OBJECTIVE To investigate the association of falling insulin requirements (FIR) among women with pre-existing diabetes with adverse obstetric outcomes and maternal biomarkers longitudinally in pregnancy.

RESEARCH DESIGN AND METHODS A multicenter prospective cohort study of 158 women (41 with type 1 diabetes and 117 with type 2 diabetes) was conducted. Women with FIR of ≥15% from the peak total daily dose after 20 weeks gestation were considered case subjects (n = 32). The primary outcome was a composite of clinical markers of placental dysfunction (pre-eclampsia, small for gestational age [≤5th centile], stillbirth, premature delivery [<30 weeks], and placental abruption). Maternal circulating angiogenic markers (placental growth factor [PlGF] and soluble fms-like tyrosine kinase 1 [sFlt-1]), placental hormones (human placental lactogen, progesterone, and tumor necrosis factor-α), HbA_1c, and creatinine were studied serially during pregnancy.

RESULTS FIR ≥15% was associated with an increased risk of the composite primary outcome (odds ratio [OR] 4.38 [95% CI 1.9–10.3]; P < 0.001), pre-eclampsia (OR 6.76 [95% CI 2.7–16.7]; P < 0.001), and was more common among women with type 1 diabetes (36.6 vs. 14.5%; P = 0.002). Creatinine was modestly elevated among women with FIR ≥15%; however, there was no difference in HbA_1c. The ratio of sFlt-1 to PlGF was significantly higher among women with FIR at 25, 30, and 36 weeks, with differences maintained in the subgroup that developed pre-eclampsia. There was no difference in placental hormones between the groups.

CONCLUSIONS This is the first prospective study to associate FIR with altered expression of placental antiangiogenic factors and pre-eclampsia. FIR is an important clinical sign, among women with pre-existing diabetes, that should alert the clinician to investigate underlying placental dysfunction.

目的探讨妊娠期糖尿病患者中胰岛素需求下降（FIR）与产科不良结局和孕产妇生物标志物之间的相关性。

研究设计和方法进行了158名妇女（41名1型糖尿病和117名2型糖尿病）的多中心前瞻性队列研究。妊娠20周后FIR≥每日总峰值峰值≥15％的女性被视为病例受试者（n = 32）。主要结局是胎盘功能障碍临床指标的综合（先兆子痫，胎龄小[≤5％]，死产，早产[<30周]和胎盘早剥）。研究了孕妇循环血管生成标记物（胎盘生长因子[PlGF]和可溶性fms样酪氨酸激酶1 [sFlt-1]），胎盘激素（人胎盘催乳素，孕激素和肿瘤坏死因子-α），HbA _1c和肌酐。在怀孕期间连续进行。

结果FIR≥15％与综合主要结局风险增加（赔率[OR] 4.38 [95％CI 1.9-10.3]；P <0.001），先兆子痫（OR 6.76 [95％CI 2.7-16.7] ]；P <0.001），并且在1型糖尿病女性中更为常见（36.6比14.5％；P = 0.002）。FIR≥15％的女性中肌酐水平适度升高；但是，HbA _1c没有差异。FIR患者在25、30和36周时sFlt-1与PlGF的比例显着更高，在先兆子痫的亚组中保持了差异。两组之间的胎盘激素没有差异。

结论这是第一项将FIR与胎盘抗血管生成因子表达改变和先兆子痫相关的前瞻性研究。在患有糖尿病的女性中，FIR是重要的临床体征，应提醒临床医生调查潜在的胎盘功能障碍。