Cohort profile: The PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension (PEACH) Study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal morbidity and mortality worldwide, with implications for maternal and neonatal well-being in the short term and for long-term maternal cardiovascular health. Although the mechanisms behind HDP remain incompletely understood, evidence suggests that preeclampsia in particular is a syndrome with more than one distinct subtype. OBJECTIVES: The PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction, Hypertension) Study was established to identify new HDP subtyping systems reflecting aetiology and prognosis and to find markers of later cardiovascular disease risk associated with preeclampsia. POPULATION: The PEACH Study recruited pregnant women referred to two Copenhagen-area hospitals with suspected preeclampsia (mean gestational age at enrolment: 36.7 weeks) and a group of frequency-matched pregnant women planning delivery at the same hospitals and healthy when enrolled mid-pregnancy. DESIGN: Prospective, longitudinal pregnancy cohort. METHODS: Participants underwent repeated third-trimester blood sample collection, longitudinal cardiac function assessments using the USCOM-1A during the third trimester and at 1 year postpartum and collection of placental samples immediately after delivery. Medical information was abstracted from medical records and hospital databases. PRELIMINARY RESULTS: During 2016-2018, we recruited 1149 pregnant women, of whom 1101 were followed to delivery. Among 691 women enrolled with suspected preeclampsia, 310 and 172 developed preeclampsia and gestational hypertension respectively. Among 410 women with healthy pregnancies when enrolled mid-pregnancy, 37 later developed hypertensive disorders of pregnancy. Of 1089 women still in the cohort 1 year postpartum, 578 (53.1%) participated in the follow-up assessment. CONCLUSIONS: The PEACH Study's rich data from women with and without HDP will enable us to identify new, clinically useful HDP subtypes to aid in decision-making regarding monitoring and treatment. Continued postpartum follow-up will help us develop algorithms to identify women at risk of persistent postpartum cardiac dysfunction and later cardiovascular disease after pregnancies complicated by HDP.

Rebozo and External Cephalic Version in breech presentation (RECEIVE): A randomised controlled study.

OBJECTIVE: To investigate if a hospital-initiated home-based rebozo intervention performed by the pregnant woman and her partner before external cephalic version (ECV) would increase the rate of cephalic presentations at birth. DESIGN: A multicentre randomised controlled trial. SETTING: Three university hospitals in Copenhagen, Denmark. POPULATION: Pregnant women with a breech or transverse presentation at 35 weeks or more of gestation eligible for ECV. METHODS: We compared rebozo before ECV with ECV alone. The randomisation was computer-generated in blocks and stratified by parity. The woman and her partner were instructed in the technique by a project midwife and performed the technique at home three times daily for 3-5 days before the scheduled ECV. Analyses were by intention-to-treat. MAIN OUTCOME MEASURE: The number of cephalic presentations at the time of birth. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: A total of 372 women were randomly assigned (1:1) to either rebozo intervention (n = 187) or control (n = 185). At birth, 95 (51%) in the intervention group versus 112 (62%) in the control group had a fetus in cephalic presentation (OR 0.61; 95% CI 0.40-0.95). No adverse events were observed in relation to the intervention. CONCLUSIONS: In breech or transverse presentation, home-based rebozo exercise before ECV lowered the overall rate of cephalic presentation at birth. TWEETABLE ABSTRACT: Home-based rebozo for breech presentation before external version reduces the rate of cephalic presentation at birth.

Differentiated timing of induction for women with intrahepatic cholestasis of pregnancy-A historical cohort study.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease characterized by pruritus and abnormal liver function tests and it has been associated with intrauterine fetal distress and stillbirth. We compared two guidelines of the management of ICP: one mandating induction at 38 weeks of gestation (Rigshospitalet and Hvidovre Hospital before 2012) and another separating ICP into mild and severe forms, and only women with severe ICP were recommended for induction at 38 weeks (Hvidovre Hospital after 2012). MATERIAL AND METHODS: We performed a historical cohort study at two Copenhagen Hospitals from 2004 to 2015. We included 62 937 women with singleton deliveries at Rigshospitalet and 71 015 at Hvidovre Hospital, of whom 971 women (1.5%) and 998 women (1.4%) were diagnosed with ICP at Rigshospitalet and Hvidovre Hospital, respectively. Data were retrieved from a local medical database. For the analysis of induction and comparison of obstetrical outcomes we only included pregnancies with an ICP diagnosis and excluded women with other medical conditions that could mandate induction. Main outcome measures were induction and cesarean section rates, asphyxia and stillbirth. RESULTS: We found no changes in the rate of spontaneous labor, cesarean section and induction over the years at Rigshospitalet (P = .17) and Hvidovre Hospital (P = .38). For women with intended vaginal delivery we found no change in the final mode of delivery over the years at Rigshospitalet (P = .28) and Hvidovre Hospital (P = .57). CONCLUSIONS: The two approaches to the management of mild ICP regarding the timing of induction are comparable. Women with mild ICP and their clinicians should be encouraged to engage in shared decision-making when discussing timing of induction.

Hypertensive disorders of pregnancy and subsequent risk of solid cancer--A nationwide cohort study.

Women with hypertensive disorders of pregnancy (HDP) have higher levels of antiangiogenic growth factors during pregnancy than women with normotensive pregnancies. Since angiogenesis is necessary for solid cancer growth and spread, we hypothesized that women with a history of HDP might have a reduced risk of solid cancers (cancers other than lymphomas, hematologic cancers and nonmelanoma skin cancers) later in life. In a register-based cohort study of 1.08 million women giving birth at least once between 1978 and 2011, we used Cox regression to estimate hazard ratios (HRs) comparing solid cancer rates for women with and without a history of HDP. In this cohort, 68,236 women (6.3%) had ≥1 pregnancy complicated by HDP and 42,236 women (3.9%) developed solid tumors during follow-up. A history of HDP was not associated with a clinically meaningful reduction in the overall rate of solid cancer (HR 0.96, 95% confidence interval 0.92-1.00), regardless of HDP severity or time since HDP, nor was there a general tendency toward reduced solid cancer rates across organ sites. A history of HDP was only significantly associated with decreased rates of breast and lung cancers and with increased rates of endometrial and urinary tract cancers. Overall, our results do not support the hypothesis that women with a history of HDP have a reduced overall risk of solid cancer due to a persistent post-HDP antiangiogenic state or an innate tendency toward antiangiogenesis. Observed associations with specific cancers may instead be due to other pregnancy-related mechanisms or to residual/unmeasured confounding.

Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy.

IMPORTANCE: Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown. OBJECTIVE: To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1,075,763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012. EXPOSURES: A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register. MAIN OUTCOMES AND MEASURES: Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months. RESULT: The women in the primary cohort had 2,067,633 eligible pregnancies during the study period, 76,108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18,211,603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100,000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173,062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100,000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697,447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100,000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213,197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100,000 person-years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy. CONCLUSIONS AND RELEVANCE: Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association.

Recurring complications in second pregnancy.

OBJECTIVE: To clarify the obstetric consequences in a second pregnancy after a first singleton pregnancy complicated by spontaneous preterm delivery or preeclampsia and stratified by the variation in fetal growth. METHODS: In a registry-based cohort study, we identified women having a first and second singleton delivery in Denmark from 1978 to 2007 (n=536,419). The exposures and endpoints were preterm delivery, preeclampsia, fetal growth, placental abruption, and stillbirth after 20 weeks of gestation. We used chi and t test to compare differences between incidences on first and second pregnancies. RESULTS: Compared with a spontaneous first delivery at term, a delivery between 32 and 36 weeks of gestation increased the risk of preterm delivery in the second pregnancy from 2.7% to 14.7% (odds ratio [OR] 6.12, 95% confidence interval [CI] 5.84-6.42) and the risk of preeclampsia from 1.1% to 1.8% (OR 1.60, 95% CI 1.41-1.81); a delivery before 28 weeks increased the risk of a second preterm delivery to 26.0% (OR 13.1, 95% CI 10.8-15.9) and a second pregnancy with preeclampsia to 3.2% (OR 2.96, 95% CI 1.80-4.88). A first delivery in preeclamptic women between 32 and 36 weeks, compared with delivery after 37 weeks, increased the risk of preeclampsia in a second pregnancy from 14.1% to 25.3% (OR 2.08, 95% CI 1.87-2.31) and a small for gestational age infant from 3.1% to 9.6% (OR 2.82, 95% CI 2.38-3.35). Compared with the mean, fetal growth 2 to 3 standard deviations below mean in the first pregnancy increased the risk of preeclampsia from 1.1% to 1.8% (OR 1.62, 95% CI 1.34-1.96) in the second pregnancy. CONCLUSION: Spontaneous preterm delivery, preeclampsia, and fetal growth deviation tend to recur and predispose to each other in a second pregnancy. Severe complications further increase these risks. LEVEL OF EVIDENCE: II.

Population-based investigations to study the association of cardiovascular polymorphisms and adverse pregnancy outcome.

Adverse pregnancy outcome refers to placenta-mediated complications that may share a common etiopathogenesis in some cases. Unraveling associations between prothrombotic genetic predispositions and these pregnancy disorders, namely recurrent fetal loss, stillbirth, severe preeclampsia, intrauterine growth restriction, and placental abruption, requires rigorous epidemiological studies involving large cohorts of patients with sufficient numbers of the adverse pregnancy outcomes in question. Such is the case with the Denmark National Birth Cohort, which was initiated in 1996 and followed pregnant women giving birth from the years 1996 to 2002. In addition, national registers exist which can be linked together. Two studies have been initiated. One is a retrospective cohort study concerning primiparous women, with singleton pregnancy and with no identifiable congenital malformation. The purpose of this study is to determine the long-term cardiovascular risk of women whose pregnancies were complicated by adverse pregnancy outcome. Preliminary evidence suggests that the presence of an adverse pregnancy outcome augments the cardiovascular disease risk by an odds ratio of 1.21 (P < 0.001). The second study focuses on pro-thrombotic and cardiovascular genetic polymorphisms in a nested-case control study comparing pregnancies with and without an adverse pregnancy outcome in the index pregnancy. This study will be adequately powered to determine the relationship between adverse pregnancy outcome and pro-thrombotic and cardiovascular genetic polymorphisms. These studies are urgently needed to accurately assess the linkage between family history, presence of adverse pregnancy outcome, and long-term cardiovascular risk.

[Systemic lupus erythematosus and pregnancy].

Systemic lupus erythematosus (SLE) is a complex autoimmune disease which most often affects women of childbearing age. Pregnancy is therefore an important issue for the patient and the responsible physician. Pregnancy outcomes in women with SLE has improved significantly over the latest decades, and current research initiatives aim towards further improvement. Pregnant women with SLE are still considered being at various levels of risk. In order to achieve the best possible outcomes for mother and child, joint care in specialised multidisciplinary teams including rheumatologists and obstetricians is recommended.

[Antiphospholipid syndrome and pregnancy]. / Antifosfolipidsyndrom og graviditet.

Antiphospholipid syndrome (APS) is the association of antiphospholipid antibodies with thromboses and/or obstetric morbidity. Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction. Although current treatment regimens including aspirin and low-molecular weight heparin have improved pregnancy outcomes, 30% of affected women have pregnancy complica-tions. Women with APS are therefore high-risk pregnancies who should be monitored in specialist centres according to international standards.

[Angiogenic factors can be used when pre-eclampsia is suspected]. / Angiogenetiske faktorer kan bruges ved mistanke omsvangerskabsforgiftning

Pre-eclampsia complicates 7% of pregnancies. The heterogeneity of the syndrome makes it difficult to assess its development and complications, and the current models have low predictive values. Studies indicate a significant difference in the levels of the angiogenic factors: placental growth factor (PlGF) and soluble fms-like tyrosin kinase 1 (sFlt-1), as well as the sFlt-1/PlGF ratio in women with pre-eclampsia compared to women without pre-eclampsia. These angiogenic factors can also be used to help find the women at risk for complications. However, before implementing PlGF and sFlt-1/PlGF ratio in the diagnosis and risk assessment, establishment and further validation of cut-offs are needed.

[Ramadan, fasting and pregnancy]. / Ramadan, faste og graviditet

In Islam, the month of Ramadan is a period of fasting lasting 29 or 30 days. Epidemiological studies among Muslims in Denmark have not been conducted, but studies show, that fasting among pregnant Muslim women is common. Fasting does not increase the risk of growth restriction or preterm delivery, but there are reports of decreased foetal movements. Furthermore, the fasting may have long-term health consequences for the offspring, especially when they reach their middle age. According to Islam and the interpretation, pregnant and breast-feeding women are allowed to postpone the fasting of the month of Ramadan to a later period.

[Obstetric dermatoses].

The specific dermatoses of pregnancy are rare and consist of pemphigoid gestationis (PG), intrahepatic cholestasis of pregnancy (ICP), polymorphic eruption of pregnancy and atopic eruption of pregnancy. The dermatoses are characterized by pruritus, and they are important to recognize since PG and ICP increase the risk of prematurity, fetal distress and stillbirth. Diagnosis is based on medical history, morphology, blood sample and biopsy. The dermatoses are treated with respectively ursodeoxycholic acid (in case of ICP) and steroids. Breast-feeding is recommended and induction of labour is not normally indicated.

OP0010. Optimizing time from diagnosis to delivery in preeclampsia based on the future health prospects of offspring.

INTRODUCTION: Limited data exist on long-term health-consequences of maternal preeclampsia for offspring. OBJECTIVES: We investigated long-term offspring morbidity following preeclampsia and related these data to the time from diagnosis to delivery. METHODS: We performed a registry based retrospective cohort study in Denmark in the years 1977-2007. The primary exposure was preeclamptic days from diagnosis to delivery. We analyzed 6 gestational age groups separately. The outcomes were groups of later disease diagnoses in offspring. RESULTS: We included 758,524 singleton offspring who had accumulated 3,537,525 medical diagnoses. Offspring delivered by severely preeclamptic women between 28 and 33weeks had an increased risk of endocrine disorders (HR 1.46; 95% CI 1.09-1.96) compared to normotensive pregnancies, independent of days between diagnosis and delivery (HR 1.000; 95% CI 0.993-1.006). Offspring delivered by mildly preeclamptic women between 37 and 38 weeks had an increased risk of behavioral disorders (HR 1.19; 95% CI 1.05-1.37) and this risk was dependent on days since diagnosis (HR 1.006; 1.001-1.011). In general, after 37-38weeks, days from diagnosis to delivery increased the risk of later diagnoses in most disease groups. CONCLUSION: Offspring from preeclamptic pregnancies have increased risks of various later diseases. The time between diagnosis and delivery modified these risks only slightly, but it seems prudent not to prolong preeclamptic pregnancies after 38weeks.

First-trimester vaginal bleeding and complications later in pregnancy.

OBJECTIVE: To evaluate the association of first-trimester bleeding without miscarriage and complications later in the first pregnancy as well as in the next pregnancy. METHODS: In a retrospective, registry-based cohort study, we identified women delivering in Denmark from 1978 to 2007 with a first singleton pregnancy (n=782,287) and first and second singleton pregnancies (n=536,419). First-trimester bleeding is defined as vaginal bleeding before 12 full weeks of gestation. We employed multivariate logistic regression with adjustment for maternal age and calendar year. RESULTS: First-trimester bleeding increased the risk of delivery in weeks 32-36 from 3.6% to 6.1% (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.57-1.77) and in weeks 28-31 from 0.3% to 0.9% (OR 2.98; 95% CI 2.50-3.54) and increased the risk of placental abruption from 1.0% to 1.4% (OR 1.48; 95% CI 1.30-1.68). First-trimester bleeding in the first pregnancy increased the risk of recurrence in the second pregnancy from 2.2% to 8.2% (OR 4.05; 95% CI 3.78-4.34), preterm delivery from 2.7% to 4.8% (OR 1.83; 95% CI 1.67-2.00), and placental abruption from 0.9% to 1.0% (OR 1.29; 95% CI 1.07-1.56) in the second pregnancy. CONCLUSION: Women with first-trimester bleeding in the first pregnancy have an increased risk of complications later in the first pregnancy and of recurrence of first-trimester bleeding and other complications in the second pregnancy.