孕期糖尿病24週前之孕婦使用metformin的療效和安全性：系統性回顧、統合分析及臨床試驗計畫書

Abstract

1.研究背景 孕期糖尿病（diabetes mellitus in pregnancy）包括孕前糖尿病（preexisting diabetes mellitus, PDM）、孕期中新診斷糖尿病（undiagnosed diabetes mellitus）及妊娠糖尿病（gestational diabetes mellitus, GDM）。 在孕前糖尿病的患者中，大多數為第2型糖尿病（type 2 diabetes mellitus, T2DM）。Metformin 作為一種口服降血糖藥物，已被證實可改善胰島素敏感性、降低肝臟葡萄糖生成並減少腸道葡萄糖吸收。目前，大多數臨床指引建議 metformin作為非懷孕T2DM患者的一線治療。然而，由於metformin會通過胎盤，加上安全性的資料相對有限，對於懷孕早期使用的安全性仍存在疑慮，目前並不建議在孕前糖尿病與妊娠糖尿病做為第一線的治療藥物，其適用性仍存在爭議。本研究的目的在於透過系統性回顧與統合分析，探討metformin在懷孕早期用於治療孕前糖尿病與早期妊娠糖尿病的療效與安全性。 2.研究方法 透過檢索PubMed、Embase及Cochrane電子資料庫平台搜尋相關醫學文獻，共篩選出152篇文獻，其中符合納入與排除條件的5篇隨機對照試驗（RCT）被納入本系統性回顧與統合分析。評估指標包括：生產前最後一次糖化血色素（HbA1c）濃度、妊娠高血壓、子癇前症及剖腹產、早產、產傷、肩難產、出生體重、產下小於胎齡兒、產下大於胎齡兒、新生兒體脂肪量、新生兒黃疸、新生兒低血糖、呼吸窘迫症候群、入住新生兒加護病房、流產、胎死腹中及新生兒死亡。 3.研究結果 本研究共納入5項研究，共1522受試者進行統合分析。使用metformin或metformin聯合胰島素與單獨使用胰島素相比，顯著降低：妊娠高血壓風險（OR 0.60 [95% CI 0.37–0.96]; p=0.03）、出生體重 Z分數（差異 -0.36 [-0.50 – -0.22]; p<0.00001）、大於胎齡兒（LGA）比例（OR 0.71 [0.56 – 0.89]; p=0.003）、新生兒加護病房（NICU）住院率（OR 0.57 [0.35 – 0.95]; p=0.03）及胎死腹中風險（OR 0.36 [0.13 – 1.00]; p=0.05）；然而，使用metformin可能會增加小於胎齡兒（SGA）出生的風險（OR 1.87 [1.27 – 2.75]; p=0.002）。 進一步的次分組分析顯示，metformin 聯合胰島素與單獨使用胰島素相比，有較低的出生體重Z分數（差異 -0.36 [-0.50 – -0.22]; p<0.00001），並可顯著降低胎死腹中風險（OR 0.36 [0.13 – 1.00]; p=0.05）。此外，單獨使用metformin相較於單獨使用胰島素可顯著降低NICU住院率（OR 0.37 [0.14 – 0.99]; p=0.05）。 4.研究結論 本統合分析顯示，在懷孕24週前使用metformin可降低妊娠高血壓、大於胎齡兒、出生體重Z分數、NICU住院率及胎死腹中。然而，受限於研究數量有限，且不同亞組分析之間存在差異，仍需進一步研究來確認在孕前糖尿病與早期妊娠糖尿病使用metformin對母體及胎兒的長期影響。

1.Background Diabetes mellitus in pregnancy includes pre-existing diabetes mellitus (PDM) and gestational diabetes mellitus (GDM). In pregnant patients with PDM, most have type 2 diabetes (T2DM). Metformin is a well-established oral hypoglycemic agent that improves insulin sensitivity, decreases hepatic glucose production, and reduces intestinal glucose absorption. Most clinical guidelines recommend metformin as the first-line medication for the non-pregnant T2DM. However, because metformin can cross the placenta, there are safety concerns regarding its use in PDM and GDM in early pregnancy. The aim of this study is to explore the efficacy and safety of metformin use in early pregnancy for the treatment of PDM and early GDM through a systematic review and meta-analysis. 2.Method A search of PubMed, Embase, and the Cochrane electronic database platform for relevant medical literature, a total of 152 articles was identified. Of these, five randomized clinical trials met the inclusion and exclusion criteria and were included in the systematic review and meta-analysis. The evaluated outcomes included final pre-delivery glycated hemoglobin (HbA1c) levels, gestational hypertension, preeclampsia, cesarean section, preterm birth, birth trauma, shoulder dystocia, birth weight, small for gestational age (SGA), large for gestational age (LGA), neonatal body fat mass, neonatal jaundice, neonatal hypoglycemia, respiratory distress syndrome, admission to the neonatal intensive care unit (NICU), miscarriage, stillbirth and neonatal death. 3.Results We identified five studies comprising 1522 participants which were included in this meta-analysis. Compared to insulin alone, metformin alone or metformin combined with insulin significantly reduces the risks of gestational hypertension (odds ratio [OR] 0.60 [95% CI 0.37-0.96]; p=0.03), birth weight Z score (difference -0.36 [-0.50 - -0.22]; p < 0.00001), LGA neonates (OR 0.71 [0.56 - 0.89]; p=0.003), NICU admissions (OR 0.57 [0.35 - 0.95]; p=0.03) and stillbirth (OR 0.36 [0.13 - 1.00]; p=0.05). However, this treatment is associated with an increased risk of delivering SGA neonates (OR 1.87 [1.27 - 2.75]; p=0.002). Subgroup analysis revealed that treatment with metformin combined with insulin group was significantly associated with reduced birth weight Z scores (difference -0.36 [-0.50 - -0.22]; p < 0.00001) and a lower the risk of stillbirth (OR 0.36 [0.13 - 1.00]; p=0.05), compared with insulin alone. Similarly, the metformin alone group significantly decreases the risk of NICU admission (rates OR 0.37 [0.14 - 0.99]; p=0.05) compared to the insulin alone group. 4.Conclusion This meta-analysis reveals that metformin use before 24 weeks of gestation reduces the risks of gestational hypertension, stillbirth, LGA, birth weight Z score and NICU admission. However, limited study numbers and subgroup differences affect generalizability, warranting further research to confirm long-term effects.