚。
总结文献，并评估与单独使用OS以及使用或未使用OS的IUI相比，自然受孕（未接受任何类型生育治疗而自然受孕的婴儿）时多胎妊娠和MCM的风险。
我们进行了一项系统评价，以确定1966年至2014年间发表在MEDLINE、EMBASE和Cochrane对照试验中央注册库中的论文。我们纳入了与单独使用OS或IUI后与自然受孕（未接受任何生育治疗而自然受孕的婴儿）相比的多胎妊娠和MCM风险相关的观察性研究和随机临床试验。使用Cochrane协作网用于评估随机对照试验偏倚风险的工具以及用于观察性研究的纽卡斯尔-渥太华量表对纳入研究进行质量评估。
本评价纳入了63项研究。我们的系统评价表明，与自然受孕相比，单独使用任何OS均与多胎妊娠风险增加相关（合并相对风险8.80，95%可信区间5.09 - 15.20；p = 0.000；9项研究）。在未使用辅助生殖技术的情况下使用枸橼酸氯米芬后，多胎妊娠风险也有类似增加。与自然受孕相比，使用或未使用OS的IUI均与多胎妊娠风险增加相关（合并相对风险9.73，95%可信区间7.52 - 12.60；p = 0.000；6项研究）。与自然受孕相比，单独使用任何OS均与任何MCM风险增加相关（合并相对风险1.18，95%可信区间1.03 - 1.36；11项研究）、主要肌肉骨骼畸形（合并相对风险1.48，95%可信区间1.21 - 1.81；7项研究）以及神经系统畸形（合并相对风险1.73，95%可信区间1.15 - 2.61；6项研究）。与自然受孕相比，使用IUI与任何MCM风险增加相关（合并相对风险1.23，95%可信区间1.10 - 1.37；10项研究）、主要泌尿生殖系统畸形（合并相对风险1.52，95%可信区间1.04 - 2.22；7项研究）以及肌肉骨骼畸形（合并相对风险1.54，95%可信区间1.20 - 1.98；7项研究）。纳入研究的总体质量是可以接受的。
本评价发现，与使用侵入性较小的生育治疗方法（如OS和IUI）相关的多胎妊娠和某些类型MCM风险增加，凸显了实践框架的重要性。OS方案的异质性、与其他生育药物的联合使用、研究数量有限以及方法学质量差异降低了我们就特定治疗得出结论的能力。需要更多使用标准化方法、在更大且临床定义更好的人群中、以多胎妊娠或MCM风险作为主要结局的观察性研究。
