Cytomegalovirus antibody status at 17 - 18 weeks of gestation and preeclampsia: a case-control study of pregnant women in Norway

Objective To assess the association between maternal cytomegalovirus (CMV) antibodies in mid-pregnancy and preeclampsia. Design Nested case–control study. Setting Pregnancies registered in the Norwegian Mother and Child Cohort Study (MoBa): a large population-based pregnancy cohort (1999–2006). Sample A cohort of 1500 women with pre-eclampsia and 1000 healthy pregnant women. Methods Plasma samples and pregnancy-related information were provided by the MoBa. Antibody status (CMV IgG and CMV IgM) and levels (CMV IgG) at 17–18 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). Main outcome measure A diagnosis of pre-eclampsia, as defined in the Medical Birth Registry of Norway. Results There was no evidence of an effect of CMV IgG seropositivity on the likelihood of developing pre-eclampsia, and CMV IgG antibody levels among women who were seropositive did not differ between groups. Adjusted for maternal age, parity and smoking, the odds ratio for pre-eclampsia in women seropositive for CMV IgG was 0.89 (95% CI 0.74–1.05; P = 0.17). The proportions of women who were seropositive for IgM did not differ between women with pre-eclampsia and women who were healthy (P = 0.98). Among nulliparous women, the proportion of women who were seropositive for CMV IgG was slightly lower among women with pre-eclampsia (53.5%) than among healthy women (59.8%) (P = 0.03). Subgroup analyses were performed for women with early or late onset pre-eclampsia, with preterm delivery and/or with neonates that were small for gestational age, but antibody status did not differ between pre-eclampsia subtypes and controls. Conclusions The presence of maternal antibodies to CMV was not associated with pre-eclampsia in our study. The results suggest that CMV infection is unlikely to be a major cause of preeclampsia

Changing patterns of cytomegalovirus seroprevalence among pregnant women in Norway between 1995 and 2009 examined in the Norwegian Mother and Child Cohort Study and two cohorts from Sør-Trøndelag County: a cross-sectional study

Objectives: To examine cytomegalovirus (CMV) seroprevalence and associated risk factors for CMV seropositivity in pregnant Norwegian women. Design: Cross-sectional study. Setting: The Norwegian Mother and Child Cohort Study (MoBa) in addition to two random samples of pregnant women from Sør-Trøndelag County in Norway. Participants: Study group 1 were 1000 pregnant women, randomly selected among 46 127 pregnancies in the MoBa (1999–2006) at 17/18 week of gestation. Non-ethnic Norwegian women were excluded. Study groups 2 (n=1013 from 1995) and 3 (n=979 from 2009) were pregnant women at 12 weeks of gestation from Sør-Trøndelag County. Outcome measures: CMV seropositivity in blood samples from pregnant Norwegian women. Results: CMV-IgG antibodies were detected in 59.9% and CMV-IgM antibodies in 1.3% of pregnant Norwegian women in study group 1. Women from North Norway demonstrated a higher CMV-IgG seroprevalence (72.1%) than women from South Norway (58.5%) (OR 1.83, 95% CI 1.17 to 2.88). The CMV-IgG seroprevalence was higher among women with low education (70.5%) compared to women with higher education (OR 2.20, 95% CI 1.24 to 3.90). Between 1995 and 2009 the CMV-IgG seroprevalence increased from 63.1% to 71.4% in pregnant women from Sør-Trøndelag County (study groups 2 and 3; p<0.001). The highest CMV-IgG seroprevalence (79.0%) was observed among the youngest pregnant women (<25 years) from Sør-Trøndelag County in 2009 (study group 3). Conclusions: The CMV-IgG seroprevalence of pregnant Norwegian women varies with geographic location and educational level. Additionally, the CMV-IgG seroprevalence appears to have increased over the last years, particularly among young pregnant women

Prelabor rupture of membranes and the association with cerebral palsy in term born children: A national registry-based cohort study.

Background Guidelines regarding management of prelabor rupture of membranes (PROM) at term vary between immediate induction and expectant management. A long interval between PROM and delivery increases the risk for perinatal infections. Severe perinatal infections are associated with excess risk for cerebral palsy (CP) and perinatal death. We investigated if increasing intervals between PROM and delivery were associated with perinatal death or CP. Methods Eligible to participate in this population-based cohort-study were term born singletons without congenital malformations born in Norway during 1999–2009. Data was retrieved from the Medical Birth Registry of Norway (MBRN) and the Cerebral Palsy Register of Norway. In line with the registration in the MBRN, intervals between PROM and delivery of more than 24 h was defined as ‘prolonged’ and intervals between 12 and 24 h as ‘intermediate’. Outcomes were stillbirth, death during delivery, neonatal mortality and CP. Logistic regression was used to calculate odds ratio (OR) with 95% confidence intervals (CI) for adverse outcomes in children born after prolonged and intermediate intervals, compared with a reference group comprising all children born less than 12 h after PROM or without PROM. Results Among 559,972 births, 34,759 children were born after intermediate and 30,332 were born after prolonged intervals. There was no association between increasing intervals and death during delivery or in the neonatal period, while the prevalence of stillbirths decreased with increasing intervals. Among children born after intermediate intervals 38 (0.11%) had CP, while among those born after prolonged intervals 46 (0.15%) had CP. Compared with the reference group, the OR for CP was 1.16 (CI; 0.83 to 1.61) after intermediate and 1.61 (CI; 1.19 to 2.18) after prolonged intervals. Adjusting for antenatal factors did not affect these associations. Among children with CP the proportion with diffuse cortical injury and basal ganglia pathology on cerebral MRI, consistent with hypoxic-ischemic injuries, increased with increasing intervals. Conclusion Intervals between PROM and delivery of more than 24 h were associated with CP, but not with neonatal mortality or death during delivery. The inverse association with stillbirth is probably due to reverse causality

Congenital anomalies and the severity of impairments for cerebral palsy

Aim: To study the prevalence of congenital anomalies among children with cerebral palsy (CP) born at term or late preterm, and if CP subtypes and clinical manifestations differ between children with and without congenital anomalies. Method: This was a cross-sectional study using data from the Cerebral Palsy Register of Norway and the Medical Birth Registry of Norway. All children with congenital CP born at and later than 34 weeks’ gestation in Norway from 1999 to 2009 were included. Anomalies were classified according to the European Surveillance of Congenital Anomalies classification guidelines. Groups were compared using Fisher's exact test, Kruskal–Wallis test, and the Mann–Whitney U test. Results: Among 685 children with CP, 169 (25%) had a congenital anomaly; 125 within the central nervous system. Spastic bilateral CP was more prevalent in children with anomalies (42%) than in children without (34%; p=0.011). Children with anomalies less frequently had low Apgar scores (p<0.001), but more often had severe limitations in gross- and fine-motor function, speech impairments, epilepsy, severe vision, and hearing impairments than children without anomalies (p<0.03). Interpretation: Although children with CP and anomalies had low Apgar scores less frequently, they had more severe limitations in motor function and more associated problems than children with CP without anomalies. What this paper adds • One in four children with cerebral palsy (CP) born at term or late preterm has a congenital anomaly. • The added value of neuroimaging to detect central nervous system anomalies in children with CP. • Children with anomalies have more severe motor impairments. • More severe clinical manifestations are not explained by perinatal complications as indicated by low Apgar scores

Congenital anomalies and the severity of impairments for cerebral palsy

Aim: To study the prevalence of congenital anomalies among children with cerebral palsy (CP) born at term or late preterm, and if CP subtypes and clinical manifestations differ between children with and without congenital anomalies. Method: This was a cross-sectional study using data from the Cerebral Palsy Register of Norway and the Medical Birth Registry of Norway. All children with congenital CP born at and later than 34 weeks’ gestation in Norway from 1999 to 2009 were included. Anomalies were classified according to the European Surveillance of Congenital Anomalies classification guidelines. Groups were compared using Fisher's exact test, Kruskal–Wallis test, and the Mann–Whitney U test. Results: Among 685 children with CP, 169 (25%) had a congenital anomaly; 125 within the central nervous system. Spastic bilateral CP was more prevalent in children with anomalies (42%) than in children without (34%; p=0.011). Children with anomalies less frequently had low Apgar scores (p<0.001), but more often had severe limitations in gross- and fine-motor function, speech impairments, epilepsy, severe vision, and hearing impairments than children without anomalies (p<0.03). Interpretation: Although children with CP and anomalies had low Apgar scores less frequently, they had more severe limitations in motor function and more associated problems than children with CP without anomalies. What this paper adds • One in four children with cerebral palsy (CP) born at term or late preterm has a congenital anomaly. • The added value of neuroimaging to detect central nervous system anomalies in children with CP. • Children with anomalies have more severe motor impairments. • More severe clinical manifestations are not explained by perinatal complications as indicated by low Apgar scores

The Norwegian preeclampsia family cohort study: a new resource for investigating genetic aspects and heritability of preeclampsia and related phenotypes

Background. Preeclampsia is a major pregnancy complication without curative treatment available. A Norwegian Preeclampsia Family Cohort was established to provide a new resource for genetic and molecular studies aiming to improve the understanding of the complex pathophysiology of preeclampsia. Methods. Participants were recruited from five Norwegian hospitals after diagnoses of preeclampsia registered in the Medical birth registry of Norway were verified according to the study’s inclusion criteria. Detailed obstetric information and information on personal and family disease history focusing on cardiovascular health was collected. At attendance anthropometric measurements were registered and blood samples were drawn. The software package SPSS 19.0 for Windows was used to compute descriptive statistics such as mean and SD. P-values were computed based on t-test statistics for normally distributed variables. Nonparametrical methods (chi square) were used for categorical variables. Results. A cohort consisting of 496 participants (355 females and 141 males) representing 137 families with increased occurrence of preeclampsia has been established, and blood samples are available for 477 participants. Descriptive analyses showed that about 60 % of the index women’s pregnancies with birth data registered were preeclamptic according to modern diagnosis criteria. We also found that about 41 % of the index women experienced more than one preeclamptic pregnancy. In addition, the descriptive analyses confirmed that preeclamptic pregnancies are more often accompanied with delivery complications. Conclusion. The data and biological samples collected in this Norwegian Preeclampsia Family Cohort will provide an important basis for future research. Identification of preeclampsia susceptibility genes and new biomarkers may contribute to more efficient strategies to identify mothers “at risk” and contribute to development of novel preventative therapies.publishedVersio

Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A

BACKGROUND &amp; AIMS: Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now.METHODS: A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies.RESULTS: One specific variant (c.-98G&gt;T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G&gt;T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2).CONCLUSIONS: c.-98G&gt;T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome.IMPACT AND IMPLICATIONS: The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident.</p