Aims/Hypothesis Higher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity coupled with a favourable metabolic profile, in a Mendelian Randomisation (MR) study comparing the effect of maternal "metabolically favourable adiposity" on offspring birth weight with the effect of maternal general adiposity (as indexed by BMI). Methods To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birth weight, we performed two sample MR. We used variants identified in large genetic association studies as associated with either higher adiposity and a favourable metabolic profile, or higher BMI (N = 442,278 and N = 322,154 for metabolically favourable adiposity and BMI, respectively). We then used data from the same variants in a large genetic study of maternal genotype and offspring birth weight independent of fetal genetic effects (N = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total N = 9,323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birth weight and cord-blood biomarkers. Results Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birth weight (-94 (95% CI: -150 to -38) grams per 1 SD (6.5%) higher maternal metabolically favourable adiposity). By contrast, higher maternal BMI was associated with higher offspring birth weight (35 (95% CI: 16 to 53) grams per 1 SD (4 kg/m2) higher maternal BMI). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures and their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels whilst maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birth weight, but the smaller sample sizes for these analyses meant the effects were imprecisely estimated. We also found evidence to suggest that maternal metabolically favourable adiposity decreases cord-blood leptin whilst maternal BMI increases it. Conclusions/Interpretation Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birth weight. Higher maternal adiposity can lead to lower offspring birth weight if accompanied by a favourable metabolic profile.

中文翻译：

---

如果具有代谢上有利的特征，则较高的母亲肥胖度可降低后代出生体重

目的/假设孕妇在怀孕期间的BMI较高会导致后代的出生体重增加，但尚不知道这是否仅是由于母亲肥胖增加的新陈代谢带来的不利后果，例如母亲胰岛素抵抗和胎儿暴露于较高的葡萄糖水平，还是非代谢性因素（例如机械性因素）会增加肥胖症。在一项孟德尔随机化（MR）研究中，我们旨在使用已知易于导致较高肥胖和有利代谢特征的遗传变异，将母亲“代谢良好肥胖”对后代出生体重的影响与母亲一般肥胖的影响进行比较（如由BMI索引）。方法为了检验母体代谢性肥胖或一般性肥胖对后代出生体重的因果关系，我们执行了两个样本MR。我们使用了在大型遗传关联研究中确定的变体，这些变体与较高的肥胖率和良好的代谢状况或较高的BMI有关（对于代谢有利的肥胖症和BMI分别为N = 442,278和N = 322,154）。然后，我们在独立于胎儿遗传影响的母体基因型和后代出生体重的大型遗传研究中使用了来自相同变体的数据（根据母体和/或胎儿基因型影响估计值，N = 406,063）。我们使用了几项敏感性分析来测试结果的可靠性。作为次要分析，我们使用了来自四个队列（总共N = 9,323对母子对）的数据来检验孕产妇代谢良好的肥胖或BMI对孕产妇妊娠葡萄糖，出生体重的人体测量学成分和脐带血生物标志物的影响。结果具有较高代谢代谢特征的较高的母亲肥胖与较低的后代出生体重相关（每1 SD（6.5％）较高的母亲代谢有利的脂肪为-94（95％CI：-150至-38）克）。相比之下，较高的母亲BMI与较高的后代出生体重相关（每1 SD（4 kg / m2）较高的母亲BMI 35克（95％CI：16至53）克）。敏感性分析与主要结果大致一致。有证据表明，两次暴露均存在异常的SNP，将其去除会略微增强新陈代谢对肥胖的影响，对BMI的影响也没有影响。我们的二级分析发现了证据，表明母亲的代谢有利的肥胖症会降低孕妇的禁食血糖水平，而母亲的BMI会增加这些指标。对新生儿人体测量学特征的影响与对出生体重的总体影响一致，但这些分析的样本量较小，意味着对影响的估计不准确。我们还发现有证据表明，孕妇代谢有利的肥胖症会降低脐血瘦素，而孕妇BMI会增加。结论/解释我们的结果表明，母亲的肥胖率较高并不一定会导致后代出生体重增加。如果伴有良好的代谢特征，较高的母亲肥胖可导致较低的后代出生体重。我们还发现有证据表明，孕妇代谢有利的肥胖症会降低脐血瘦素，而孕妇BMI会增加。结论/解释我们的结果表明，母亲的肥胖率较高并不一定会导致后代出生体重增加。如果伴有良好的代谢特征，较高的母亲肥胖可导致较低的后代出生体重。我们还发现有证据表明，孕妇代谢有利的肥胖症会降低脐血瘦素，而孕妇BMI会增加。结论/解释我们的结果表明，母亲的肥胖率较高并不一定会导致后代出生体重增加。如果伴有良好的代谢特征，较高的母亲肥胖可导致较低的后代出生体重。