Recurrence of postpartum hemorrhage, maternal and paternal contribution, and the effect of offspring birthweight and sex: a population-based cohort study

Purpose: This study examines individual aggregation of postpartum hemorrhage (PPH), paternal contribution and how offspring birthweight and sex influence recurrence of PPH. Further, we wanted to estimate the proportion of PPH cases attributable to a history of PPH or current birthweight. Methods: We studied all singleton births in Norway from 1967 to 2017 using data from Norwegian medical and administrational registries. Subsequent births in the parents were linked. Multilevel logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PPH defined as blood loss > 500 ml, blood loss > 1500 ml, or the need for blood transfusion in parous women. Main exposures were previous PPH, high birthweight, and fetal sex. We calculated adjusted population attributable fractions for previous PPH and current high birthweight. Results: Mothers with a history of PPH had three- and sixfold higher risks of PPH in their second and third deliveries, respectively (adjusted OR 2.9; 95% CI 2.9–3.0 and 6.0; 5.5–6.6). Severe PPH (> 1500 ml) had the highest risk of recurrence. The paternal contribution to recurrence of PPH in deliveries with two different mothers was weak, but significant. If the neonate was male, the risk of PPH was reduced. A history of PPH or birthweight ≥ 4000 g each accounted for 15% of the total number of PPH cases. Conclusion: A history of PPH and current birthweight exerted strong effects at both the individual and population levels. Recurrence risk was highest for severe PPH. Occurrence and recurrence were lower in male fetuses, and the paternal influence was weak.publishedVersio

Recurrence of postpartum hemorrhage in relatives: A population-based cohort study

Introduction Studies on the family aggregation of postpartum hemorrhage (PPH) are scarce and with inconsistent results, and to what extent current birthweight influences recurrence between relatives remains to be studied. Further, family aggregation of PPH has been studied from an individual, but not from a public heath perspective. We aimed to investigate family aggregation of PPH in Norway, how birthweight influences these effects, and to estimate the proportion of PPH cases attributable to a family history of PPH and current birthweight. Material and methods Using data from the Medical Birth Registry of Norway, Statistics Norway, and Central Population Registry of Norway we identified individuals as newborns, parents, grandparents, and full and half-siblings, and studied 1 002 687 mother–offspring, 841 164 father–offspring, and 761 011 both-parents–offspring pairs. We used multilevel logistic regression to calculate odds ratios (OR) with 95% CI. Results If the birth of the mother but not of the father involved PPH, then the OR of PPH (>500 mL) in the next generation was 1.44 (95% CI 1.39–1.49). If the birth of the father but not of the mother involved PPH, then OR was 1.12 (95% CI 1.08–1.16). These effects were stronger in severe PPH. Recurrence between siblings was highest between full sisters (OR 1.47, 95% CI 1.41–1.52), followed by maternal half-sisters, paternal half-sisters, and partners of full brothers. A family history of PPH or birthweight of 4000 g or more accounted for ≤5% and 15% of the total number of PPH cases, respectively. Conclusions A history of PPH in relatives influenced the recurrence risk of PPH in a dose–response pattern consistent with the anticipated proportion of shared genes. The recurrence was highest through the maternal line.publishedVersio

Put your weight behind it—Effect of body mass index on the active second stage of labour: A retrospective cohort study

Objective: To explore the duration of the active phase of the second stage of labour in relation to maternal pre-pregnant body mass index (BMI). Design: Retrospective cohort study. Setting: Labour wards of three Norwegian university hospitals, 2012–2019. Population: Nulliparous and parous women without previous caesarean section with a live singleton fetus in cephalic presentation and spontaneous onset of labour, corresponding to the Ten Group Classification System (TGCS) group 1 and 3. Methods: Women were stratified to BMI groups according to WHO classification, and estimated median duration of the active phase of the second stage of labour was calculated using survival analyses. Caesarean sections and operative vaginal deliveries during the active phase were censored. Main outcome measures: Estimated median duration of the active phase of second stage of labour. Results: In all, 47 942 women were included in the survival analyses. Increasing BMI was associated with shorter estimated median duration of the active second stage in both TGCS groups. In TGCS group 1, the estimated median durations (interquartile range) were 44 (26–75), 43 (25–71), 39 (22–70), 33 (18–63), 34 (19–54) and 29 (16–56) minutes in BMI groups 1–6, respectively. In TGCS group 3, the corresponding values were 11 (6–19), 10 (6–17), 10 (6–16), 9 (5–15), 8 (5–13) and 7 (4–11) minutes. Increasing BMI remained associated with shorter estimated median duration in analyses stratified by oxytocin augmentation and epidural analgesia. Conclusion: Increasing BMI was associated with shorter estimated median duration of the active second stage of labour.publishedVersio

Neonatal outcomes associated with time from a high fetal blood lactate concentration to operative delivery

Introduction: Adjunctive technologies to cardiotocography intend to increase the specificity of the diagnosis of fetal hypoxia. If correctly diagnosed, time to delivery could affect neonatal outcome. In the present study, we aimed to investigate the effect of time from when fetal distress is indicated by a high fetal blood sample (FBS) lactate concentration to operative delivery on the risk of adverse neonatal outcomes. Material and methods: We conducted a prospective observational study. Deliveries with a singleton fetus in cephalic presentation at 36+0weeks of gestation or later were included. Adverse neonatal outcomes, related to decision-to-delivery interval (DDI), were investigated in operative deliveries indicated by an FBS lactate concentration of at least 4.8 mmol/L. We applied logistic regression to estimate crude and adjusted odds ratios (aOR) of various adverse neonatal outcomes, with associated 95% confidence intervals (CI), for a DDI exceeding 20 minutes, compared with a DDI of 20 minutes or less. ClinicalTrials.gov Identifier: NCT04779294. Results: The main analysis included 228 women with an operative delivery indicated by an FBS lactate concentration of 4.8 mmol/L or greater. The risk of all adverse neonatal outcomes was significantly increased for both DDI groups compared with the reference group (deliveries with an FBS lactate below 4.2 mmol/L within 60 minutes before delivery). In operative deliveries indicated by an FBS lactate concentration of 4.8 mmol/L or more, there was a significantly increased risk of a 5-minute Apgar score less than 7 if the DDI exceeded 20 minutes, compared with a DDI of 20 minutes or less (aOR 8.1, 95% CI 1.1–60.9). We found no statistically significant effect on other short-term outcomes for deliveries with DDI longer than 20 minutes, compared with those with DDI of 20 minutes or less (pH ≤7.10: aOR 2.0, 95% CI 0.5–8.4; transfer to the neonatal intensive care unit: aOR 1.1, 95% CI 0.4–3.5). Conclusions: After a high FBS lactate measurement, the increased risk of adverse neonatal outcome is further augmented if the DDI exceeds 20 minutes. These findings give support to current Norwegian guidelines for intervention in cases of fetal distress.publishedVersio

Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study

Background: Metformin is prescribed to women with polycystic ovary syndrome (PCOS) to prevent pregnancy complications. Children exposed to metformin vs. placebo in utero, have increased head circumference at birth and are more overweight and obese at 8 years of age. Also, maternal PCOS-status seems to alter the long-term cardio-metabolic health of offspring. We hypothesized that the long-term effects of metformin-exposure and/or maternal PCOS may be mediated by circulatory adaptations during fetal life. Material and methods: This is a sub-study of a larger double-blinded, placebo-controlled trial, where women with PCOS were randomized to metformin (2g/day) or placebo in pregnancy, a total of 487 women. A sub-group of participants (N = 58) took part in this sub-study and had an extended ultrasound examination at gestational week 32, including blood flow velocity and diameter measurements of the umbilical vein (UV), the ductus venosus (DV) and the portal vein (PV). Blood flow volume was calculated and adjusted for estimated fetal weight (EFW) (normalized flow). Metformin exposed fetuses were compared to placebo exposed fetuses. Fetuses of mothers with PCOS (metformin [n = 30] and placebo [n = 28]) were compared to a low-risk reference population (N = 160) by z-score statistics. Results: There was no difference in fetal liver flow between metformin vs. placebo-exposed fetuses. Fetuses of mothers with PCOS had higher EFW (0.63 [95% CI 0.44–0.83] p<0.001), lower normalized UV, DV, PV, and lower total venous liver blood flows than the reference population. Conclusion: Metformin during pregnancy did not affect fetal liver blood-flow. In our population, maternal PCOS-status was associated with reduced total venous liver blood-flow, which may explain altered growth and metabolism later in life.publishedVersio

Placental histology predicted adverse outcomes in extremely premature neonates in Norway-population-based study

Aim We evaluated the role of placental pathology in predicting adverse outcomes for neonates born extremely preterm (EPT) before 28 weeks of gestation. Methods This was a prospective observational study of 123 extremely preterm singletons born in a hospital in western Norway, and the placentas were classified according to the Amsterdam criteria. The associations between histologic chorioamnionitis (HCA), by the presence or the absence of a foetal inflammatory response (FIR+ or FIR−), maternal vascular malperfusion (MVM) as a whole and adverse neonatal outcomes were evaluated by logistic regression analyses. Adverse outcomes were defined as perinatal death, necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD), brain pathology by magnetic resonance imaging at term-equivalent age, retinopathy of prematurity and early-onset neonatal sepsis. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results HCA was associated with NEC (OR 12.2, 95% CI 1.1 to 137.1). HCA/FIR+ was associated with BPD (OR 14.9, 95% CI 1.8–122.3) and brain pathology (OR 9.8, 95% CI 1.4–71.6), but HCA/FIR− was not. The only neonatal outcome that MVM was associated with was low birthweight. Conclusion Placental histology provided important information when assessing the risk of adverse neonatal outcomes following EPT birth.publishedVersio

Single umbilical artery and risk of congenital malformations: a population-based study in Norway.

Objectives: Single umbilical artery (SUA) is associated with congenital malformations in most organ systems, but reported findings have not been consistent. While it has been suggested that genetic and persisting environmental factors influence the development of SUA, it is not known whether there is an increased risk of recurrence in a subsequent pregnancy of the same woman. The aims of this study were to investigate the occurrence of, and risk factors for, SUA in Norway, to assess its association with congenital malformations and trisomies 13, 18 and 21 and to study the risk of recurrence of SUA in subsequent pregnancies. Methods: This was a population‐based study of all (n  = 918 933) singleton pregnancies of > 16 weeks' gestation recorded in the Medical Birth Registry of Norway from 1999 to 2014. To identify risk factors and congenital malformations associated with SUA, generalized estimating equations and logistic regression were used to calculate odds ratios (OR) with 95% CIs. ORs were also calculated for the recurrence of SUA in subsequent pregnancy. Results: The occurrence of SUA in our population was 0.46% (4241/918 933). Parity ≥ 4, smoking, maternal pregestational diabetes, epilepsy, chronic hypertension, previous Cesarean delivery and conception by assisted reproductive technology increased the odds of having SUA. There was a particularly strong association between SUA and gastrointestinal atresia or stenosis in the neonate, with ORs of 25.8 (95% CI, 17.0–39.1) and 20.3 (95% CI, 13.4–30.9) for esophageal and anorectal atresia or stenosis, respectively, followed by an OR of 5.9 (95% CI, 1.9–18.5) for renal agenesis. SUA was associated with an up to 7–8 times increased risk of congenital heart defects. There was an association with microcephaly, congenital hydrocephalus and other congenital malformations of the brain and spinal cord. Diaphragmatic hernia, limb reductions and cleft lip or palate had a weaker association with SUA, with ORs ranging from 4.8 to 2.8. The associations with trisomy 18 and 13 were equally strong (OR 14.4 (95% CI, 9.3–22.4) and OR 13.6 (95% CI, 6.7–27.8), respectively), and the risk of trisomy 21 was doubled (OR 2.1 (95% CI, 1.2–3.6)). Pregnancies with SUA, with or without an associated malformation, had a 2‐fold increased risk for SUA in a subsequent pregnancy. Conclusions: SUA is associated strongly with gastrointestinal atresia or stenosis, suggesting common developmental mechanisms. The increased risk of recurrence of SUA suggests that genetic and/or persisting environmental factors influence the risk. We found that SUA had equally strong associations with trisomies 13 and 18

Single umbilical artery and risk of congenital malformations: a population-based study in Norway.

Objectives: Single umbilical artery (SUA) is associated with congenital malformations in most organ systems, but reported findings have not been consistent. While it has been suggested that genetic and persisting environmental factors influence the development of SUA, it is not known whether there is an increased risk of recurrence in a subsequent pregnancy of the same woman. The aims of this study were to investigate the occurrence of, and risk factors for, SUA in Norway, to assess its association with congenital malformations and trisomies 13, 18 and 21 and to study the risk of recurrence of SUA in subsequent pregnancies. Methods: This was a population‐based study of all (n  = 918 933) singleton pregnancies of > 16 weeks' gestation recorded in the Medical Birth Registry of Norway from 1999 to 2014. To identify risk factors and congenital malformations associated with SUA, generalized estimating equations and logistic regression were used to calculate odds ratios (OR) with 95% CIs. ORs were also calculated for the recurrence of SUA in subsequent pregnancy. Results: The occurrence of SUA in our population was 0.46% (4241/918 933). Parity ≥ 4, smoking, maternal pregestational diabetes, epilepsy, chronic hypertension, previous Cesarean delivery and conception by assisted reproductive technology increased the odds of having SUA. There was a particularly strong association between SUA and gastrointestinal atresia or stenosis in the neonate, with ORs of 25.8 (95% CI, 17.0–39.1) and 20.3 (95% CI, 13.4–30.9) for esophageal and anorectal atresia or stenosis, respectively, followed by an OR of 5.9 (95% CI, 1.9–18.5) for renal agenesis. SUA was associated with an up to 7–8 times increased risk of congenital heart defects. There was an association with microcephaly, congenital hydrocephalus and other congenital malformations of the brain and spinal cord. Diaphragmatic hernia, limb reductions and cleft lip or palate had a weaker association with SUA, with ORs ranging from 4.8 to 2.8. The associations with trisomy 18 and 13 were equally strong (OR 14.4 (95% CI, 9.3–22.4) and OR 13.6 (95% CI, 6.7–27.8), respectively), and the risk of trisomy 21 was doubled (OR 2.1 (95% CI, 1.2–3.6)). Pregnancies with SUA, with or without an associated malformation, had a 2‐fold increased risk for SUA in a subsequent pregnancy. Conclusions: SUA is associated strongly with gastrointestinal atresia or stenosis, suggesting common developmental mechanisms. The increased risk of recurrence of SUA suggests that genetic and/or persisting environmental factors influence the risk. We found that SUA had equally strong associations with trisomies 13 and 18

Pre-gestational diabetes: Maternal body mass index and gestational weight gain are associated with augmented umbilical venous flow, fetal liver perfusion, and thus birthweight

Objectives To assess how maternal body mass index and gestational weight gain are related to on fetal venous liver flow and birthweight in pregnancies with pre-gestational diabetes mellitus. Methods In a longitudinal observational study, 49 women with pre-gestational diabetes mellitus were included for monthly assessments (gestational weeks 24–36). According to the Institute Of Medicine criteria, body mass index was categorized to underweight, normal, overweight, and obese, while gestational weight gain was classified as insufficient, appropriate or excessive. Fetal size, portal flow, umbilical venous flow and distribution to the fetal liver or ductus venosus were determined using ultrasound techniques. The impact of fetal venous liver perfusion on birthweight and how body mass index and gestational weight gain modified this effect, was compared with a reference population (n = 160). Results The positive association between umbilical flow to liver and birthweight was more pronounced in pregnancies with pre-gestational diabetes mellitus than in the reference population. Overweight and excessive gestational weight gain were associated with higher birthweights in women with pre-gestational diabetes mellitus, but not in the reference population. Fetuses of overweight women with pre-gestational diabetes mellitus had higher umbilical (p = 0.02) and total venous liver flows (p = 0.02), and a lower portal flow fraction (p = 0.04) than in the reference population. In pre-gestational diabetes mellitus pregnancies with excessive gestational weight gain, the umbilical flow to liver was higher than in those with appropriate weight gain (p = 0.02). Conclusions The results support the hypothesis that umbilical flow to the fetal liver is a key determinant for fetal growth and birthweight modifiable by maternal factors. Maternal pre-gestational diabetes mellitus seems to augment this influence as shown with body mass index and gestational weight gain

Altered development of fetal liver perfusion in pregnancies with pregestational diabetes

Background: Pregestational diabetes is associated with fetal macrosomia, and umbilical perfusion of the fetal liver has a role in regulating fetal growth. We therefore hypothesized that pregestational diabetes alters fetal liver blood flow depending on degree of glycemic control. Methods: In a prospective study, 49 women with pregestational diabetes underwent monthly ultrasound examinations during 24–36 gestational weeks. Blood flow was determined in the umbilical vein, ductus venosus and portal vein, and blood velocity was measured in the left portal vein, the latter reflecting the watershed between splanchnic and umbilical flow. The measurements were compared with reference values by z-score statistics, and the effect of HbA1c assessed. Results: The umbilical venous flow to the liver (z-score 0.36, p = 0.002), total venous liver flow (z-score 0.51, p<0.001) and left portal vein blood velocity (z-score 0.64, p<0.001), were higher in the study group. Normalized portal venous flow was lower (z-score -0.42, p = 0.002), and normalized total venous liver flow tended to be lower after 30 gestational weeks (z-score -0.54, p = 0.047) in the diabetic pregnancies compared with reference values from a low-risk population. The left portal vein blood velocity was positively, and the portal fraction of total venous liver flow negatively correlated with first trimester HbA1C. Conclusions: In spite of increased umbilical blood distribution to the fetal liver, graded according to glycemic control, the total venous liver flow did not match third trimester fetal growth in pregnancies with pregestational diabetes, thus contributing towards increased perinatal risks and possibly altered liver function with long-term metabolic consequences