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Introduction Studies have shown associations between a first-born boy and increased risks of pregnancy loss, stillbirth, decreased birthweight, and preterm birth in subsequent pregnancies, but with limited precision. Material and methods We examined associations between sex of the first-born and obstetric complications in second births. We calculated the relative risks (RR)s of preeclampsia/eclampsia, placental abruption, stillbirth, and preterm birth in approximately 2.3 million second births comparing women with a preceding first-born boy to those with a first-born girl using the Medical Birth Registries of Denmark, Finland, Norway, and Sweden 1980-2008. Results In second births following a first-born boy rather than a girl, the RR was 4% higher for preeclampsia/eclampsia (RR = 1.04, 95% CI 1.02-1.06), 9% higher for placental abruption (RR = 1.09, 95% CI 1.05-1.13), 9% higher for stillbirth (RR = 1.09, 95% CI 1.04-1.14), and 8% higher for preterm birth (RR = 1.08, 95% CI 1.07-1.09). The population attributable risks ranged from 2% to 4.5%. Conclusions Male sex of the first-born is associated with small increases in risks of obstetric complications in the second birth. Exploration of the underlying mechanisms is needed to increase our knowledge and treatment options for these serious obstetric complications.

Background: Women with one lifetime singleton pregnancy have increased risk of cardiovascular disease (CVD) mortality compared with women who continue reproduction particularly if the pregnancy had complications. Women with twins have higher risk of pregnancy complications, but CVD mortality risk in women with twin pregnancies has not been fully described. Objectives: We estimated risk of long-term CVD mortality in women with naturally conceived twins compared to women with singleton pregnancies, accounting for lifetime number of pregnancies and pregnancy complications. Methods: Using linked data from the Medical Birth Registry of Norway and the Norwegian Cause of Death Registry, we identified 974,892 women with first pregnancy registered between 1967 and 2013, followed to 2020. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for maternal CVD mortality were estimated by Cox regression for various reproductive history (exposure categories): (1) Only one twin pregnancy, (2) Only one singleton pregnancy, (3) Only two singleton pregnancies, (4) A first twin pregnancy and continued reproduction, (5) A first singleton pregnancy and twins in later reproduction and (6) Three singleton pregnancies (the referent group). Exposure categories were also stratified by pregnancy complications (pre-eclampsia, preterm delivery or perinatal loss). Results: Women with one lifetime pregnancy, twin or singleton, had increased risk of CVD mortality (adjusted hazard [HR] 1.72, 95% confidence interval [CI] 1.21, 2.43 and aHR 1.92, 95% CI 1.78, 2.07, respectively), compared with the referent of three singleton pregnancies. The hazard ratios for CVD mortality among women with one lifetime pregnancy with any complication were 2.36 (95% CI 1.49, 3.71) and 3.56 (95% CI 3.12, 4.06) for twins and singletons, respectively. Conclusions: Women with only one pregnancy, twin or singleton, had increased long-term CVD mortality, however highest in women with singletons. In addition, twin mothers who continued reproduction had similar CVD mortality compared to women with three singleton pregnancies. publishedVersion

Introduction With increasing cesarean section rates, adverse pregnancy outcomes such as preterm delivery and small-for-gestational-age continue to be public health challenges. Besides having high co-occurrence and interrelation, it is suggested that these outcomes, along with preeclampsia, are associated with reduced subsequent fertility. On the other hand, the loss of a child during the perinatal period is associated with increased reproduction. Failure to consider this factor when estimating the effects of pregnancy outcomes on future reproduction may lead to erroneous conclusions. However, few studies have explored to what degree a perinatal loss contributes to having a next pregnancy in various adverse pregnancy outcomes. Material and methods This was a population-based study of mothers giving birth to their first singleton infant (≥22 gestational weeks) during 1967-2007 who were followed for the occurrence of a second birth in the Medical Birth Registry of Norway until 2014. Relative risks with 95% confidence intervals for having one lifetime pregnancy by preterm delivery, small-for-gestational-age, preeclampsia and cesarean section were obtained by generalized linear models for the binary family and adjusted for maternal age at first birth, education and year of first childbirth. Main outcome measure was having one lifetime pregnancy. Results Nearly 900 000 women gave birth to their first singleton infant in 1967-2007, of which 16% had only one lifetime pregnancy. These women were older at first delivery, had less education and there was a higher proportion of unmarried women than women with two or more births. In women with pregnancy complications where the infant survived the perinatal period, there were the following relative risks for one lifetime pregnancy: increased preterm delivery: 1.21 (1.19-1.22)], small-for-gestational-age: 1.13 (1.12-1.15), preeclampsia: 1.09 (1.07-1.11), cesarean section: 1.24 (1.23-1.25). The risk was significantly reduced if the child was lost (preterm delivery: 0.63 [0.59-0.68], small-for-gestational-age: 0.57 [0.51-0.63], preeclampsia: 0.69 [0.59-0.80], cesarean section: 0.67 [0.56-0.79]), compared with women with no perinatal loss and no adverse outcome. Conclusions The associations between adverse outcomes of pregnancy and the risk of having one lifetime pregnancy were strongly modified by child survival in the perinatal period.

Objective: To estimate recurrence risk of gestational diabetes mellitus (GDM) by interpregnancy weight change. Design: Population-based cohort study. Setting and population: Data from the Swedish (1992–2010) and the Norwegian (2006–2014) Medical Birth Registries on 2763 women with GDM in first pregnancy, registered with their first two singleton births and available information on height and weight. Methods: Interpregnancy weight change (BMI in second pregnancy minus BMI in first pregnancy) was categorised in six groups by BMI units. Relative risks (RRs) of GDM recurrence were obtained by general linear models for the binary family and adjusted for confounders. Analyses were stratified by BMI in first pregnancy (2 units (RR 0.72, 95% CI 0.59–0.89) and increased if BMI increased by ≥4 units (RR 1.26, 95% CI 1.05–1.51) compared wth women with stable BMI (−1 to 1 units). In normal weight women (BMI

ObjectiveTo explore conditions and outcomes of a first delivery at term that might predict later preterm birth.DesignPopulation based, prospective register based study.SettingMedical Birth Registry of Norway, 1999-2015.Participants302 192 women giving birth (live or stillbirth) to a second singleton child between 1999 and 2015.Main outcome measuresMain outcome was the relative risk of preterm delivery (ResultsWomen with any of the five complications at term showed a substantially increased risk of preterm delivery in the next pregnancy. The absolute risks for preterm delivery in a second pregnancy were 3.1% with none of the five term complications (8202/265 043), 6.1% after term pre-eclampsia (688/11 225), 7.3% after term placental abruption (41/562), 13.1% after term stillbirth (72/551), 10.0% after term neonatal death (22/219), and 6.7% after term small for gestational age (463/6939). The unadjusted relative risk for preterm birth after term pre-eclampsia was 2.0 (95% confidence interval 1.8 to 2.1), after term placental abruption was 2.3 (1.7 to 3.1), after term stillbirth was 4.2 (3.4 to 5.2), after term neonatal death was 3.2 (2.2 to 4.8), and after term small for gestational age was 2.2 (2.0 to 2.4). On average, the risk of preterm birth was increased 2.0-fold (1.9-fold to 2.1-fold) with one term complication in the first pregnancy, and 3.5-fold (2.9-fold to 4.2-fold) with two or more complications. The associations persisted after excluding recurrence of the specific complication in the second pregnancy. These links between term complications and preterm delivery were also seen in the reverse direction: preterm birth in the first pregnancy predicted complications in second pregnancies delivered at term.ConclusionsPre-eclampsia, placental abruption, stillbirth, neonatal death, or small for gestational age experienced in a first term pregnancy are associated with a substantially increased risk of subsequent preterm delivery. Term complications seem to share important underlying causes with preterm delivery that persist from pregnancy to pregnancy, perhaps related to a mother’s predisposition to disorders of placental function.

STUDY QUESTION Are women with a history of first-onset postpartum psychiatric disorders after their first liveborn delivery less likely to have a subsequent live birth? SUMMARY ANSWER Women with incident postpartum psychiatric disorders are less likely to go on to have further children. WHAT IS KNOWN ALREADY Women are particularly vulnerable to psychiatric disorders in the postpartum period. The potential effects of postpartum psychiatric disorders on the mother’s future chances of live birth are so far under-researched. STUDY DESIGN, SIZE, DURATION A population-based cohort study consisted of 414 571 women who had their first live birth during 1997–2015. We followed the women for a maximum of 19.5 years from the date of the first liveborn delivery until the next conception leading to a live birth, emigration, death, their 45th birthday or 30 June 2016, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS Postpartum psychiatric disorders were defined as filling a prescription for psychotropic medications or hospital contact for psychiatric disorders for the first time within 6 months postpartum. The outcome of interest was time to the next conception leading to live birth after the first liveborn delivery. Records on the death of a child were obtained through the Danish Register of Causes of Death. Cox regression was used to estimate the hazard ratios (HRs), stratified by the survival status of the first child. MAIN RESULTS AND THE ROLE OF CHANCE Altogether, 4327 (1.0%) women experienced postpartum psychiatric disorders after their first liveborn delivery. The probability of having a subsequent live birth was 69.1% (95% CI: 67.4–70.7%) among women with, and 82.3% (95% CI: 82.1–82.4%) among those without, postpartum psychiatric disorders. Women with postpartum psychiatric disorders had a 33% reduction in the rate of having second live birth (HR = 0.67, 95% CI: 0.64–0.69), compared to women without postpartum psychiatric disorders. The association disappeared if the first child died (HR = 1.01, 95% CI: 0.85–1.20). If postpartum psychiatric disorders required hospitalisations, this was associated with a more pronounced reduction in live birth rate, irrespective of the survival status of the first child (HR = 0.54, 95% CI: 0.47–0.61 if the first child survived, and HR = 0.49, 95% CI: 0.23–1.04 if the first child died). LIMITATIONS, REASONS FOR CAUTION The use of population-based registers allows for the inclusion of a representative cohort with almost complete follow-up. The large sample size enables us to perform detailed analyses, accounting for the survival status of the child. However, we did not have accurate information on stillbirths and miscarriages, and only pregnancies that led to live birth were included. WIDE IMPLICATIONS OF THE FINDINGS Our study is the first study to investigate subsequent live birth after postpartum psychiatric disorders in a large representative population. The current study indicates that postpartum psychiatric disorders have a significant impact on subsequent live birth, as women experiencing these disorders have a decreased likelihood of having more children. However, the variations in subsequent live birth rate are influenced by both the severity of the disorders and the survival status of the first-born child, indicating that both personal choices and decreased fertility may have a role in the reduced subsequent live birth rate among women with postpartum psychiatric disorders. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Danish Council for Independent Research (DFF-5053-00156B), the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 837180, AUFF NOVA (AUFF-E 2016-9-25), iPSYCH, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (R155-2014-1724), Niels Bohr Professorship Grant from the Danish National Research Foundation and the Stanley Medical Research Institute, the National Institute of Mental Health (NIMH) (R01MH104468) and Fabrikant Vilhelm Pedersen og Hustrus Legat. The authors do not declare any conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Study question: Among babies born by ART, do singleton survivors of a vanishing twin have lower birth weight than other singletons? Summary answer: Vanishing-twin syndrome was associated with lower birth weight among ART singletons; a sibship analysis indicated that the association was not confounded by maternal characteristics that remain stable between deliveries. What is known already known: Previous studies indicate that ART singletons with vanishing-twin syndrome have increased risk of adverse pregnancy outcomes, compared with other ART singletons. The potential contribution of unmeasured maternal background characteristics has been unclear. Study design, size and duration: This was a Norwegian population-based registry study, including 17,368 mothers with 20,410 ART singleton deliveries between January 1984 and December 2013.Participants/materials, setting, methods: The study population included 17,291 ART singletons without vanishing-twin syndrome, 638 ART singletons with vanishing-twin syndrome, and 2,418 ART singletons with uncertain vanishing-twin status. We estimated differences in birth weight and gestational age comparing ART singletons with vanishing-twin syndrome first to all ART singletons without vanishing-twin syndrome, and subsequently to their ART siblings without vanishing-twin syndrome, using random- and fixed-effects linear regression, respectively. The corresponding comparisons for the associations with preterm birth and small-for-gestational age (SGA) were conducted using random-and fixed-effects logistic regression. The sibling analysis of preterm birth included 587 discordant siblings, while the sibling analysis of SGA included 674 discordant siblings.Main results and the role of chance: ART singletons with vanishing-twin syndrome had lower birth weight when compared to all ART singletons without vanishing-twin syndrome, with an adjusted mean difference (95% CI) of -116 grams (-165, -67). When we compared ART singletons with vanishing-twin syndrome to their ART singletons sibling without vanishing-twin syndrome, the adjusted mean difference was -112 grams (-209, -15). ART singletons with vanishing-twin syndrome also had increased risk of being born SGA, with an adjusted odds ratio (95% CI) of 1.48 (1.07, 2.03) compared to all ART singletons without vanishing twin-syndrome, and 2.79 (1.12, 6.91) in the sibship analyses. ART singletons with vanishing-twin syndrome were also more likely to be born preterm, although this difference did not reach statistical significance.Limitations, reasons for caution: We did not have information on maternal socio-economic status, but this factor is accounted for in the sibship analyses. We have no information on whether fresh or frozen embryos were replaced.Wider implications of the findings: The reduction in birth weight and increased SGA in ART singletons with vanishing-twin syndrome may suggest the presence of harmful intrauterine factors with long-term health impact. While vanishing twins are not routinely observed in naturally conceived pregnancies, loss of a twin is potentially a risk factor for the surviving fetus in any pregnancy. This could be further explored in large samples of naturally conceived pregnancies with the necessary information. Study funding/competing interest(s): The authors of this study are supported in part by the UK Medical Research Council, US National Institute of Environmental Health Sciences, and the Norwegian Research Council. The authors have no conflicts of interest.

Background: There is an established association between adverse events during perinatal life and chronic hypertension in adult life. However, disadvantageous conditions often coexist in the same pregnancy. We investigated single and joint perinatal exposure to preeclampsia, being born small for gestational age (SGA) or preterm and subsequent risk of chronic hypertension. Methods: The study population consisted of 731,008 primiparous women from Norway and Sweden registered in the Medical Birth Registers, both as infants and as first time mothers between 1967-2009 (Norway) and 1973-2010 (Sweden). Risk of chronic hypertension in early pregnancy was calculated in women perinatally exposed to preeclampsia, born SGA or preterm by log-binominal regression analysis, and adjusted for maternal age and level of education in the 1st generation. Results: The rate of chronic hypertension was 0.4%. Risk of chronic hypertension was associated with single perinatal exposure to preeclampsia, being born SGA or preterm with adjusted relative risks (95% confidence intervals, CI) 2.2 (95% CI 1.8, 2.7), 1.1 (95% CI 1.0, 1.3) and 1.3 (95% CI 1.0, 1.5) respectively. The risks increased after joint exposures, with an almost 4-fold risk increase after perinatal exposure to preeclampsia and preterm birth. Additional adjustment for BMI and smoking in the 2nd generation in a subset of the cohort only had a minor impact on the results. Conclusions: Perinatal exposure to preeclampsia, being born SGA or preterm is independently associated with increased risk of chronic hypertension. The highest risk was seen after exposure to preeclampsia, especially if combined with SGA or preterm birth.

Hypertensive disorders of pregnancy (HDP) tend to recur from one pregnancy to the next. The aims of the study were to assess the recurrence risk according to type of HDP defined by gestational age at birth and to examine whether recurrence is associated with the following additional risk factors for HDP: maternal age, smoking, inter delivery interval, diabetes, body mass index, as well as fetal growth restriction, and to assess temporal trends in these associations. All women with two singleton births in the Medical Birth Registry of Norway 1967-2012 (n= 742 980) were included in this population based cohort study. Logistic regression was used to calculate odds ratios for the risk of recurrent HDP according to type of HDP. The highest odds ratio of recurrence was observed for the same type of HDP based on gestational age at delivery. After gestational hypertension and term preeclampsia the risk increased tenfold for the same type to recur, whereas after late and early preterm preeclampsia, the risk increased 27 and 97 fold, respectively. The recurrence of early preterm preeclampsia was less influenced by additional risk factors than term HDP. Recurrence of early preterm HDP was significantly lower from 1993 onwards. Recurrent HDP tended to be of the same type as the previous HDP. Risk of recurrence associated with additional risk factors were observed particularly after term. The odds ratio of recurrence of early preterm HDP was significantly lower from 1993 onwards. This article is protected by copyright. All rights reserved.

Objective To explore conditions and outcomes of a first delivery at term that might predict later preterm birth. Design Population based, prospective register based study. Setting Medical Birth Registry of Norway, 1999-2015. Participants 302 192 women giving birth (live or stillbirth) to a second singleton child between 1999 and 2015. Main outcome measures Main outcome was the relative risk of preterm delivery ( Results Women with any of the five complications at term showed a substantially increased risk of preterm delivery in the next pregnancy. The absolute risks for preterm delivery in a second pregnancy were 3.1% with none of the five term complications (8202/265 043), 6.1% after term pre-eclampsia (688/11 225), 7.3% after term placental abruption (41/562), 13.1% after term stillbirth (72/551), 10.0% after term neonatal death (22/219), and 6.7% after term small for gestational age (463/6939). The unadjusted relative risk for preterm birth after term pre-eclampsia was 2.0 (95% confidence interval 1.8 to 2.1), after term placental abruption was 2.3 (1.7 to 3.1), after term stillbirth was 4.2 (3.4 to 5.2), after term neonatal death was 3.2 (2.2 to 4.8), and after term small for gestational age was 2.2 (2.0 to 2.4). On average, the risk of preterm birth was increased 2.0-fold (1.9-fold to 2.1-fold) with one term complication in the first pregnancy, and 3.5-fold (2.9-fold to 4.2-fold) with two or more complications. The associations persisted after excluding recurrence of the specific complication in the second pregnancy. These links between term complications and preterm delivery were also seen in the reverse direction: preterm birth in the first pregnancy predicted complications in second pregnancies delivered at term. Conclusions Pre-eclampsia, placental abruption, stillbirth, neonatal death, or small for gestational age experienced in a first term pregnancy are associated with a substantially increased risk of subsequent preterm delivery. Term complications seem to share important underlying causes with preterm delivery that persist from pregnancy to pregnancy, perhaps related to a mother’s predisposition to disorders of placental function.

Background Gestational age estimation by last menstrual period (LMP) vs. ultrasound (or best obstetric estimate in the US) may result in discrepant classification of preterm vs. term birth. We investigated whether such discrepancies are associated with adverse infant outcomes. Methods We studied singleton livebirths in the Medical Birth Registries of Norway, Sweden and Finland and US live birth certificates from 1999 to the most recent year available. Risk ratios (RR) with 95% confidence intervals (CI) by discordant and concordant gestational age estimation for infant, neonatal and post-neonatal mortality, Apgar score

Objective Questions have been raised about potential risks of prenatal exposure to mercury from amalgam fillings during pregnancy. The aim of this study was to assess possible associations between exposure to amalgam fillings in pregnant women participating in a large cohort study and adverse pregnancy outcome. Methods In the Norwegian Mother and Child Cohort Study (MoBa), a valid information about the number of teeth with amalgam fillings and dental treatment, including new amalgam fillings placed or removed during pregnancy, was available from 69 474 pregnancies. The information was obtained from two questionnaires sent to the women at 17 and 30 weeks of pregnancy, and the data were linked to the Medical Birth Registry of Norway. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) as a measure of association between pregnancy outcome and prenatal exposure to amalgam fillings. Results Logistic regression models, including mothers′ age, education, BMI, parity, smoking during pregnancy, and alcohol consumption during pregnancy revealed no significant associations between the number of teeth with amalgam fillings and early preterm delivery, late preterm delivery, low birthweight, malformation or stillbirth. Conclusions We found no evidence for serious perinatal consequences of maternal exposure to amalgam fillings during pregnancy.

Background Previous studies have demonstrated that low birth weight (LBW) is associated with higher risk for end-stage renal disease (ESRD). However, both LBW and ESRD cluster in families. The present study investigates whether familial factors explain the association between LBW and ESRD. Study Design Retrospective registry-based cohort study. Setting & Participants Since 1967, the Medical Birth Registry of Norway has recorded medical data for all births in the country. Sibling data are available through the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. Individuals registered in the Medical Birth Registry with at least 1 registered sibling were included. Predictor LBW in the participant and/or LBW in at least 1 sibling. Outcome ESRD. Results Of 1,852,080 included individuals, 527 developed ESRD. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR for ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.18-2.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53). Similar results were observed for individuals who were small for gestational age (SGA). Separate analyses for the association of age 18 to 42 years and noncongenital ESRD showed stronger associations for SGA than for LBW, and the associations were not statistically significant for age 18 to 42 years for LBW. Limitations Follow-up only until 42 years of age. Conclusions LBW and SGA are associated with higher risk for ESRD during the first 40 years of life, and the associations were not explained by familial factors. Our results support the hypothesis that impaired intrauterine nephron development may be a causal risk factor for progressive kidney disease.

Importance Clinicians have been urged to delay the use of obstetric interventions (eg, labor induction, cesarean delivery) until 39 weeks or later in the absence of maternal or fetal indications for intervention. Objective To describe recent trends in late preterm and early term birth rates in 6 high-income countries and assess association with use of clinician-initiated obstetric interventions. Design Retrospective analysis of singleton live births from 2006 to the latest available year (ranging from 2010 to 2015) in Canada, Denmark, Finland, Norway, Sweden, and the United States. Exposures Use of clinician-initiated obstetric intervention (either labor induction or prelabor cesarean delivery) during delivery. Main Outcomes and Measures Annual country-specific late preterm (34-36 weeks) and early term (37-38 weeks) birth rates. Results The study population included 2 415 432 Canadian births in 2006-2014 (4.8% late preterm; 25.3% early term); 305 947 Danish births in 2006-2010 (3.6% late preterm; 18.8% early term); 571 937 Finnish births in 2006-2015 (3.3% late preterm; 16.8% early term); 468 954 Norwegian births in 2006-2013 (3.8% late preterm; 17.2% early term); 737 754 Swedish births in 2006-2012 (3.6% late preterm; 18.7% early term); and 25 788 558 US births in 2006-2014 (6.0% late preterm; 26.9% early term). Late preterm birth rates decreased in Norway (3.9% to 3.5%) and the United States (6.8% to 5.7%). Early term birth rates decreased in Norway (17.6% to 16.8%), Sweden (19.4% to 18.5%), and the United States (30.2% to 24.4%). In the United States, early term birth rates decreased from 33.0% in 2006 to 21.1% in 2014 among births with clinician-initiated obstetric intervention, and from 29.7% in 2006 to 27.1% in 2014 among births without clinician-initiated obstetric intervention. Rates of clinician-initiated obstetric intervention increased among late preterm births in Canada (28.0% to 37.9%), Denmark (22.2% to 25.0%), and Finland (25.1% to 38.5%), and among early term births in Denmark (38.4% to 43.8%) and Finland (29.8% to 40.1%). Conclusions and Relevance Between 2006 and 2014, late preterm and early term birth rates decreased in the United States, and an association was observed between early term birth rates and decreasing clinician-initiated obstetric interventions. Late preterm births also decreased in Norway, and early term births decreased in Norway and Sweden. Clinician-initiated obstetric interventions increased in some countries but no association was found with rates of late preterm or early term birth.

Objective To study prepregnancy serum lipid levels and the association with the number of children. Design Prospective, population-based cohort. Setting Linked data from the Cohort of Norway and the Medical Birth Registry of Norway. Participants 2645 women giving birth to their first child during 1994–2003 (488 one-child mothers and 2157 women with ≥2 births) and 1677 nulliparous women. Main outcome measures ORs for no and one lifetime pregnancy (relative to ≥2 pregnancies) obtained by multinomial logistic regression, adjusted for age at examination, education, body mass index (BMI), smoking, time since last meal and oral contraceptive use. Results Assessed in quintiles, higher prepregnant triglyceride (TG) and TG to high-density lipoprotein (TG:HDL-c) ratio levels were associated with increased risk of one lifetime pregnancy compared with having ≥2 children. Compared with the highest quintile, women in the lowest quintile of HDL cholesterol levels had an increased risk of one lifetime pregnancy (OR 1.7, 95% CI 1.2 to 2.4), as were women with the highest low-density lipoprotein (LDL) cholesterol, TG and TG:HDL-c ratio quintiles (compared with the lowest) (OR 1.2, 95% CI 0.8 to 1.7; OR 2.2, 95% CI 1.5 to 3.2; and OR 2.2, 95% CI 1.5 to 3.2, respectively). Similar effects were found in women with BMI≥25 and the highest LDL and total cholesterol levels in risk of lifetime nulliparity. Conclusion Women with unfavourable prepregnant lipid profile had higher risk of having no or only one child. These findings substantiate an association between prepregnant serum lipid levels and number of children. Previously observed associations between low parity and increased cardiovascular mortality may in part be due to pre-existing cardiovascular disease lipid risk factors.

IntroductionChildren born after assisted reproductive technology, particularly singletons, have been shown to have an increased risk of congenital malformations compared with children born after spontaneous conception. We wished to study whether there has been a change in the past 20 years in the risk of major congenital malformations in children conceived after assisted reproductive technology compared with children spontaneously conceived. Material and methodsPopulation-based cohort study including 90 201 assisted reproductive technology children and 482 552 children spontaneously conceived, born in Denmark, Finland, Norway and Sweden. Both singletons and twins born after in vitro fertilization, intracytoplasmatic sperm injection and frozen embryo transfer were included. Data on children were taken from when the national Nordic assisted reproductive technology registries were established until 2007. Multiple logistic regression analyses were used to estimate the risks and adjusted odds ratios for congenital malformations in four time periods: 1988-1992, 1993-1997, 1998-2002 and 2003-2007. Only major malformations were included. ResultsThe absolute risk for singletons of being born with a major malformation was 3.4% among assisted reproductive technology children vs. 2.9% among children spontaneously conceived during the study period. The relative risk of being born with a major congenital malformation between all assisted reproductive technology children and children spontaneously conceived remained similar through all four time periods (p = 0.39). However, we found that over time the number of children diagnosed with a major malformation increased in both groups across all four time periods. ConclusionWhen comparing children conceived after assisted reproductive technology and spontaneously conceived, the relative risk of being born with a major congenital malformation did not change during the study period.

ObjectivesThe aim was to gain knowledge regarding the risk of perinatal death related to exposure to dental amalgam fillings in the mother.DesignPopulation-based observational cohort study.SettingThe Norwegian Mother and Child Cohort Study, a Norwegian birth cohort of children born in 1999-2008 conducted by the Norwegian Institute of Public Health.Participants72,038 pregnant women with data on the number of teeth filled with dental amalgam.Main outcome measuresData on perinatal death (stillbirth ≥ 22 weeks plus early neonatal death 0-7 days after birth) were obtained from the Medical Birth Registry of Norway.ResultsThe absolute risk of perinatal death ranged from 0.20% in women with no amalgam-filled teeth to 0.67% in women with 13 or more teeth filled with amalgam. Analyses including the number of teeth filled with amalgam as a continuous variable indicated an increased risk of perinatal death by increasing number of teeth filled with dental amalgam (crude OR 1.065, 95% CI 1.034 to 1.098, pConclusionThe current findings suggest that the risk of perinatal death could increase in a dose-dependent way based on the mother's number of teeth filled with dental amalgam. However, we cannot exclude that the relatively modest odds ratios could be a result of residual confounding. Additional studies on the relationship between exposure to dental amalgam fillings during pregnancy and perinatal death are warranted.

Background: Preterm birth is a common, costly and dangerous pregnancy complication. Seasonality of risk would suggest modifiable causes. Methods: We examine seasonal effects on preterm birth, using data from the Medical Birth Registry of Norway (2 321 652 births), and show that results based on births are misleading and a fetuses-at-risk approach is essential. In our harmonic-regression Cox proportional hazards model we consider fetal risk of birth between 22 and 37 completed weeks of gestation. We examine effects of both day of year of conception (for early effects) and day of ongoing gestation (for seasonal effects on labour onset) as modifiers of gestational-age-based risk. Results: Naive analysis of preterm rates across days of birth shows compelling evidence for seasonality (P

Study question Is the risk of hypertensive disorders in pregnancies conceived following specific assisted reproductive technology (ART) procedures different from the risk in spontaneously conceived (SC) pregnancies? Summary answer ART pregnancies had a higher risk of hypertensive disorders, in particular following cryopreservation, with the highest risk seen in twin pregnancies following frozen-thawed cycles. What is known already The risk of hypertensive disorders is higher in ART pregnancies than in SC pregnancies. The increased risk may be partly explained by multiple pregnancies and underlying infertility, but a contribution from specific ART procedures has not been excluded. Study design, size, duration Population-based cohort study, including sibling design with nationwide data from health registers in Sweden, Denmark and Norway. Participants/materials, setting, methods All registered ART pregnancies and a sample of SC pregnancies with gestational age ≥22 weeks from 1988 to 2007 were included. ART singleton pregnancies (n = 47 088) were compared with SC singleton pregnancies (n = 268 599), matched on parity and birth year. ART twin pregnancies (n = 10 918) were compared with SC twin pregnancies (46 674). We used logistic regression to estimate adjusted odds ratios and risk differences for hypertensive disorders in pregnancies following IVF, ICSI and fresh or frozen-thawed cycles. We also compared fresh and frozen-thawed cycles within mothers who had conceived following both procedures using conditional logistic regression (sibling analysis). Main results and the role of chance Hypertensive disorders were reported in 5.9% of ART singleton and 12.6% of ART twin pregnancies. Comparing singleton pregnancies, the risk of hypertensive disorders was higher after all ART procedures. The highest risk in singleton pregnancies was seen after frozen-thawed cycles [risk 7.0%, risk difference 1.8%, 95% confidence interval (CI) 1.2-2.8]. Comparing twin pregnancies, the risk was higher after frozen-thawed cycles (risk 19.6%, risk difference 5.1%, 95% CI 3.0-7.1), but not after fresh cycles. In siblings, the risk was higher after frozen-thawed cycles compared with fresh cycles within the same mother (odds ratio 2.63, 95% CI 1.73-3.99). There were no clear differences in risk for IVF and ICSI. Limitations, reasons for caution The number of ART siblings in the study was limited. Residual confounding cannot be excluded. In addition, we did not have information on all SC pregnancies in each woman's history, and could therefore not compare risk in ART versus SC pregnancies in the same mother. Wider implications of the findings Pregnancies following frozen-thawed cycles have a higher risk of hypertensive disorders, also when compared with fresh cycle pregnancies by the same mother. The safety aspects in frozen-thawed cycles merit further attention. Study funding/competing interests Funding was received from the European Society for Human Reproduction and Embryology, the University of Copenhagen, the Danish Agency for Science, Technology and Innovation, the Nordic Federation of Societies of Obstetrics and Gynecology and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. None of the authors has any competing interests to declare.

To estimate gestational age-specific risks of fetal death in pregnancies complicated by preeclampsia.Population-based cohort study comprising all singleton births (N=554,333) without preexisting chronic hypertension recorded in the Norwegian Medical Birth Registry from 1999 to 2008. Additional data come from a subset of preeclamptic pregnancies enrolled in the Norwegian Mother and Child Cohort Study with available medical records (n=3,037). The risk of fetal death, expressed per 1,000 fetuses exposed to preeclampsia, was calculated using a life table approach.Preeclampsia was recorded in 3.8% (n=21,020) of all pregnancies. Risk of stillbirth was 3.6 per 1,000 overall and 5.2 per 1,000 among pregnancies with preeclampsia (relative risk 1.45, 95% confidence interval [CI] 1.20-1.76). However, relative risk of stillbirth was markedly elevated with preeclampsia in early pregnancy. At 26 weeks of gestation, there were 11.6 stillbirths per 1,000 pregnancies with preeclampsia compared with 0.1 stillbirths per 1,000 pregnancies without (relative risk 86, 95% CI 46-142). Fetal risk with preeclampsia declined as pregnancy advanced, but at 34 weeks of gestation remained more than sevenfold higher than pregnancies without preeclampsia.For clinical purposes, the fetal risk of death associated with preeclampsia begins when preeclampsia becomes clinically apparent. Using a method that takes into account the clinical diagnosis of preeclampsia and the population of fetuses at risk, we find a remarkably high relative risk of fetal death among pregnancies diagnosed with preeclampsia in the preterm period.II.

Study questions Has the perinatal outcome of children conceived after assisted reproductive technology (ART) improved over time? Summary answer The perinatal outcomes in children born after ART have improved over the last 20 years, mainly due to the reduction of multiple births. What is known and what this paper adds A Swedish study has shown a reduction in unwanted outcomes over time in children conceived after ART. Our analyses based on data from more than 92 000 ART children born in four Nordic countries confirm these findings. Study design Nordic population-based matched cohort study with ART outcome and health data from Denmark, Finland, Norway and Sweden. Participants, setting and methods We analysed the perinatal outcome of 62 379 ART singletons and 29 758 ART twins, born from 1988 to 2007 in four Nordic countries. The ART singletons were compared with a control group of 362 215 spontaneously conceived singletons. Twins conceived after ART were compared with all spontaneously conceived twins (n = 122 763) born in the Nordic countries during the study period. The rates of several adverse perinatal outcomes were stratified into the time periods: 1988-1992; 1993-1997; 1998-2002 and 2003-2007 and presented according to multiplicity. Main results and role of chance For singletons conceived after ART, a remarkable decline in the risk of being born preterm and very preterm was observed. The proportion of ART singletons born with a low and very low birthweight also decreased. Finally, the stillbirth and infant death rates have declined among both ART singletons and twins. Throughout the 20 year period, fewer ART twins were stillborn or died during the first year of life compared with spontaneously conceived twins, presumably due to the lower proportion of monozygotic twins among the ART twins. Limitations, reasons for caution We were not able to adjust for some potential confounders such as BMI, smoking, length or cause of infertility. The Nordic ART populations have changed over time, and in recent years, both less as well as severely reproductive ill couples are being treated. This may have affected the observed trends. Wider implications of the findings It is assuring that data from four countries confirm an overall improvement over time in the perinatal outcomes of children conceived after ART. Furthermore, data show the beneficial effect of single embryo transfer, not only in regard to lowering the rate of multiples but also concerning the health of singletons. Study funding/competing interests The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen and the Danish Agency for Science, Technology and Innovation has supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Federation of Obstetrics and Gynecology (NFOG). None of the authors has any competing interests to declare.

Background Being overweight is an important risk factor for Gestational Diabetes Mellitus (GDM), but the underlying mechanisms are not understood. Weight change between pregnancies has been suggested to be an independent mechanism behind GDM. We assessed the risk for GDM in second pregnancy by change in Body Mass Index (BMI) from first to second pregnancy and whether BMI and gestational weight gain modified the risk. Methods and findings In this observational cohort, we included 24,198 mothers and their 2 first pregnancies in data from the Medical Birth Registry of Norway (2006–2014). Weight change, defined as prepregnant BMI in second pregnancy minus prepregnant BMI in first pregnancy, was divided into 6 categories by units BMI (kilo/square meter). Relative risk (RR) estimates were obtained by general linear models for the binary family and adjusted for maternal age at second delivery, country of birth, education, smoking in pregnancy, interpregnancy interval, and year of second birth. Analyses were stratified by BMI (first pregnancy) and gestational weight gain (second pregnancy). Compared to women with stable BMI (−1 to 1), women who gained weight between pregnancies had higher risk of GDM—gaining 1 to 2 units: adjusted RR 2.0 (95% CI 1.5 to 2.7), 2 to 4 units: RR 2.6 (2.0 to 3.5), and ≥4 units: RR 5.4 (4.0 to 7.4). Risk increased significantly both for women with BMI below and above 25 at first pregnancy, although it increased more for the former group. A limitation in our study was the limited data on BMI in 2 pregnancies. Conclusions The risk of GDM increased with increasing weight gain from first to second pregnancy, and more strongly among women with BMI < 25 in first pregnancy. Our results suggest weight change as a metabolic mechanism behind the increased risk of GDM, thus weight change should be acknowledged as an independent factor for screening GDM in clinical guidelines. Promoting healthy weight from preconception through the postpartum period should be a target., Linn Sorbye and colleagues identify weight gain between pregnancies as an independent risk factor for gestational diabetes, using data from a large Norwegian birth registry., Author summary Why was this study done? Being overweight during pregnancy is an important risk factor for Gestational Diabetes Mellitus (GDM); however, the underlying mechanisms are not clear. Recent evidence has found that women who increase their weight from first to second pregnancy increase the risk of GDM, suggesting weight as a causal mechanism behind GDM. Research is not consistent on whether the association is dependent on the woman’s weight status when she enters her first pregnancy. What did the researchers do and find? In this observational cohort study, we used data from the population-based Medical Birth Registry of Norway and included 24,198 mothers with their first and second pregnancy during 2006–2014. We investigated if a change in Body Mass Index (BMI) between first and second pregnancy affected the risk of GDM in the second pregnancy and if the association was dependent on the woman’s prepregnant BMI in first pregnancy The risk of GDM in second pregnancy increased with increasing weight gain between pregnancies, and more strongly among women who had a BMI below 25 (kilo/meters squared) in first pregnancy. Decreasing BMI by >2 units from first to second pregnancy had a preventive effect on GDM in overweight and obese women. What do these findings mean? Weight gain between pregnancies should be evaluated as an independent risk factor for screening GDM in clinical antenatal guidelines. Our results need to be replicated in other populations, and they underline the importance of future research on pathophysiologic mechanisms behind the development of GDM. Efforts to promote healthy weight in the reproductive population need to expand their focus to include healthy maternal weight from preconception throughout reproduction.

Background: Preeclampsia (PE) is a dangerous and unpredictable pregnancy complication. A seasonal pattern of risk would suggest that there are potentially preventable environmental contributors, but prior analyses have not adjusted for confounding by PE risk factors that are associated with season of conception. Methods: Seasonal effects were modeled and tested by representing each day of the year as an angle on a unit circle and using trigonometric functions of those angles in predictive models, using “harmonic analysis.” We applied harmonic Cox regression to model confounder-adjusted effects of the estimated day of the year of conception on risk of PE for births from the Medical Birth Registry of Norway for deliveries between 1999 and 2009. We also examined effect measure modification by parity, latitude (region), fetal sex, and smoking. Results: In adjusted models, PE risk was related to season, with higher risk in spring conceptions and lower risk in autumn conceptions, with a risk amplitude (maximum compared with minimum) of about 20%. The pattern replicated across subpopulations defined by parity, latitude (region), fetal sex, and smoking. Conclusions: These results suggest that there is a seasonal driver for PE, with effects that are not modified by parity, latitude, fetal sex, or smoking. https://doi.org/10.1289/EHP963

Objective To examine the risk of pre-eclampsia (PE) in women conceiving after assisted reproductive technologies (ART). Potential confounding from maternal age, long intervals between births, new partner and smoking were evaluated. Design and setting Population-based cohort study with data from the Medical Birth Registry of Norway. Population A total of 501 766 mothers with offspring from 1988 to 2009. Methods Births to the same mother were linked in sibship data files with information of ART. Main outcome measures Odds ratio (OR) (95% confidence intervals) of PE in pregnancies conceived by ART compared with spontaneous conception, stratified by parity. Results The prevalence of PE was 5.1% in first, 2.2% in second and 2.1% in third pregnancies. Corresponding figures in ART pregnancies were 6.0%, 3.3% and 4.4%. Hence, the odds ratios of PE in ART pregnancies relative to spontaneous pregnancies increased from 1.2 (1.1–1.3) in first, 1.5 (1.3–1.8) in second to 2.1 (1.4–3.3) in third pregnancies. Adjusting by maternal age lowered the odds ratio to 1.3 (1.1–1.6) and 1.8 (1.2–2.8) in second and third pregnancies, respectively. Multi-adjusted, birth interval had more impact than change of partner. Smoking was associated with a strongly reduced PE risk (odds ratio 0.65; 0.62–0.69), but there was no confounding by smoking on the ART associated risk. Conclusions Assisted reproductive technologies increases the risk of PE, and the risk may increase by parity. The association between ART pregnancies and PE is to some extent explained by interbirth intervals and advanced maternal age, but not to change of partner or smoking.

Objective To identify high-risk fetuses at the first routinely performed ultrasound examination by making use of information from the mother's previous pregnancy. Design A population-based cohort study. Setting Norway, 1999–2009. Population All singleton first live births and their second-born siblings registered in the Medical Birth Registry of Norway (166 786 eligible sibling pairs). Methods Odds ratios were calculated by logistic regression. Main outcome measures Very small for gestational age (vSGA; birthweight ≤−1.96 standard deviations) and perinatal death (stillbirth at ≥22 weeks of gestation or death within 28 days of life). Results Small fetal size at ultrasound (i.e. a fetus smaller than expected by last menstrual period, LMP) is only weakly predictive of vSGA or perinatal death; however, if the firstborn sibling was vSGA at birth, ultrasound measures in the next pregnancy become strongly informative of risk. The smaller the fetal size on ultrasound, the higher its risk of vSGA (3–18%; Ptrend

Study question Is the risk of stillbirth and perinatal deaths increased after assisted reproductive technology (ART) compared with pregnancies established by spontaneous conception (SC)? Summary answer A significantly increased risk of stillbirth in ART singletons was only observed before 28 + 0 gestational weeks. What is known already The current literature indicates that children born after ART have an increased risk of perinatal death. The knowledge on stillbirth in ART pregnancies is limited. Study design, size, duration A population based case-control study. Participants/materials, setting and methods A total of 62 485 singletons and 29 793 twins born after ART in Denmark, Finland, Norway and Sweden, from 1982 to 2007, were compared with 362 798 spontaneously conceived (SC) singletons and 132 181 twins. Main results and the role of chance The adjusted rate ratio for stillbirth at gestational weeks 22 + 0 to 27 + 6 was 2.08 [95% confidence interval (CI) 1.55-2.78] for ART versus SC singletons. After 28 + 0 gestational weeks there was no significant difference in the risk of stillbirth between ART and SC singletons. ART twins had a lower risk of stillbirth compared with SC twins, but when restricting the analysis to opposite-sex twins and excluding all monozygotic twins, there was no significant difference between the groups. Singletons conceived by ART had an overall increased risk of early neonatal death (adjusted odds ratio 1.54, 95% CI 1.28-1.85) and death within the first year after birth (1.45, 1.26-1.68). No difference regarding these two parameters was found when further adjusting for the gestational age [(0.97, 0.80-1.18) and (0.99, 0.85-1.16), respectively]. ART twins had a lower risk of early neonatal and infant deaths than SC twins, but no difference was found when restricting the analyses to opposite-sex twins. Limitations, reason for caution We were not able to adjust for potential confounders, such as a prior history of stillbirth, induction of labour, body mass index or smoking. Wider implications of the findings The risk of stillbirth in ART versus SC singletons was only increased for very early gestational ages (before 28 weeks). This might indicate that the current clinical management of ART pregnancies is sufficient regarding prevention of stillbirth during the third trimester. Study funding/competing interest(s) No conflict of interest was reported. The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen, Denmark, the Danish Agency for Science, Technology and Innovation and Sahlgrenska University Hospital, Gothenburg, Sweden supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Society of Obstetrics and Gynecology (NFOG).

Do children and young adults born after assisted reproductive technology (ART) have an increased risk of cancer?Children born after ART showed no overall increase in the rate of cancer when compared with children born as a result of spontaneous conception.Children born after ART have more adverse perinatal outcomes, i.e. preterm births, low birthweights and birth defects. Previous studies have shown divergent results regarding the risk of cancer among children born after ART.A retrospective Nordic population-based cohort study was performed, comprising all children born after ART in Sweden, Denmark, Finland and Norway between 1982 and 2007. The mean (±standard deviation) follow-up time was 9.5 (4.8) years.Children born after ART (n = 91 796) were compared with a control group of children born after spontaneous conception. This control group was almost 4-fold the size of the ART group (n = 358 419) and matched for parity, year of birth and country. Data on perinatal outcomes and cancer were obtained from the National Medical Birth Registries, the Cancer Registries, the Patient Registries and the Cause of Death Registries. The cancer diagnoses were divided into 12 main groups. Hazard ratios (HRs) and adjusted HR were calculated. Adjustments were carried out for country, maternal age, parity, sex, gestational age and birth defects.There was no significant increase in overall cancer rates among children born after ART when compared with children born after spontaneous conception (adjusted HR 1.08; 95% CI 0.91-1.27). Cancer, of any form, was found among 181 children born after ART (2.0/1000 children, 21.0/100 000 person-years) compared with 638 children born after spontaneous conception (1.8/1000 children, 18.8/100 000 person-years). Leukaemia was the most common type of cancer (n = 278, 0.62/1000 children) but no significantly increased incidence was found among children born after ART. An increased risk was observed for 2 of 12 cancer groups. They were central nervous system tumours (adjusted HR 1.44; 95% CI 1.01-2.05) and malignant epithelial neoplasms (adjusted HR 2.03; 95% CI 1.06-3.89); the absolute risks were 0.46/1000 and 0.15/1000 children, respectively, corresponding to an absolute increased risk of 0.14/1000 and 0.08/1000 children, respectively.As this is an observational study, the main limitation is the fact that it is not possible to adjust for all potential confounders. We were not able to control for confounders such as socio-economic status and perinatal factors, such as Apgar score, which other studies have suggested affect cancer rates.The results of this large population-based cohort study are in agreement with most previously published studies. The main findings are reassuring for couples undergoing ART, children born after ART and clinicians working with ART.No conflict of interest was reported. The study was supported by grants from The European Society for Human Reproduction and Embryology (ESHRE), Sahlgrenska University Hospital, Gothenburg, Sweden, the University of Copenhagen, Denmark, the Danish Agency of Science, Technology and Innovation and the Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).

Background Smoking during pregnancy is linked to having a small for gestational age (SGA) baby. We estimated SGA risk among women who smoked persistently, quit smoking or started smoking during their first two pregnancies. Methods Data from the population-based Medical Birth Registry of Norway was used to evaluate self-reported smoking at the beginning and end of two successive pregnancies among 118 355 Nordic women giving birth 1999–2014. Relative risks (RR) with 95% confidence intervals (CI) of SGA in the second pregnancy were estimated using adjusted generalised linear models with non-smokers during both pregnancies serving as referent category. Results Daily smokers throughout both pregnancies had almost threefold increased SGA risk in the second pregnancy (RR 2.9, 95% CI 2.7, 3.1). Daily smokers in the first pregnancy, who abstained in the second, had a 1.3-fold increased risk (95% CI 1.1, 1.5). Intermediate risks were found among persistent daily smokers who quit by the end of the second pregnancy (RR 2.0, 95% CI 1.6, 2.4) and non-smokers in first pregnancy who smoked daily throughout their second (RR 1.8, 95% CI 1.4, 2.3). Persistently smoking women without SGA in first pregnancy, had a 2.7-fold increased risk of SGA in second pregnancy (95% CI 2.5, 3.0). Conclusions Smoking throughout two successive pregnancies was associated with the greatest increased SGA risk compared with non-smokers, while cessation before or during the second pregnancy reduced this risk. Women who smoked in the first pregnancy without experiencing SGA are not protected against SGA in second pregnancy if they continue smoking.

Summary Background and objectives Women with preeclampsia have increased risk of developing ESRD. This study assessed whether this can be explained by preeclampsia itself or by familial aggregation of common risk factors. Design, setting, participants, & measurements Since 1967, the Medical Birth Registry of Norway has registered data on all births in the country. By linkage with the Norwegian Population Registry, different, but overlapping, cohorts were defined: the first and second cohorts included women and a sibling (first cohort) or child (second cohort) with a registered first birth between 1967 and 2008. Similar cohorts were defined for men. The Norwegian Renal Registry provided data on ESRD from 1980 to June 2009. Results Cohort 1 was used for the main analyses and included 570,675 women, 291 of whom developed ESRD after a median 18.2 years. Compared with women without preeclampsia and no siblings with preeclampsia, women without preeclampsia but a sibling with preeclampsia had a relative risk (RR) of ESRD of 0.96 (95% confidenceinterval,0.59–1.6),womenwithpreeclampsiabut nosiblingswithpreeclampsia hadaRR of6.0 (4.4– 8.1), and women with preeclampsia and a sibling with preeclampsia had a RR of 2.8 (0.88–8.6). Further analyses of women showed no increased risk of ESRD if a child had preeclampsia in first pregnancy. Conclusions FamilialaggregationofriskfactorsdoesnotseemtoexplainincreasedESRDriskafterpreeclampsia. These findings support the hypothesis that preeclampsia per se may lead to kidney damage. Clin J Am Soc Nephrol 7: 1819–1826, 2012. doi: 10.2215/CJN.01820212

Objective: To compare the effect of maternal age on assisted reproductive technology (ART) and spontaneous conception (SC) pregnancies regarding maternal and neonatal complications. Design: Nordic retrospective population-based cohort study. Data from national ART registries were cross-linked with national medical birth registries. Setting: Not applicable. Patient(s): A total of 300,085 singleton deliveries: 39,919 after ART and 260,166 after SC. Intervention(s): None. Main Outcome Measure(s): Hypertensive disorders in pregnancy (HDP), placenta previa, cesarean delivery, preterm birth (PTB; = 28 weeks). Adjusted odds ratios (AORs) were calculated. Associations between maternal age and outcomes were analyzed. Result(s): The risk of placenta previa (AOR 4.11-6.05), cesarean delivery (AOR 1.18-1.50), PTB (AOR 1.23-2.19), and LBW (AOR 1.44-2.35) was significantly higher in ART than in SC pregnancies for most maternal ages. In both ART and SC pregnancies, the risk of HDP, placenta previa, cesarean delivery, PTB, LBW, and SGA changed significantly with age. The AORs for adverse neonatal outcomes at advanced maternal age (>35 years) showed a greater increase in SC than in ART. The change in risk with age did not differ between ART and SC for maternal outcomes at advanced maternal age. Conclusion(s): Having singleton conceptions after ART results in higher maternal and neonatal outcome risks overall, but the impact of age seems to be more pronounced in couples conceiving spontaneously. (C) 2016 by American Society for Reproductive Medicine.

Supplemental Digital Content is available in the text., Preconception predictors of gestational hypertension and preeclampsia may identify opportunities for early detection and improve our understanding of the pathogenesis and life course epidemiology of these conditions. Female participants in community-based Cohort Norway health surveys, 1994 to 2003, were prospectively followed through 2012 via record linkages to Medical Birth Registry of Norway. Analyses included 13 217 singleton pregnancies (average of 1.59 births to 8321 women) without preexisting hypertension. Outcomes were gestational hypertension without proteinuria (n=237) and preeclampsia (n=429). Mean age (SD) at baseline was 27.9 years (4.5), and median follow-up was 4.8 years (interquartile range 2.6–7.8). Gestational hypertension and preeclampsia shared several baseline risk factors: family history of diabetes mellitus, pregravid diabetes mellitus, a high total cholesterol/high-density lipoprotein cholesterol ratio (>5), overweight and obesity, and elevated blood pressure status. For preeclampsia, a family history of myocardial infarction before 60 years of age and elevated triglyceride levels (≥1.7 mmol/L) also predicted risk while physical activity was protective. Preterm preeclampsia was predicted by past-year binge drinking (≥5 drinks on one occasion) with an adjusted odds ratio of 3.7 (95% confidence interval 1.3–10.8) and by past-year physical activity of ≥3 hours per week with an adjusted odds ratio of 0.5 (95% confidence interval 0.3–0.8). The results suggest similarities and important differences between gestational hypertension, preeclampsia, and preterm preeclampsia. Modifiable risk factors could be targeted for improving pregnancy outcomes and the short- and long-term sequelae for mothers and offspring.

Background Maternal age at delivery and cesarean section rates are increasing. In older women, the decision on delivery mode may be influenced by a reported increased risk of surgical interventions during labor and complications with increasing maternal age. We examined the association between maternal age and adverse outcomes in low-risk primiparous women, and the risk of adverse outcomes by delivery modes, both planned and performed (elective and emergency cesarean section, operative vaginal delivery, and unassisted vaginal delivery) in women aged ≥ 35 years. Methods A population-based registry study was conducted using data from the Medical Birth Registry of Norway and Statistics Norway including 169,583 low-risk primiparas with singleton, cephalic labors at ≥ 37 weeks during 1999 − 2009. Outcomes studied were obstetric blood loss, maternal transfer to intensive care units, 5-min Apgar score, and neonatal complications. We adjusted for potential confounders using relative risk models and multinomial logistic regression. Results Most adverse outcomes increased with increasing maternal age. However, the increase in absolute risks was low, except for moderate obstetric blood loss and transfer to the neonatal intensive care unit (NICU). Operative deliveries increased with increasing maternal age and in women aged ≥ 35 years, the risk of maternal complications in operative delivery increased. Neonatal adverse outcomes increased mainly in emergency operative deliveries. Moderate blood loss was three times more likely in elective and emergency cesarean section than in unassisted vaginal delivery, and twice as likely in operative vaginal delivery. Low Apgar score and neonatal complications occurred two to three times more often in emergency operative deliveries than in unassisted vaginal delivery. However, comparing outcomes after elective cesarean section and planned vaginal delivery, only moderate blood loss (higher in elective cesarean section), neonatal transfer to NICU and neonatal infections (both higher in planned vaginal delivery) differed significantly. Conclusions Most studied adverse outcomes increased with increasing maternal age, as did operative delivery. Although emergency operative procedures were associated with an increased risk of adverse outcomes, the absolute risk difference in complications between the modes of delivery was low for the majority of outcomes studied. Electronic supplementary material The online version of this article (doi:10.1186/s12884-016-1028-3) contains supplementary material, which is available to authorized users.

In the present study, the authors investigated the role of the intrauterine environment in childhood adiposity by comparing the maternal-offspring body mass index (BMI) association with the paternal-offspring BMI association when the offspring were 3 years of age, using parental prepregnancy BMI (measured as weight in kilograms divided by height in meters squared). The parent-offspring trios (n = 29,216) were recruited during pregnancy from 2001 to 2008 into the Norwegian Mother and Child Cohort Study conducted by The Norwegian Institute of Public Health. Data from self-administered questionnaires were used in linear regression analyses. Crude analyses showed similar parental-offspring BMI associations; the mean difference in offspring BMI was 0.15 (95% confidence interval: 0.13, 0.16) per each 1-standard-deviation increase in maternal BMI and 0.15 (95% confidence interval: 0.13, 0.17) per each 1-standard-deviation increase in paternal BMI. After all adjustments, the mean difference in offspring BMI per each 1-standard-deviation increment of maternal BMI was 0.12, and the mean difference in offspring BMI per each 1-standard-deviation increment of paternal BMI was 0.13. There was no strong support for heterogeneity between the associations (P > 0.6). In conclusion, results from the present large population-based study showed similar parental-offspring BMI associations when the offspring were 3 years of age, which indicates that the maternal-offspring association may be explained by shared familial (environmental and genetic) risk factors rather than by the intrauterine environment.

The study's purpose was to examine the associations between exercise performed at different time points during pregnancy and gestational age (GA) in a population-based cohort study.Data included 61,098 singleton pregnancies enrolled between 2000 and 2006 in the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health. Self-reported exercise was collected from two questionnaires in pregnancy weeks 17 and 30. GA was determined on the basis of the expected date of delivery according to ultrasound, as registered in the Medical Birth Registry of Norway. We used logistic regression to analyze preterm (37 completed weeks) and postterm births (≥ 42 wk). Comparison of mean GA by exercise levels was estimated by a general linear model.Mean GA for women exercising three to five times a week in week 17 was 39.51 (95% confidence interval [CI] = 39.48-39.54) compared with 39.34 (95% CI = 39.30-39.37) completed weeks for nonexercisers (P0.001). Mean differences remained for all categories of exercise after adjusting for confounding with the greatest mean difference between exercising three to five times per week in week 17 and nonexercisers (equals 1 d). Similar mean differences in GA were observed by exercise levels in week 30. The greatest protective effect on risk of preterm birth was observed for women exercising three to five times a week in week 17 or 30 (adjusted odds ratio (aOR) = 0.82, 95% CI = 0.73-0.91 and aOR = 0.74, 95% CI = 0.65-0.83, respectively) compared with nonexercisers. On the other hand, women exercising one to two or three to five times per week in week 17 were slightly more likely to have a postterm birth (aOR = 1.14, 95% CI = 1.04-1.24 and aOR = 1.15, 95% CI = 1.04-1.26, respectively). Mean GA did not differ by type of exercise performed during pregnancy.Exercise performed during pregnancy shifted the GA distribution slightly upward resulting in reduced preterm births and slightly increased postterm births.

Objective To examine the association between maternal age and elective cesarean section in primiparous and para one women in a low-risk population. Design Population-based registry study. Setting Norway. Population The source population was all mothers giving birth to their first or second child from 1 January 1999 to 31 December 2006. The final study population comprised 229 370 primiparous and para one low-risk mothers. Methods Data were extracted from the Medical Birth Registry of Norway. We constructed a low-risk population by excluding pregnancies with medical conditions associated with elective cesarean section and maternal age. The association between maternal age and elective cesarean was analysed by relative-risk models. Main outcome measures Elective cesarean section. Results In this low-risk population, the proportion of cesarean section was 9%, and 27% of these were elective. Cesarean delivery increased substantially with increasing maternal age, especially elective cesarean section. In primipara, elective cesarean section increased from 0.6 to 7.5% of all deliveries, corresponding to a relative risk of 11.7 (95% confidence interval 8.9-15.4) in women ≥ 40 years relative to 20-24 years. When comparing women ≥ 40 years with those aged below 25 years, the relative risk in para one without previous cesarean section was 4.5 (95% confidence interval 3.5-5.8; the proportion increasing from 1.4 to 6.2%), while in para one with previous cesarean section it was 2.9 (95% confidence interval 2.4-3.6; the proportion increasing from 17.5 to 51.5%). Conclusions We found a close association between maternal age and elective cesarean section in a low-risk population.

IntroductIon : Underreporting of smoking in epidemiologic studies is common and may constitute a validity prob lem, leading to biased association measures. In this prospective study, we validated self-reported tobacco use against nico tine exposure assessed by plasma cotinine in the Norwegian Mother and child c ohort study (MoBa). Methods : The study was based on a subsample of 2,997 women in the MoBa study who delivered infants during the period 2002–2003. self-reported tobacco use (test variable) and plasma cotinine concentrations (gold standard) were assessed at approximately gestational week 18. r esults : Daily smoking was reported by 9% of the women, occasional smoking by 4%, and nonsmoking by 86% of the women. sensitivity and specificity for self-reported smoking status were calculated using a cotinine cut-off estimated from the study population (30 nmol/l). Plasma cotinine concentrations ≥30 nmol/l were found in 94% of self-reported daily smokers, 66% of occasional smokers, and 2% of nonsmokers. after the numbers of self-reported nonsmokers with cotinine concentrations above the cut-off limit were added, the daily smoking prevalence increased from 9 to 11%. The sensitivity and specificity for self-reported daily smoking, using 30 nmol/l as the cut-off concentration, were 82 and 99%, respectively. dIscussIon : These findings suggest that self-reported tobacco use is a valid marker for tobacco exposure in the MoBa cohort.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known about risk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birth complications and ADHD in adulthood.We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approved for medical treatment for ADHD, with the remaining population born during the same years, 1967-1987, and surviving into adulthood (n = 1,170,073). Relative risks (RR) adjusted for potential confounders were calculated.Preterm (37 weeks of gestation) and extremely preterm birth (28 weeks of gestation) were associated with 1.3- and 5-fold increased risks of ADHD, respectively. Birth weights2500 g and1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval [CI]: 1.2-1.8, and RR: 2.1, 95% CI: 1.3-3.6, respectively). Five-minute Apgar scores4 and7 were associated with 2.8- and 1.5-fold increased risks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1-2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6-4.9) occurred more frequently among adult ADHD patients.This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight, preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms.

Perfluorinated and polyfluorinated compounds (PFCs) are man-made chemicals produced since the 1950s and extensively used in a wide range of industrial and consumer applications, including polymers, repellents, surfactants, adhesives, food packaging, and fire-fighting foams.1 These compounds are characterized by a hydrophilic head moiety attached to a hydrophobic carbon chain of varying length that is saturated with fluorine atoms (perfluorinated).2 Due to their extreme resistance to degradation and potential to bioaccumulate, PFCs have been found in practically all environmental media and biota worldwide, including humans.3,4 PFCs have been found in non-occupationally exposed adults, children, cord blood, and human breastmilk.5-9 The most widely studied PFCs are perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Their half-lives in humans have been determined in retired workers from PFC production facilities, with a median of 4.6 years for PFOS and 3.4 years for PFOA.10 Due to the environmental behavior and toxicity of PFCs, the major producer of PFOS has phased out its production, and its use has been restricted under the Stockholm Convention on Persistent Organic Pollutants (http://chm.pops.int). Further measures have been introduced to reduce industrial emissions of PFOA.11 Following these measures, studies have demonstrated a decrease in body burdens of PFOS and PFOA since around the year 2000.12,13 Nevertheless, human health concerns regarding exposure to low levels of PFCs persist. The toxicity of PFOS and PFOA has been extensively studied in experimental animals, with hepatotoxicty, developmental toxicity, immunotoxicity, hormonal effects, and carcinogenicity identified as the effects of most concern.14,15 In contrast, epidemiologic studies of the relation between PFCs and various health outcomes are limited and inconsistent. A recent study of pregnant women in the Danish National Birth Cohort linked maternal serum concentrations of PFCs with subfecundity,16 finding increased relative odds of subfecundity among women in the highest quartile of both PFOS (odds ratio [OR]=1.8 [95% confidence interval (CI)=1.1-3.0]) and PFOA (2.5 [1.5-4.4]). A woman’s pregnancy history and previous duration of breastfeeding may be important determinants of her PFC body burden and, therefore, influence her PFC plasma concentration.17,18 PFOS and PFOA have been quantified in cord blood, demonstrating their ability to cross the placental barrier.5,8,9 Studies have also documented declining maternal levels of PFOS and PFOA during pregnancy5,9 and declining maternal levels of PFOA following delivery.5 Further, PFCs have been detected in breast milk7, a recent study among primarily breastfed infants reported lower maternal PFOS and PFOA concentrations six months after birth compared with pregnancy levels.5 Further, the PFC body burden among parous women will be affected by the elapsed time since the previous birth (interpregnancy interval). The longer the interpregnancy interval, the greater amount of time there will be for PFC levels to increase toward prepregnancy baseline following the previous birth. The interpregnancy interval is also a reflection, in part, of the woman’s underlying fecundability, which is the construct being measured by time to pregnancy. It is possible among parous women for an association between PFC levels and time to pregnacy, to be due to reverse causality. That is, parous women with long times to pregnancy have higher PFC levels because they also have long interpregnancy intervals. In the previous Danish study of PFC levels and subfecundity, separate effect estimates for parous and nulliparous women were not provided. Due to the potential for reverse causality, it is important to distinguish between women with or without a prior pregnancy. The goal of the present study was to examine the relation between PFOS and PFOA and subfecundity, with separate analyses for parous and nulliparous women.

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

OBJECTIVE To assess the effects of socioeconomic factors on the association between parity and long-term maternal mortality. METHODS This was a population-based cohort study of mothers with births registered in the Medical Birth Registry of Norway during the period 1967-2009. We estimated age-specific (40-69 years) cardiovascular and noncardiovascular mortality ratios by number of births using Cox proportional hazard models. To assess effect modification by mothers' attained education, we stratified on low (less than 11 years) and high (11 years or greater) educational level. We further evaluated fathers' mortality by number of births using the same analytical approach. RESULTS Mothers with low education had higher mortality (cardiovascular: hazard ratio 2.62, 95% confidence interval [CI] 2.34-2.93, noncardiovascular: hazard ratio 1.67, 95% CI 1.62-1.73). Among mothers with low education, cardiovascular mortality increased linearly with each additional birth above one (P trend=.02). In contrast, among mothers with high education, cardiovascular mortality declined with added births (P trend=.045). For noncardiovascular mortality there was no association among mothers with low education, whereas mortality declined with increasing number of births among mothers with high education (P trend