The Generation R Study Group, Erasmus MC, University Medical Centre, PO Box 2040, 3000 Rotterdam, CA, The Netherlands Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, PO Box 2040, 3000 Rotterdam, CA, The Netherlands
The Generation R Study Group, Erasmus MC, University Medical Centre, PO Box 2040, 3000 Rotterdam, CA, The Netherlands Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, PO Box 2040, 3000 Rotterdam, CA, The Netherlands.
Hum Reprod. 2015 Jun;30(6):1302-13. doi: 10.1093/humrep/dev070. Epub 2015 Apr 8.
What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) concentrations on fetal and childhood growth patterns?
An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PlGF concentrations and higher sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth.
An imbalance in maternal and fetal sFlt-1 and PlGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown.
STUDY DESIGN, SIZE, DURATION: This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005).
PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA).
Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birthweight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PlGF concentrations in the lowest quintile were associated with a reduced weight growth pattern resulting in a smaller birthweight (difference in birthweight -0.34 SDS; 95% CI -0.44, -0.25), an increased risk of SGA (OR 3.48; 95% CI 2.39-5.08) and a lower weight growth throughout childhood. An early pregnancy maternal sFlt-1:PlGF ratio in the highest quintile was associated with a higher fetal weight growth pattern from 30 weeks onwards, resulting in a higher weight at birth (difference in birthweight 0.09 SDS; P-value <0.05), which remained present until the age of 2 years. Newborns with higher umbilical cord sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio showed a lower fetal and childhood weight growth from 30 weeks gestation onwards until the age of 6 years (P-value <0.05). Similar patterns were observed in relation to fetal and childhood length growth.
LIMITATIONS, REASONS FOR CAUTION: The study is an observational study. Therefore, no causal relationships can be established.
Both a maternal and fetal angiogenic imbalance may affect fetal and childhood growth. Changes in angiogenic profiles may be involved in the pathways linking fetal growth restriction with the long-term risk of vascular disease in adulthood.
STUDY FUNDING/COMPETING INTERESTS: The first phase of the Generation R Study is made possible by financial support from The Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.W.V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI). M.I.B.-B. is financially supported by the Bo Hjelt foundation (grant 2009). The authors have no competing interests.
母体和胎儿可溶性 fms 样酪氨酸激酶 1（sFlt-1）和胎盘生长因子（PlGF）浓度对胎儿和儿童生长模式有什么影响？
在妊娠早期母体 sFlt-1 和 PlGF 浓度较低且脐带血中 sFlt-1 浓度较高、PlGF 浓度较低或 sFlt-1:PlGF 比值较高的情况下，其特征为血管生成谱异常，与胎儿和儿童生长受限相关。
母体和胎儿 sFlt-1 和 PlGF 浓度失衡已被认为会影响妊娠结局。然而，它们对胎儿和儿童纵向生长的影响在很大程度上仍然未知。
研究设计、规模、持续时间：本研究在荷兰鹿特丹的一项基于人群的前瞻性队列研究——Generation R 研究中进行，该研究从胎儿期开始一直进行到 2001-2005 年。共有 5980 名母亲及其 4108 名子女参与了该研究。
参与者/材料、设置、方法：在妊娠早期和中期以及分娩时从母亲的静脉中抽取血液样本。通过超声和体格检查反复测量胎儿和儿童的生长特征（体重和长度），直到 6 岁。我们使用重复测量回归模型评估母体和胎儿血管生成因子与胎儿和儿童生长之间的关联。使用逻辑回归模型确定血管生成因子与出生体重不足（SGA）的关系。
与妊娠早期母体 sFlt-1 浓度最低五分位数相比，妊娠早期母体 sFlt-1 浓度最高五分位数与胎儿体重增长较高相关，导致出生体重较高（出生体重差异 0.33 标准差分数（SDS）；95%置信区间（CI）0.25-0.41），SGA 风险降低（优势比（OR）0.36；95%CI 0.27-0.48），直至 6 岁时体重增长更高。妊娠早期母体 PlGF 浓度最低五分位数与体重增长模式相关，导致出生体重较小（出生体重差异-0.34 SDS；95%CI-0.44，-0.25），SGA 风险增加（OR 3.48；95%CI 2.39-5.08），儿童期体重增长较低。妊娠早期母体 sFlt-1:PlGF 比值最高五分位数与 30 周后胎儿体重增长模式较高相关，导致出生体重较高（出生体重差异 0.09 SDS；P 值<0.05），直至 2 岁时仍存在。脐带血中 sFlt-1 浓度较高、PlGF 浓度较低或 sFlt-1:PlGF 比值较高的新生儿，从 30 孕周开始，胎儿和儿童体重增长较慢，直至 6 岁（P 值<0.05）。与胎儿和儿童长度生长也观察到类似的模式。
局限性、谨慎的原因：该研究是一项观察性研究。因此，不能建立因果关系。
母体和胎儿血管生成失衡可能会影响胎儿和儿童的生长。血管生成谱的变化可能参与了将胎儿生长受限与成年后血管疾病的长期风险联系起来的途径。
研究资金/利益冲突：Generation R 研究的第一阶段得到了鹿特丹伊拉斯谟医学中心、鹿特丹伊拉斯谟大学和荷兰健康研究与发展组织（ZonMw 21000074）的财政支持。V.W.V.J. 还获得了荷兰健康研究与发展组织（ZonMw VIDI）的额外资助。M.I.B.-B. 得到了 Bo Hjelt 基金会（2009 年）的资助。作者没有利益冲突。
