Markers of placental insufficiency: etiology and the risk of cerebral palsy:Population based studies of preeclampsia, low birth weight, and abnormal placental weight

Abstract

Placental insufficiency may be defined as a placenta not able to perform its central tasks; namely, delivery of sufficient oxygen and nutrients to the developing fetus. In this thesis, preeclampsia, fetal growth restriction (FGR), and abnormal placental weight were applied as markers of placental insufficiency. Abnormal interaction between fetal and maternal tissues during placentation, leading to shallow placentation, may be the commencing step of placental insufficiency. Cytomegalovirus (CMV), a virus capable of infecting the placenta, has been suggested to potentially harm placentation and thereby initiate the pathophysiological cascade leading to preeclampsia. However, results from epidemiological studies assessing maternal CMV antibodies in pregnancy and development of preeclampsia have been inconclusive. At the other end of placental insufficiency, is its potential to compromise the fetus by limiting oxygen supply and ultimately cause fetal death. The etiology of cerebral palsy (CP), a disorder often considered to be an intermediate outcome between a healthy infant and neonatal death, remains largely unknown. The placenta has recently been highlighted as an area of major interest in CP etiology. The aim of this thesis was to assess CMV infection as a potential etiological factor in preeclampsia (paper I) and to study the association between markers of placental insufficiency and CP (papers II and III). Paper I was a case control study based on the Norwegian Mother and Child Cohort Study and included 1500 women with preeclampsia (cases) and 1000 women without preeclampsia (controls). Maternal antibodies to CMV were analyzed in plasma samples collected at 17-18 weeks of gestation. The proportion of women seropositive for CMV antibodies did not differ between cases and controls. Thus, this study could not find evidence of CMV infection as a potential etiological factor in preeclampsia pathogenesis. Data for papers II and III were obtained by linkage of the Cerebral Palsy Register of Norway (CPRN) and the Medical Birth Registry of Norway (MBRN). The CPRN contains detailed clinical data about children with CP, and pregnancy and perinatal data were available in the MBRN. In Paper II, the association between preeclampsia and cerebral palsy was assessed, and singleton children that survived the first week of life in Norway during 1996-2006 were included. Preeclampsia was associated with an increased risk of CP. This association was mainly mediated through the children being born preterm and/or small for gestational age (SGA- a proxy for FGR). Children exposed to preeclampsia and born at term with normal birth weight had no excess risk of CP, indicating that preeclampsia may not have a direct effect on the risk of CP. In Paper III, we analyzed the association between low or high placental weight and CP, and included all singleton infants born alive in Norway during 1999-2008. Low placental weight, low placental weight/birth weight ratio, and low placental weight/birth length ratio were associated with an increased risk of CP. Regarding CP subtypes, the most consistent finding was a high risk of spastic bilateral CP associated with low placental weight and low placental weight/birth length ratio. These results warrant further study of poor placental reserve as a potential cause of CP. Thus, the main conclusions of this thesis are that CMV infection in early pregnancy unlikely is a major contributing factor in the pathogenesis of preeclampsia, and that placental insufficiency may play a significant role in the etiology of CP, in particular through its effect on fetal growth and preterm delivery.