Life after placental dysfunction: the mother's renal function and her child's health

Introduction: over the last decades it has become apparent that implications of pregnancy complications are not limited to the pregnancy itself, but extend to later life, not only for the exposed mother, but also for the exposed child. After placental dysfunction, characterized by the development of preeclampsia and/or fetal growth restriction (FGR), women and their children are reported to have an increased risk of cardiovascular and kidney disease. This thesis aimed to elucidate mechanisms that contribute to these long-term cardiovascular consequences in both groups.

The mother’s renal and vascular function: in two large Dutch cohorts we examined kidney function after preeclampsia and other hypertensive disorders of pregnancy.Despite the presence of increased cardiovascular risk profiles, we observed only subtle alterations in kidney function without a clinically relevant decline in renal function in women after hypertensive disorders of pregnancy. Since our populations contained high use of anti-hypertensive medication, we expect that screening for blood pressure instead of kidney function and early start of blood pressure lowering therapy might adequately prevent the increased renal risk in these women to translate into overt renal disease. In a mechanistic study in humans we show impaired sodium dependent adaption of arterial stiffness in response to low sodium diet in women with a history of preeclampsia. As this finding might be related to the higher filtration fraction and increased angiotensin II sensitivity reported in the same cohort, this implicates renin-angiotensin system (RAS) blockade as preferential blood pressure lowering strategy in women after preeclampsia. A animal study showed that exposure to experimental placental ischemia is accompanied by postpartum subclinical impairment of heart and kidney function and thereby supports the theory that preeclampsia itself might leave subtle, but long lasting, scars. This suggests that preventing preeclampsia and/or recurrent preeclampsia might reduce maternal cardiovascular risk subsequent to these pregnancy complications.

Placental function and the child’s health: the association between placental dysfunction and increased risk of cardiovascular disease in the child is thought to result from exposure to an adverse intrauterine environment that negatively influences the development of organ function and structure (a process called programming or developmental plasticity). To expand our knowledge on factors that influence placental function and fetal growth, we assessed epigenetic disturbances in placenta from pregnancies affected by FGR. We show that the FGR placenta exhibits substantial genome-wide alterations in H3K27 acetylation, with corresponding changes in transcription profiles in several chromosomal regions relevant to placental function. In addition we performed a preclinical meta-analysis on the effects of a potential new intervention, the phosphodiesterase inhibitor sildenafil, for the treatment of placental dysfunction and show that sildenafil can increase fetal growth by up to 10%.

Conclusion: mechanistic studies in women and children after placental dysfunction help to identify effective targets for screening and prevention programs aimed at reducing cardiovascular disease after placental dysfunction. Future research should investigate whether risk for cardiovascular disease after placental dysfunction as well as FGR can simultaneously be modulated before and during pregnancy by optimization of periconceptional and perinatal care.