二甲双胍对后代健康的长期影响:当前证据及未来方向综述

Long-term effects of metformin on offspring health: A review of current evidence and future directions.

作者信息

Mayadunne Tharaka, Saadati Saeede, Asmelash Daniel, Mason Taitum, Vanky Eszter, Teede Helena, Mousa Aya

机构信息

School of Medicine, Deakin University, Geelong, Victoria, Australia.

Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.

出版信息

Diabetes Obes Metab. 2025 Jun;27 Suppl 3(Suppl 3):48-63. doi: 10.1111/dom.16418. Epub 2025 May 6.

Abstract

Metformin is widely prescribed for the management of type 2 diabetes mellitus, polycystic ovary syndrome, and gestational diabetes mellitus in pregnancy. Its use is driven by factors including oral administration, lower patient and health system burden and cost, and benefits including lower risk of excess gestational weight gain and hypoglycemia compared with insulin. Metformin use appears safe in pregnancy; however, there remain concerns regarding long-term effects of intrauterine metformin exposure on offspring health. Randomized controlled trial follow-up studies suggest that metformin-exposed offspring may have altered postnatal growth trajectories and increased adiposity in childhood, although data are limited. Whether this is a transient adaptation or a precursor to long-term metabolic dysfunction is unclear, as data on cardiometabolic and neurodevelopmental parameters, including glucose homeostasis, lipid metabolism, and cognitive function, are sparse and inconsistent. Methodological challenges include heterogeneous study designs, high attrition rates, and inadequate control for confounding variables. Given these uncertainties, further well-powered, long-term prospective studies and individual patient data meta-analyses, harmonizing data and adjusting for confounders, are needed to clarify risks and benefits of metformin use in pregnancy. Until such data are available, clinicians must weigh the benefits and advantages of metformin use in pregnancy against the unknowns regarding potential long-term impact on offspring health. PLAIN LANGUAGE SUMMARY: Metformin is a medicine often used during pregnancy to help manage conditions such as type 2 diabetes, gestational diabetes, and polycystic ovary syndrome (PCOS). It is commonly chosen because it is taken as a tablet rather than by injection, has a lower risk of causing low blood sugar, and is generally easier and less expensive to use than insulin. Research has shown that metformin is safe for use during pregnancy in the short term. However, there are still questions about whether it has any lasting effects on children who were exposed to it before birth. This review explores this topic in detail. Some studies have found that children exposed to metformin during pregnancy may have slightly different growth patterns, such as having more body fat or being heavier in early childhood. However, these results are inconsistent and most studies show no clear differences in overall health outcomes, including in heart health, metabolism, or brain development. The results are mixed, and many studies are small or have design limitations, which makes it difficult to draw strong conclusions. At this stage, there is no clear evidence that metformin causes harm to children in the long term. However, because some studies suggest there may be effects on childhood growth and development, researchers emphasize the need for further long-term research. These future studies should follow children into adolescence and adulthood to better understand any lasting impacts. Until more is known, doctors and patients will need to carefully consider the known benefits of metformin in pregnancy alongside the current uncertainties about long-term effects on child health.

摘要

二甲双胍被广泛用于治疗2型糖尿病、多囊卵巢综合征和妊娠期糖尿病。其使用的驱动因素包括口服给药、较低的患者和卫生系统负担及成本,以及与胰岛素相比,具有较低的妊娠期体重过度增加和低血糖风险等益处。二甲双胍在孕期使用似乎是安全的;然而,宫内暴露于二甲双胍对后代健康的长期影响仍令人担忧。随机对照试验随访研究表明,尽管数据有限,但暴露于二甲双胍的后代可能出生后生长轨迹改变,儿童期肥胖增加。这是短暂的适应性变化还是长期代谢功能障碍的先兆尚不清楚,因为关于心脏代谢和神经发育参数(包括葡萄糖稳态、脂质代谢和认知功能)的数据稀少且不一致。方法学挑战包括研究设计的异质性、高失访率以及对混杂变量控制不足。鉴于这些不确定性,需要进一步开展有足够效力的长期前瞻性研究和个体患者数据荟萃分析,整合数据并对混杂因素进行调整,以阐明孕期使用二甲双胍的风险和益处。在获得此类数据之前,临床医生必须权衡孕期使用二甲双胍的益处与对后代健康潜在长期影响的未知因素。

通俗易懂的总结

二甲双胍是孕期常用的一种药物,用于帮助控制2型糖尿病、妊娠期糖尿病和多囊卵巢综合征(PCOS)等病症。通常选择它是因为它是口服片剂而非注射用药,导致低血糖的风险较低,而且总体上比胰岛素使用起来更方便、成本更低。研究表明,二甲双胍在孕期短期使用是安全的。然而,对于它是否会对出生前接触过该药物的儿童产生任何持久影响,仍存在疑问。这篇综述详细探讨了这个话题。一些研究发现,孕期接触二甲双胍的儿童可能生长模式略有不同,比如在幼儿期体脂更多或体重更重。然而,这些结果并不一致,大多数研究表明在总体健康结果方面没有明显差异,包括心脏健康、新陈代谢或大脑发育。结果好坏参半,而且许多研究规模较小或存在设计缺陷,这使得难以得出强有力的结论。现阶段,没有明确证据表明二甲双胍会对儿童产生长期危害。然而,由于一些研究表明可能对儿童生长发育有影响,研究人员强调需要进一步开展长期研究。这些未来的研究应该跟踪儿童到青少年期和成年期,以更好地了解任何持久影响。在了解更多情况之前,医生和患者需要仔细权衡二甲双胍在孕期的已知益处以及目前对儿童健康长期影响的不确定性。

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