Nils-Halvdan Morken

Preterm birth in Sweden 1973-2001: Rate, subgroups, and effect of changing patterns in multiple births, maternal age, and smoking

Background.  The objectives of this report are to evaluate changes in the preterm birth rate in Sweden 1973–2001. Furthermore, describe the proportion of spontaneous and indicated preterm births and assess risk factors for the subgroups of preterm birth during the period from 1991 to 2001.

Secular trends in the epidemiology of pre-eclampsia throughout 40 years in Norway: prevalence, risk factors and perinatal survival

Pre-eclampsia is a leading complication of pregnancy, associated with maternal and neonatal morbidity. The present study describes the epidemiology of pre-eclampsia in Norway, with data from the Medical Birth Registry of Norway, covering 40 years. We aimed at describing time trends in prevalence, selected risk factors and perinatal mortality. We also analysed time trends in recurrence risk of total pre-eclampsia and pre-eclampsia with preterm delivery. A total of 2,416,501 women giving birth during 1967-2008 were included. Prevalence of pre-eclampsia increased from 1967 to 1999 and decreased thereafter, with an overall prevalence of 3%. Rates increased more over time among younger than older women, resulting in a significantly lower excess risk of pre-eclampsia associated with high maternal age in later years. For example, relative risk (RR) of pre-eclampsia among primiparae aged ≥35 relative to <25 years changed from 2.4 [95% confidence interval (CI) 2.1, 2.7] in 1967-1976 to 1.2 [95% CI 1.1, 1.3] in 1999-2008. For recurrence risk, subsequent pregnancies to a mother were linked, with the mother being the unit of analysis. Recurrence risk of pre-eclampsia was high, particularly recurrence of preterm pre-eclampsia, with overall RR close to 50 of a second pregnancy with pre-eclampsia and preterm birth compared with women without pre-eclampsia in first pregnancies. Finally, stillbirth associated with pre-eclampsia decreased more than neonatal mortality over time, and in the last 5 years only a moderate excess risk of stillbirth and neonatal death was observed.

Quantification of Ureaplasma urealyticum DNA in the amniotic fluid from patients in PTL and pPROM and its relation to inflammatory cytokine levels.

Objective. To study the effect of the amniotic fluid quantity of Ureaplasma urealyticum DNA on inflammatory response levels in women with preterm labor (PTL) and preterm prelabor rupture of membranes (pPROM). Design. A prospective multi‐center follow up study. Setting. Sahlgrenska University Hospital, Göteborg, Sweden and Turku University Hospital, Turku, Finland. Sample. Eleven U. urealyticum positive samples obtained after transabdominal amniocenteses in 197 women presenting with PTL and pPROM. Methods. The U. urealyticum positive samples were analyzed with real‐time polymerase chain reaction, using the Lightcycler instrument with primers specific for U. urealyticum 16 S rDNA. The amniotic fluid samples were analyzed for tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, IL‐1β and IL‐10 with enzyme‐linked immunosorbent assays. Main outcome measures. Correlation between U. urealyticum DNA concentrations in the amniotic fluid and inflammatory cytokine levels. Results. The concentrations of U. urealyticum DNA varied between 0.024 and 934 μg/mL. A significant correlation between U. urealyticum DNA and TNF‐α level was observed. No correlation with the other cytokines was found. Women with PTLhad higher levels of U. urealyticum DNA and a different cytokine pattern than women with pPROM. Conclusions. U. urealyticum in the amniotic fluid induces an inflammatory reaction in a dose dependent manner and the quantity of U. urealyticum DNA is well correlated with the level of the inflammatory cytokine TNF‐α.

Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK)

Background Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight. Objectives We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS–birth weight association observed in epidemiologic studies might be attributable to GFR. Methods We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta-analysis of epidemiologic data. Results The reduction in birth weight for each 1-ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: –3.40, –2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: –8.46, –5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR–birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: –21.66, –7.78) and 14.72 g (95% CI: –8.92, –1.09) reductions in birth weight, respectively. Conclusion Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy. Citation Verner MA, Loccisano AE, Morken NH, Yoon M, Wu H, McDougall R, Maisonet M, Marcus M, Kishi R, Miyashita C, Chen MH, Hsieh WS, Andersen ME, Clewell HJ III, Longnecker MP. 2015. Associations of perfluoroalkyl substances (PFAS) with lower birth weight: an evaluation of potential confounding by glomerular filtration rate using a physiologically based pharmacokinetic model (PBPK). Environ Health Perspect 123:1317–1324; http://dx.doi.org/10.1289/ehp.1408837

PLACENTA PERCRETA- TWO CASES AND REVIEW OF THE LITERATURE

Two cases of placenta pecreta confirmed histologically were treated conservatively with retention of the uterus. Both later went on to have successful pregnancies.

Reference population for international comparisons and time trend surveillance of preterm delivery proportions in three countries

BackgroundInternational comparison and time trend surveillance of preterm delivery rates is complex. New techniques that could facilitate interpretation of such rates are needed.MethodsWe studied all live births and stillbirths (≥ 28 weeks gestation) registered in the medical birth registers in Sweden, Denmark and Norway from 1995 through 2004. Gestational age was determined by best estimate. A reference population of pregnant women was designed using the following criteria: 1) maternal age 20–35, 2) primiparity, 3) spontaneously conceived pregnancy, 4) singleton pregnancy and 5) mother born in the respective country. National preterm delivery rate, preterm delivery rate in the reference population and rate of spontaneous preterm delivery in the reference population were calculated for each country.ResultsThe total national preterm delivery rate (< 37 completed gestational weeks), increased in both Denmark (5.3% to 6.1%, p < 0.001) and Norway (6.0% to 6.4%, p = 0.006), but remained unchanged in Sweden, during 1995–2004. In Denmark, the preterm delivery rate in the reference population (5.3% to 6.3%, p < 0.001) and the spontaneous preterm delivery rate in the reference population (4.4% to 6.8%, p < 0.001) increased significantly. No similar increase was evident in Norway. In Sweden, rates in the reference population remained stable.ConclusionReference populations can facilitate overview and thereby explanations for changing preterm delivery rates. The model also permits comparisons over time. This model may in its simplicity prove to be a valuable supplement to assessments of national preterm delivery rates for public health surveillance.

Pre‐pregnant body mass index, gestational weight gain and the risk of operative delivery

To estimate the risk of operative delivery according to maternal pre‐pregnant body mass index (BMI) and gestational weight gain.

Maternal and Fetal Genetic Associations of PTGER3 and PON1 with Preterm Birth

Objective The purpose of this study was to identify associations between maternal and fetal genetic variants in candidate genes and spontaneous preterm birth (PTB) in a Norwegian population and to determine the effect size of those associations that corroborate a previous study of PTB. Methods DNA from 434 mother-baby dyads (214 cases and 220 controls) collected from the Norwegian Mother and Child Cohort (MoBa) was examined for association between 1,430 single nucleotide polymorphisms in 143 genes and PTB. These results were compared to a previous study on European Americans (EA) from Centennial Womens Hospital in Nashville, TN, USA. Odds ratios for SNPs that corroborated the Cenntennial study were determined on the combined MoBa and Centennial studies. Results In maternal samples the strongest results that corroborated the Centennial study were in the prostaglandin E receptor 3 gene (PTGER3; rs977214) (combined genotype p = 3×10−4). The best model for rs977214 was the AG/GG genotypes relative to the AA genotype and resulted in an OR of 0.55 (95% CI = 0.37–0.82, p = 0.003), indicating a protective effect. In fetal samples the most significant association in the combined data was rs854552 in the paraoxonase 1 gene (PON1) (combined allele p = 8×10−4). The best model was the TT genotype relative to the CC/CT genotypes, and resulted in an OR of 1.32 (95% CI = 1.13–1.53, p = 4×10−4). Conclusions These studies identify single locus associations with preterm birth for both maternal and fetal genotypes in two populations of European ancestry.

Maternal glomerular filtration rate in pregnancy and fetal size.

Background The relationship of maternal glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized as it impacts an ongoing debate about confounding effect of maternal GFR in investigations of important environmental contaminants. We aimed to characterize the size of the association between maternal GFR and infant birth weight. Materials and Methods A sub-cohort of 953 selected women (470 women with and 483 women without preeclampsia) in the Norwegian Mother and Child Cohort (MoBa), recruited during 2003–2007 were analyzed. GFR in the second trimester was estimated based on plasma creatinine. Birth weight was ascertained from the Medical Birth Registry of Norway. Multivariate linear regression was used to evaluate the association between maternal GFR in second trimester (estimated by the Cockroft-Gault [GFR-CG] and the modification of diet in renal disease [GFR-MDRD] formulas) and infant birth weight. Partial correlation coefficients were also calculated. Results Maternal GFR-CG (β: 0.73 g/ml/min, p = 0.04) and GFR-MDRD (β: 0.83 g/ml/min, p = 0.04) were associated with infant birth weight in models adjusted for maternal weight in kilograms, preeclampsia, and gestational age at delivery (days). Partial correlation coefficients for the association between infant birth weight and GFR were 0.07 for both formulas. Although the birth weight-GFR association was stronger among the women with preeclampsia, the difference from women without preeclampsia was not statistically significant. Conclusion These data support an association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations.

X-chromosomal maternal and fetal SNPs and the risk of spontaneous preterm delivery in a Danish/Norwegian genome-wide association study.

Background Recent epidemiological studies suggest that the maternal genome is an important contributor to spontaneous preterm delivery (PTD). There is also a significant excess of males among preterm born infants, which may imply an X-linked mode of inheritance for a subset of cases. To explore this, we examined the effect of maternal and fetal X-chromosomal single nucleotide polymorphisms (SNPs) on the risk of PTD in two independent genome-wide association studies and one replication study. Methods Participants were recruited from the Danish National Birth Cohort and the Norwegian Mother and Child cohort studies. Data from these two populations were first analyzed independently, and then combined in a meta-analysis. Overall, we evaluated 12,211 SNPs in 1,535 case-mother dyads and 1,487 control-mother dyads. Analyses were done using a hybrid design that combines case-mother dyads and control-mother dyads, as implemented in the Haplin statistical software package. A sex-stratified analysis was performed for the fetal SNPs. In the replication study, 10 maternal and 16 fetal SNPs were analyzed using case-parent triads from independent studies of PTD in the United States, Argentina and Denmark. Results In the meta-analysis, the G allele at the maternal SNP rs2747022 in the FERM domain containing 7 gene (FRMD7) increased the risk of spontaneous PTD by 1.2 (95% confidence interval (CI): 1.1, 1.4). Although an association with this SNP was confirmed in the replication study, it was no longer statistically significant after a Bonferroni correction for multiple testing. Conclusion We did not find strong evidence in our data to implicate X-chromosomal SNPs in the etiology of spontaneous PTD. Although non-significant after correction for multiple testing, the mother’s G allele at rs2747022 in FRMD7 increased the risk of spontaneous PTD across all populations in this study, thus warranting further investigation in other populations.