FDA警告：慎用硫酸镁阻止早产

圣路易斯(MD Consult)——2013年5月30日，美国食品药品管理局(FDA)发布了一则警告，反对硫酸镁注射剂用于阻止孕妇早产的用药时间＞5~7天，以免导致胎儿风险。胎儿可能出现低钙水平、骨质减少以及骨折，可导致损害的最短治疗时间尚不清楚。

硫酸镁已被批准用于预防先兆子痫患者癫痫以及控制子痫患者癫痫发作，而用于阻止早产则属于超适应证使用。

FDA已通过其不良事件报告系统确认了18例有关宫内硫酸镁暴露新生儿骨骼异常的报告。此外，文献也记述了硫酸镁被用于孕妇安胎的病例情况。平均宫内硫酸镁暴露时间为9.6周(范围为8~12周)，估计孕妇平均总给药剂量为3,700 g。已发表的病例报告认为新生儿骨骼异常与骨质减少有关，部分新生儿肋骨和长骨发生多处骨折。在报告结局的病例中，骨质减少和骨折为一过性并得到缓解。

基于文献报道的病例，新生儿骨骼异常似乎与宫内硫酸镁持续暴露相关。骨质减少和骨折可能是由于高镁血症所致，后者进而导致发育中的胎儿出现低钙血症。

FDA还查阅了已发表的流行病学研究结果。一项研究显示，与宫内硫酸镁暴露时间＜3天的新生儿相比，暴露时间＞7天者的骨骼异常增加具有统计学显著意义。另一项研究显示，无宫内硫酸镁暴露的新生儿与暴露时间＞1周者相比，出生时血清镁、钙、磷和骨钙素水平具有显著差异，但桡骨骨矿含量未见差异。在这些研究中，新生儿骨骼异常被认为与宫内硫酸镁暴露＞5~7天相关，包括X线检查可见长骨(如肱骨)干骺端透亮带。

上述大部分流行病学研究是基于对医院病历的回顾性分析。流行病学数据表明，对实验室指标的影响在出生后数天内得以恢复。但由于随访时间较短，尚未研究对骨骼的长期影响。

产品说明书中已添加了有关上述风险的新警告。此外，说明书中新修订的生产与分娩部分强调了未批准持续使用硫酸镁用于治疗早产，用于该适应证的安全性和有效性尚不明确。

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ST LOUIS (MD Consult) - On May 30, 2013, the US Food and Drug Administration (FDA) issued a warning against the use of magnesium sulfate injection for more than 5 to 7 days to stop preterm labor in pregnant women because it may pose a risk to the fetus. Low calcium levels, osteopenia, and fractures could occur in the fetus. The shortest duration of treatment that can result in harm is unknown.

Magnesium sulfate is approved to prevent seizures in patients with preeclampsia, and for the control of seizures in patients with eclampsia. Use of the product to stop preterm labor is considered off-label.

The FDA has identified 18 case reports through its Adverse Event Reporting System that describe skeletal abnormalities in neonates exposed in utero to magnesium sulfate. In addition, the literature describes cases of magnesium sulfate being administered to mothers for tocolysis in pregnancy. The average duration of in-utero exposure to magnesium sulfate was 9.6 weeks (range 8-12 weeks), and the estimated average total maternal dose administered was 3,700 grams. The published case series describes neonates experiencing skeletal abnormalities related to osteopenia; some experienced multiple fractures involving the ribs and long bones. The osteopenia and fractures were transient and resolved in cases in which the outcome was reported.

On the basis of the literature cases, it is plausible that bone abnormalities in neonates were associated with prolonged in-utero exposure to magnesium sulfate. Osteopenia and fractures may result from hypermagnesemia, which in turn causes hypocalcemia in the developing fetus.

The FDA also reviewed published epidemiologic studies. One study found a statistically significant increase in bone abnormalities in neonates with in-utero exposure to magnesium sulfate for more than 7 days, compared with those exposed for less than 3 days. Another study found a significant difference at birth in the serum values of magnesium, calcium, phosphorus, and osteocalcin between neonates unexposed to magnesium sulfate and those exposed in utero to magnesium sulfate for more than 1 week; no difference in radius bone mineral content in the 2 groups was reported. In these studies, the neonatal bone abnormalities described in association with in-utero magnesium sulfate exposure beyond 5 to 7 days included radiographic findings of radiolucent transverse metaphyseal bands of long bones such as the humerus.

Most of the epidemiologic studies that were reviewed were based on retrospective reviews of charts in individual hospitals. The epidemiologic data indicate that the effects on laboratory values resolved within days of birth. However, because of short follow-up periods, the long-term bone effects could not be studied.

A new warning about this risk has been added to the product label. Furthermore, a new Labor and Delivery section in the label emphasizes that continuous administration of magnesium sulfate injection to treat preterm labor is not approved and that the safety and efficacy of use for this indication are not established.
 

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