孕期使用胃复安的安全性得到证实

《美国医学会杂志》发表的一项研究显示，妊娠期间使用胃复安与明显先天畸形、自然流产、死产、早产、低出生体重或胎儿生长受限的风险增高无关。该研究中纳入的暴露妊娠数是既往所有关于妊娠期使用胃复安安全性的队列研究中暴露妊娠数总和的10倍(JAMA 2013;310:1601-11)。


Björn Pasternak博士

在这项以注册为基础的队列研究中，哥本哈根市Statens Serum研究所的Björn Pasternak博士及其合作者对1997~2011年间丹麦的1,222,503例妊娠进行了评估，其中包括45,002 (3.7%)例母亲使用胃复安的妊娠，推测使用胃复安的目的为治疗恶心或呕吐。研究者对20种不同的先天畸形进行了检查。

“本项研究纳入的妊娠数巨大，允许进行关于多数妊娠结局的准确风险估计的分析，也允许对罕见严重不良结局开展分析。”

Pasternak博士及其同事首先在28,486例孕早期暴露于胃复安的活产婴儿和年龄、出生年份和倾向性评分相匹配的113,698例未暴露于胃复安的婴儿中对明显先天畸形进行了评估。结果显示，在暴露婴儿和未暴露婴儿中，任何明显畸形的发生率分别为25.3/1,000例和26.6/1,000例，无统计学差异。然后，他们对20种先天畸形进行了独立分析，如神经管畸形、肾盂积水、室间隔或房间隔缺损、尿道下裂、畸形足或唇裂。结果显示，胃复安与任何类型的畸形均无显著相关性。

研究者还对37,946例暴露于胃复安的妊娠和151,661例匹配的未暴露妊娠中发生的10,171例自然流产进行了评估。结果显示，暴露妊娠中自然流产发生率略低于未暴露妊娠。这一结果“并非预料之外”，因为胃复安的应用目的为治疗恶心和呕吐，已知在一般人群中，恶心和呕吐与自然流产发生率较低相关。“实际上，既往研究中恶心和呕吐与自然流产之间的相关性的统计学效度与本项研究中胃复安暴露和自然流产之间的相关性相似。”

他们还发现，40,306例暴露于胃复安的妊娠与161,098例匹配的未暴露妊娠中的死产发生率无统计学差异，分别为3.5/1,000例和3.9/1,000例。可见，这种药物也未增加死产风险。进一步分析显示，胃复安暴露与早产、低出生体重或小于胎龄儿等次要结局均无相关性。

研究者还进行了一些敏感性分析，结果均与主要分析相似。例如，仅接受一次胃复安处方和接受多次处方的女性在所有不良结局发生率方面无统计学差异，提示不存在量效反应。他们还在因明显胎儿畸形而终止的妊娠中评估了可能的暴露效应，结果再次显示，未见胃复安暴露导致总体畸形或某种畸形风险增高的证据。

该研究由丹麦医学研究委员会资助。研究者未报告任何利益冲突。

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By: MARY ANN MOON, Ob.Gyn. News Digital Network

The use of metoclopramide during pregnancy was not associated with any increased risk of major congenital malformations, spontaneous abortion, stillbirth, preterm birth, low birth weight, or fetal growth restriction in a study assessing 10 times as many exposed pregnancies as all previous cohort studies of this issue combined.

This registry-based cohort study assessed 1,222,503 pregnancies throughout Denmark from 1997 through 2011, including 45,002 (3.7%) in which the mother took metoclopramide, presumably to treat nausea or vomiting. It examined 20 different categories of congenital malformation, said Dr. Björn Pasternak and his associates of the Statens Serum Institut, Copenhagen.

"The number of included pregnancies in our study permitted analyses with precise estimation of risk for most outcomes and allowed analyses of serious adverse outcomes that are rare," the authors noted in a report online Oct. 15 in JAMA.
 
The findings confirm and significantly extend those of previously published cohort studies of metoclopramide taken during pregnancy, which included only 4,261 exposed pregnancies in total.

Dr. Pasternak and his colleagues first assessed major congenital malformations in 28,486 liveborn infants exposed to metoclopramide during the first trimester and 113,698 infants who were not exposed and who were matched for age, year of birth, and propensity score. The rate of any major malformation was 25.3 per 1,000 among the exposed infants and 26.6 per 1,000 among the unexposed infants, a nonsignificant difference.

They then analyzed 20 individual categories of congenital malformation, such as neural tube defects, hydronephrosis, ventricular or atrial septal defects, hypospadias, clubfoot, or cleft lip. There were no significant associations between metoclopramide and any type of malformation.

The researchers also assessed 10,171 cases of spontaneous abortion that occurred among 37,946 metoclopramide-exposed pregnancies and 151,661 matched unexposed pregnancies. The rate of spontaneous abortion was slightly lower in exposed than in unexposed pregnancies.

This finding was "not unexpected" because the drug is given to treat nausea and vomiting, conditions that are known to correlate with lower rates of spontaneous abortion in the general population. "Indeed, the strength of the association between nausea and vomiting and spontaneous abortion in previous studies was similar in magnitude to the association between metoclopramide exposure and spontaneous abortion observed in our study," Dr. Pasternak and his associates reported (JAMA 2013;310:1601-11).

They also found that the rate of stillbirth among 40,306 metoclopramide-exposed pregnancies (3.5 per 1,000) was not significantly different from that among 161,098 matched unexposed pregnancies (3.9 per 1,000). So the drug did not raise the risk of stillbirth.

Further analyses showed that metoclopramide exposure was not associated with any of the secondary outcomes of preterm birth, low birth weight, or small-for-gestational-age infants.

The investigators also performed several sensitivity analyses, all of which yielded results similar to those of the primary analyses. For example, the rates of all adverse outcomes were not significantly different between women who filled only one prescription for the drug and those who filled multiple prescriptions, indicating that there was no dose-response effect.

They also assessed a possible exposure effect among pregnancies that were terminated because of major fetal malformations. Again, there was no evidence of an increased risk of malformations overall or of particular types of malformations after exposure to metoclopramide.

These findings "may help inform clinical decisions when treatment with metoclopramide is considered in pregnancy," Dr. Pasternak and his associates said.

This study was supported by the Danish Medical Research Council. No financial conflicts of interest were reported.