Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Biomedical Informatics & Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
J Nutr. 2021 Mar 11;151(3):556-569. doi: 10.1093/jn/nxaa354.
Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway.
Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS.
We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured.
Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P < 0.001). In Pakistani participants, SQLNS increased the placental rpS6(T37/46):rpS6 ratio (1.5-fold) and decreased the AMPKA(T172):AMPKA ratio. Placental IGF1 mRNA expression was positively correlated with birth length and birth weight z-scores. Placental PAPP-A (30-fold) and maternal serum zinc (1.2-fold) increased with SQLNS. In Guatemalan participants SQLNS did not influence placental mTOR signaling. Placental IGF-1R protein expression was positively associated with birth length and birth weight z-scores. SQLNS increased placental PAPP-A (40-fold) and maternal serum IGFBP-4 (1.6-fold).
In Pakistani pregnant women with poor nutritional status, preconceptional SQLNS activated placental mTOR and IGF-1 signaling and was associated with improved fetal growth. In contrast, in Guatemalan women SQLNS did not activate placental nutrient-sensing pathways. In populations experiencing childhood stunting, preconceptional SQLNS improves placental function and fetal growth only in the context of poor maternal nutrition. This trial was registered at clinicaltrials.gov as NCT01883193.
正如“妇女第一孕期营养预试验（WF）”所示，母亲在受孕前小剂量脂质营养补充（SQLNS）可改善子宫内线性生长。胎儿的生长取决于营养物质的供应，并通过胰岛素样生长因子 1（IGF-1）来调节，这是通过改变胎盘的转移能力来实现的，而这种能力是由机械靶标雷帕霉素（mTOR）途径介导的。
我们的目的是评估 2 个资源匮乏国家的孕妇在接受受孕前 SQLNS 后，胎盘 mTOR 和 IGF-1 信号对胎儿生长的作用。这些国家的胎儿生长迟缓发生率很高。
我们研究了 48 名来自危地马拉和巴基斯坦的妇女，她们在受孕前到分娩期间接受了 SQLNS 或未接受 SQLNS，这是 WF 研究的一部分。在分娩时获得胎盘样本（对照组，n=24；SQLNS 组，n=24）。测定胎盘真核起始因子结合蛋白-1（4E-BP1）、核糖体蛋白 S6（rpS6）、AMP 激活蛋白激酶α（AMPKA）、IGF-1、胰岛素样生长因子受体（IGF-1R）和妊娠相关血浆蛋白（PAPP）-A 的胎盘蛋白或 mRNA 表达，以及 IGF1 启动子的 DNA 甲基化。测定母体血清 IGF-1、胰岛素样生长因子结合蛋白（IGFBP）-3、IGFBP-4、IGFBP-5、PAPP-A、PAPP-A2 和锌的水平。
参与者的平均母体孕前 BMI 在危地马拉（26.5±1.3）和巴基斯坦（19.8±0.7）之间存在差异（P<0.001）。在巴基斯坦参与者中，SQLNS 增加了胎盘 rpS6（T37/46）：rpS6 比值（1.5 倍），并降低了 AMPKA（T172）：AMPKA 比值。胎盘 IGF1 mRNA 表达与出生长度和体重 Z 分数呈正相关。胎盘 PAPP-A（30 倍）和母体血清锌（1.2 倍）随 SQLNS 而增加。在危地马拉参与者中，SQLNS 并未影响胎盘 mTOR 信号。胎盘 IGF-1R 蛋白表达与出生长度和体重 Z 分数呈正相关。SQLNS 增加了胎盘 PAPP-A（40 倍）和母体血清 IGFBP-4（1.6 倍）。
在营养状况较差的巴基斯坦孕妇中，受孕前 SQLNS 激活了胎盘 mTOR 和 IGF-1 信号，并与胎儿生长改善有关。相比之下，在危地马拉妇女中，SQLNS 并没有激活胎盘营养感应途径。在经历儿童期生长迟缓的人群中，受孕前 SQLNS 仅在母体营养不良的情况下才能改善胎盘功能和胎儿生长。这项试验在 clinicaltrials.gov 上注册为 NCT01883193。
