Early pregnancy maternal and fetal angiogenic factors and fetal and childhood growth: the Generation R Study.

STUDY QUESTION: 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?

SUMMARY ANSWER: 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.

WHAT IS KNOWN ALREADY: 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).

MAIN RESULTS AND THE ROLE OF CHANCE: 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.

WIDER IMPLICATIONS OF THE FINDINGS: 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.