Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations.

OBJECTIVE: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. METHODS: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. RESULTS: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. INTERPRETATION: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Heterogeneity in the risk of cardiovascular disease mortality after the hypertensive disorders of pregnancy across mothers' lifetime reproductive history.

BACKGROUND: Prior studies on maternal cardiovascular disease (CVD) mortality and hypertensive disorders of pregnancy (HDP) have focused only on a woman's first birth and have not accounted for successive affected pregnancies. OBJECTIVES: The objective of this study is to identify mothers' risk of CVD mortality considering lifetime reproductive history. METHODS: We used data from the Medical Birth Registry of Norway, the Norwegian Cause of Death Registry, and the Norwegian National Population Register to identify all mothers who gave birth from 1967 to 2020. Our outcome was mothers' CVD death before age 70. The primary exposure was the lifetime history of HDP. The secondary exposure was the order of HDP and gestational age at delivery of pregnancies with HDP. We used Cox regression models to estimate hazard ratio (HR) and 95% confidence interval (CI), adjusting for education, mother's age, and year of last birth. These models were stratified by the lifetime number of births. RESULTS: Among 987,378 mothers, 86,294 had HDP in at least one birth. The highest CVD mortality, relative to mothers without HDP, was among those with a pre-term HDP in their first two births, although this represented 1.0% of mothers with HDP (HR 5.12, 95% CI 2.66, 9.86). Multiparous mothers with term HDP in their first birth only had no increased risk of CVD relative to mothers without HDP (36.9% of all mothers with HDP; HR 1.12, 95% CI 0.95, 1.32). All other mothers with HDP had a 1.5- to 4-fold increased risk of CVD mortality. CONCLUSIONS: This study identified heterogeneity in the risk of CVD mortality among mothers with a history of HDP. A third of these mothers are not at higher risk compared to women without HDP, while some less common patterns of HDP history are associated with severe risk of CVD mortality.

Trends in severe postpartum haemorrhage among nulliparous women with spontaneous onset of labour: A population-based cohort study.

OBJECTIVE: To investigate the incidence of severe postpartum haemorrhage among nulliparous women with a spontaneous onset of labour at term from 2000 to 2020. DESIGN: Population-based cohort study. SETTING: National, using the Medical Birth Registry of Norway. POPULATION: Women (n = 330 244) who gave birth to their first singleton child in a cephalic presentation after a spontaneous onset of labour at term. METHODS: Cross-tabulations and regression analysis with generalised linear models were used to assess time trends and adjust for potential confounding factors. We also stratified the analyses by maternal age groups, obstetric interventions, mode of delivery and institution size. Time trends were analysed using periods of 5 or 6 years as a unit, and the period from 2000 to 2004 was used as the reference. MAIN OUTCOME MEASURES: Severe postpartum haemorrhage (PPH) was defined as blood loss of >1500 mL within 24 h and/or in combination with blood transfusion. RESULTS: Severe PPH occurred in 7601/330 244 (2.30%) women. The incidence increased from 1.24% in 2000-2004 to 3.83% in 2015-2020 (adjusted relative risk, aRR 2.90; 95% CI 2.70-3.12). Changes in maternal characteristics or obstetric interventions did not explain the increase, and we found similar increases across institutions of all sizes. CONCLUSIONS: The incidence of severe PPH among nulliparous women increased almost threefold over 21 years. The current high incidence warrants urgent efforts to assess unknown risk factors, the health care provided and health system factors that may contribute to the increase, to inform improvements in care.

Risk of adverse pregnancy outcomes in twin- and singleton-born women: An inter-generational cohort study.

OBJECTIVE: To compare the risk of adverse pregnancy outcomes between twin-born and singleton-born women. We also evaluated whether in utero exposure to pre-eclampsia or preterm delivery affected adverse pregnancy outcomes in women's own pregnancies. DESIGN: Population-based cohort study. SETTING: Medical Birth Registry of Norway 1967-2020. POPULATION: 9184 twin-born and 492 894 singleton-born women during 1967-2005, with their later pregnancies registered during 1981-2020. METHODS: Data from an individual's birth were linked to their later pregnancies. We used generalised linear models with log link binomial distribution to obtain exponentiated regression coefficients that estimated relative risks (RRs) with 95% confidence intervals (CIs) for associations between twin- or singleton-born women and later adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Pre-eclampsia, preterm delivery or perinatal loss in twin-born compared with singleton-born women. RESULTS: There was no increased risk for adverse outcomes in twin-born compared with singleton-born women: adjusted RRs for pre-eclampsia were 1.00 (95% CI 0.93-1.09), for preterm delivery 0.96 (95% CI 0.90-1.02) and for perinatal loss 1.00 (95% CI 0.84-1.18). Compared with singleton-born women exposed to pre-eclampsia in utero, twin-born women exposed to pre-eclampsia had lower risk of adverse outcomes in their own pregnancies; the aRR for pre-eclampsia was 0.73 (95% CI 0.58-0.91) and for preterm delivery was 0.71 (95% CI 0.56-0.90). Compared with preterm singleton-born women, preterm twin-born women did not differ in terms of risk of pre-eclampsia (aRR 1.05, 95% CI 0.92-1.21) or perinatal loss (aRR 0.99, 95% CI 0.71-1.37) and had reduced risk of preterm delivery (RR 0.83, 95% CI 0.74-0.94). CONCLUSIONS: Twin-born women did not differ from singleton-born women in terms of risk of adverse pregnancy outcomes. Twin-born women exposed to pre-eclampsia in utero, had a lower risk of pre-eclampsia and preterm delivery compared with singleton-born women exposed to pre-eclampsia.

Early suppression policies protected pregnant women from COVID-19 in 2020: A population-based surveillance from the Nordic countries.

INTRODUCTION: The Coronavirus 2019 Disease (COVID-19) pandemic reached the Nordic countries in March 2020. Public health interventions to limit viral transmission varied across different countries both in timing and in magnitude. Interventions indicated by an Oxford Stringency Index ≥50 were implemented early (March 13-17, 2020) in Denmark, Finland, Norway and Iceland, and on March 26, 2020 in Sweden. The aim of the current study was to assess the incidence of COVID-19-related admissions of pregnant women in the Nordic countries in relation to the different national public health strategies during the first year of the pandemic. MATERIAL AND METHODS: This is a meta-analysis of population-based cohort studies in the five Nordic countries with national or regional surveillance in the Nordic Obstetric Surveillance System (NOSS) collaboration: national data from Denmark, Finland, Iceland and Norway, and regional data covering 31% of births in Sweden. The source population consisted of women giving birth in the included areas March 1-December 31, 2020. Pregnant women with a positive SARS-CoV-2 PCR test ≤14 days before hospital admission were included, and admissions were stratified as either COVID-19-related or non-COVID (other obstetric healthcare). Information about public health policies was retrieved retrospectively. RESULTS: In total, 392 382 maternities were considered. Of these, 600 women were diagnosed with SARS-CoV-2 infection and 137 (22.8%) were admitted for COVID-19 symptoms. The pooled incidence of COVID-19 admissions per 1000 maternities was 0.5 (95% confidence interval [CI] 0.2 to 1.2, I2 = 77.6, tau2 = 0.68, P = 0.0), ranging from no admissions in Iceland to 1.9 admissions in the Swedish regions. Interventions to restrict viral transmission were less stringent in Sweden than in the other Nordic countries. CONCLUSIONS: There was a clear variation in pregnant women's risk of COVID-19 admission across countries with similar healthcare systems but different public health interventions to limit viral transmission. The meta-analysis indicates that early suppression policies protected pregnant women from severe COVID-19 disease prior to the availability of individual protection with vaccines.

Birth Weight in Consecutive Pregnancies and Maternal Cardiovascular Disease Mortality Among Spontaneous and Iatrogenic Term Births: A Population-Based Cohort Study.

Knowledge on the association between offspring birth weight and long-term risk of maternal cardiovascular disease (CVD) mortality is often based on firstborn infants without consideration of women's consecutive births. We studied long-term CVD mortality according to offspring birth weight patterns among women with spontaneous and iatrogenic term deliveries in Norway (1967-2020). We constructed birth weight quartiles (Qs) by combining standardized birth weight with gestational age in quartiles (Q1, Q2/Q3, and Q4) for the women's first 2 births. Mortality was estimated using Cox regression and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Changes in offspring birth weight quartiles were associated with long-term maternal CVD mortality. Compared with women who had 2 term infants in Q2/Q3, women with a first offspring in Q2/Q3 and a second in Q1 had higher mortality risk (HR = 1.33, 95% CI: 1.18, 1.50), while risk was lower if the second offspring was in Q4 (HR = 0.78, 95% CI: 0.67, 0.91). The risk increase associated with having a first infant in Q1 was eliminated if the second offspring was in Q4 (HR = 0.99, 95% CI: 0.75, 1.31). These patterns were similar for women with iatrogenic and spontaneous deliveries. Inclusion of information from subsequent births revealed heterogeneity in maternal CVD mortality which was not captured when using only information based on the first offspring.

Severe Congenital Heart Defects and Cerebral Palsy.

OBJECTIVE: To report the prevalence of cerebral palsy (CP) in children with severe congenital heart defects (sCHD) and the outcome/severity of the CP. METHODS: Population-based, data linkage study between CP and congenital anomaly registers in Europe and Australia. The EUROCAT definition of severe CHD (sCHD) was used. Linked data from 4 regions in Europe and 2 in Australia were included. All children born in the regions from 1991 through 2009 diagnosed with CP and/or sCHD were included. Linkage was completed locally. Deidentified linked data were pooled for analyses. RESULTS: The study sample included 4989 children with CP and 3684 children with sCHD. The total number of livebirths in the population was 1 734 612. The prevalence of CP was 2.9 per 1000 births (95% CI, 2.8-3.0) and the prevalence of sCHD was 2.1 per 1000 births (95% CI, 2.1-2.2). Of children with sCHD, 1.5% (n = 57) had a diagnosis of CP, of which 35 (61%) children had prenatally or perinatally acquired CP (resulting from a brain injury at ≤28 days of life) and 22 (39%) children had a postneonatal cause (a brain injury between 28 days and 2 years). Children with CP and sCHD more often had unilateral spastic CP and more intellectual impairments than children with CP without congenital anomalies. CONCLUSIONS: In high-income countries, the proportion of children with CP is much higher in children with sCHD than in the background population. The severity of disease in children with CP and sCHD is milder compared with children with CP without congenital anomalies.

Amniotic band syndrome and limb body wall complex in Europe 1980-2019.

Amniotic band syndrome (ABS) and limb body wall complex (LBWC) have an overlapping phenotype of multiple congenital anomalies and their etiology is unknown. We aimed to determine the prevalence of ABS and LBWC in Europe from 1980 to 2019 and to describe the spectrum of congenital anomalies. In addition, we investigated maternal age and multiple birth as possible risk factors for the occurrence of ABS and LBWC. We used data from the European surveillance of congenital anomalies (EUROCAT) network including data from 30 registries over 1980-2019. We included all pregnancy outcomes, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. ABS and LBWC cases were extracted from the central EUROCAT database using coding information responses from the registries. In total, 866 ABS cases and 451 LBWC cases were included in this study. The mean prevalence was 0.53/10,000 births for ABS and 0.34/10,000 births for LBWC during the 40 years. Prevalence of both ABS and LBWC was lower in the 1980s and higher in the United Kingdom. Limb anomalies and neural tube defects were commonly seen in ABS, whereas in LBWC abdominal and thoracic wall defects and limb anomalies were most prevalent. Twinning was confirmed as a risk factor for both ABS and LBWC. This study includes the largest cohort of ABS and LBWC cases ever reported over a large time period using standardized EUROCAT data. Prevalence, clinical characteristics, and the phenotypic spectrum are described, and twinning is confirmed as a risk factor.

The relationship between cesarean delivery and fecundability: a population-based cohort study.

BACKGROUND: Previous studies have found that women who undergo cesarean delivery have fewer pregnancies. Cesarean delivery is also more common among women with lower fecundability. The potential role of cesarean delivery in reduced fecundability is not known. OBJECTIVE: This study aimed to assess the bidirectional relationship between cesarean delivery and fecundability. STUDY DESIGN: This was a prospective cohort study based on data from the Norwegian Mother, Father, and Child Cohort study linked with the Medical Birth Registry of Norway. We estimated the fecundability ratio (per cycle probability of pregnancy) and relative risk of infertility (time to pregnancy ≥12 months) by mode of delivery in the previous delivery among 42,379 women. For the reverse association, we estimated the relative risk of having a cesarean delivery by fecundability (the number of cycles women needed to conceive) among 74,024 women. RESULTS: The proportion of women with infertility was 7.3% (2707/37,226) among women with a previous vaginal delivery and 9.9% (508/5153) among women with a previous cesarean delivery, yielding an adjusted relative risk of 1.21 (95% confidence interval, 1.10-1.33). Women with a previous cesarean delivery also had a lower fecundability ratio (0.90; 95% confidence interval, 0.88-0.93) than women with a previous vaginal delivery. When assessing the reverse association between fecundability and cesarean delivery, we found that women who did not conceive within 12 or more cycles had a higher risk for cesarean delivery (adjusted relative risk, 1.57; 95% confidence interval, 1.48-1.66) than women who conceived within the first 2 cycles. The associations remained after controlling for sociodemographic and clinical risk factors and were observed across parity groups. CONCLUSION: Among women with more than 1 child, those who had a previous cesarean delivery subsequently had a lower fecundability ratio and an increased infertility risk than those who had a vaginal delivery. However, women who needed a longer time to conceive were also more prone to be delivered by cesarean delivery, indicating a bidirectional relationship between cesarean delivery and fecundability. This could suggest a common underlying explanatory mechanism and that the surgical procedure itself may not or only partly directly influence fecundability.

Labor epidural analgesia and subsequent risk of offspring autism spectrum disorder and attention-deficit/hyperactivity disorder: a cross-national cohort study of 4.5 million individuals and their siblings.

BACKGROUND: A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown. OBJECTIVE: This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding. STUDY DESIGN: We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987-2005), Norway (1999-2015), and Sweden (1987-2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6-16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models. RESULTS: A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10-1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19-1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93-1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96-1.02). CONCLUSION: In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder.

Adjusting for outcome risk factors in immigrant datasets: total or direct effects?

BACKGROUND: When quantifying differences in health outcomes between immigrants and non-immigrants, it is common practice to adjust for observed differences in outcome risk factors between the groups being compared. However, as some of these outcome risk factors may act as mediators on the causal path between the exposure and outcome, adjusting for these may remove effects of factors that characterize the immigrants rather than removing a bias between immigrants and non-immigrants. METHODS: This study investigates the underlying conditions for which adjusting for outcome risk factors in regression models can lead to the estimation of either total or direct effect for the difference in health outcomes between immigrants and non-immigrants. For this investigation, we use modern tools in causal inference to construct causal models that we believe are highly relevant in an immigrant dataset. In these models, the outcome risk factor is modeled either as a mediator, a selection factor, or a combined mediator/selection factor. Unlike mediators, selection factors are variables that affect the probability of being in the immigrant dataset and may contribute to a bias when comparing immigrants and non-immigrants. RESULTS: When the outcome risk factor acts both as a mediator and selection factor, the adjustment for the risk factor in regression models leads to the estimation of what is known as a "controlled" direct effect. When the outcome risk factor is either a selection factor or a mediator alone, the adjustment for the risk factor in regression models leads to the estimation of a total effect or a controlled direct effect, respectively. In all regression analyses, also adjusting for various confounding paths, including mediator-outcome confounding, may be necessary to obtain valid controlled direct effects or total effects. CONCLUSIONS: Depending on the causal role of the outcome risk factors in immigrant datasets, regression adjustment for these may result in the estimation of either total effects or controlled direct effects for the difference in outcomes between immigrants and non-immigrants. Because total and controlled direct effects are interpreted differently, we advise researchers to clarify to the readers which types of effects are presented when adjusting for outcome risk factors in immigrant datasets.

Long-term cardiovascular mortality in women with twin pregnancies by lifetime reproductive history.

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.

Risk factors for mortality in infancy and childhood in children with major congenital anomalies: A European population-based cohort study.

BACKGROUND: Preterm birth and young maternal age are known risk factors for infant and childhood mortality. There is limited knowledge of the impact of these risk factors in children born with major congenital anomalies (CAs), who have inherently higher risks of death compared with other children. OBJECTIVES: To investigate the risk factors for mortality up to age 10 years in children born with specific major CAs. METHODS: This population-based cohort study involved 150,198 livebirths from 1995 to 2014 in 13 European CA registries linked to mortality data. Cox proportional hazards models estimated the association of gestational age, maternal age and child's sex with death <1 year and 1-9 years for the whole cohort and by CA subgroup. Hazard ratios (HR) from each registry were pooled using multivariate meta-analysis. RESULTS: Preterm birth had a dose-response association with mortality; compared with infants born at 37+ weeks gestation, those born at <28, 28-31 and 32-36 weeks had 14.88 (95% CI 12.57, 17.62), 8.39 (95% CI 7.16, 9.85) and 3.88 (95% CI 3.40, 4.43) times higher risk of death <1 year, respectively. The corresponding risks at 1-9 years were 4.99 (95% CI 2.94, 8.48), 3.09 (95% CI 2.28, 4.18) and 2.04 (95% CI 1.69, 2.46) times higher, respectively. Maternal age <20 years (versus 20-34 years) was a risk factor for death <1 year (HR 1.30, 95% CI 1.09, 1.54) and 1-9 years (HR 1.58, 95% CI 1.19, 2.10). Females had 1.22 (95% CI 1.07, 1.39) times higher risk of death between 1 and 9 years than males. CONCLUSION: Preterm birth was associated with considerably higher infant and childhood mortality in children with CAs, comparable to estimates reported elsewhere for the background population. Additional risk factors included young maternal age and female sex. Information on risk factors could benefit clinical care and guide counselling of parents following CA diagnoses.

Birthweight of the subsequent singleton pregnancy following a first twin or singleton pregnancy.

INTRODUCTION: Birthweight is an important pregnancy indicator strongly associated with infant, child, and later adult life health. Previous studies have found that second-born babies are, on average, heavier than first-born babies, indicating an independent effect of parity on birthweight. Existing data are mostly based on singleton pregnancies and do not consider higher order pregnancies. We aimed to compare birthweight in singleton pregnancies following a first twin pregnancy relative to a first singleton pregnancy. MATERIAL AND METHODS: This was a prospective registry-based cohort study using maternally linked offspring with first and subsequent pregnancies registered in the Medical Birth Registry of Norway between 1967 and 2020. We studied offspring birthweights of 778 975 women, of which 4849 had twins and 774 126 had singletons in their first pregnancy. Associations between twin or singleton status of the first pregnancy and birthweight (grams) in subsequent singleton pregnancies were evaluated by linear regression adjusted for maternal age at first delivery, year of first pregnancy, maternal education, and country of birth. We used plots to visualize the distribution of birthweight in the first and subsequent pregnancies. RESULTS: Mean combined birthweight of first-born twins was more than 1000 g larger than mean birthweight of first-born singletons. When comparing mean birthweight of a subsequent singleton baby following first-born twins with those following first-born singletons, the adjusted difference was just 21 g (95% confidence interval 5-37 g). CONCLUSIONS: Birthweights of the subsequent singleton baby were similar for women with a first twin or a first singleton pregnancy. Although first twin pregnancies contribute a greater combined total offspring birthweight including more extensive uterine expansion, this does not explain the general parity effect seen in birthweight. The physiological reasons for increased birthweight with parity remain to be established.

Pregnancy complications in last pregnancy and mothers' long-term cardiovascular mortality: does the relation differ from that of complications in first pregnancy? A population-based study.

BACKGROUND: Women who experience complications in first pregnancy are at increased risk of cardiovascular disease (CVD) later in life. Little corresponding knowledge is available for complications in later pregnancies. Therefore, we assessed complications (preeclampsia, preterm birth, and offspring small for gestational age) in first and last pregnancies and the risk of long-term maternal CVD death, taking women´s complete reproduction into account. DATA AND METHODS: We linked data from the Medical Birth Registry of Norway to the national Cause of Death Registry. We followed women whose first birth took place during 1967-2013, from the date of their last birth until death, or December 31st 2020, whichever occurred first. We analysed risk of CVD death until 69 years of age according to any complications in last pregnancy. Using Cox regression analysis, we adjusted for maternal age at first birth and level of education. RESULTS: Women with any complications in their last or first pregnancy were at higher risk of CVD death than mothers with two-lifetime births and no pregnancy complications (reference). For example, the adjusted hazard ratio (aHR) for women with four births and any complications only in the last pregnancy was 2.85 (95% CI, 1.93-4.20). If a complication occurred in the first pregnancy only, the aHR was 1.74 (1.24-2.45). Corresponding hazard ratios for women with two births were 1.82 (CI, 1.59-2.08) and 1.41 (1.26-1.58), respectively. CONCLUSIONS: The risk for CVD death was higher among mothers with complications only in their last pregnancy compared to women with no complications, and also higher compared to mothers with a complication only in their first pregnancy.

Temporal and geographical variations in survival of children born with congenital anomalies in Europe: A multi-registry cohort study.

BACKGROUND: Congenital anomalies are a major cause of perinatal, neonatal and infant mortality. OBJECTIVES: The aim was to investigate temporal changes and geographical variation in survival of children with major congenital anomalies (CA) in different European areas. METHODS: In this population-based linkage cohort study, 17 CA registries members of EUROCAT, the European network for the surveillance of CAs, successfully linked data on 115,219 live births with CAs to mortality records. Registries estimated Kaplan-Meier survival at 28 days and 5 years of age and fitted Cox's proportional hazards models comparing mortality at 1 year and 1-9 years of age for children born during 2005-2014 with those born during 1995-2004. The hazard ratios (HR) from each registry were combined centrally using a random-effects model. The 5-year survival conditional on having survived to 28 days of age was calculated. RESULTS: The overall risk of death by 1 year of age for children born with any major CA in 2005-2014 decreased compared to 1995-2004 (HR 0.68, 95% confidence interval [CI] 0.53, 0.89). Survival at 5 years of age ranged between registries from 97.6% to 87.0%. The lowest survival was observed for the registry of OMNI-Net (Ukraine) (87.0%, 95% CI 86.1, 87.9). CONCLUSIONS: Survival of children with CAs improved for births in 2005-2014 compared with 1995-2004. The use of CA registry data linked to mortality data enables investigation of survival of children with CAs. Factors such as defining major CAs, proportion of terminations of pregnancy for foetal anomaly, source of mortality data and linkage methods are important to consider in the design of future studies and in the interpretation of the results on survival of children with CAs.

Association of sweetened carbonated beverage consumption during pregnancy and ADHD symptoms in the offspring: a study from the Norwegian Mother, Father and Child Cohort Study (MoBa).

PURPOSE: Intrauterine exposures influence offspring health and development. Here we investigated maternal intake of sweetened carbonated beverages (SCB) during pregnancy and its association with ADHD symptoms in the offspring. METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. Maternal diet mid-pregnancy was assessed using a food frequency questionnaire (FFQ). All mothers who responded to the FFQ and a questionnaire when their child was 8 years of age were included (n = 39,870). The exposure was defined as maternal intake (daily servings) of SCB, using no daily intake as reference. Outcome was offspring ADHD symptoms, evaluated as a continuous standardized ADHD score and as a binary outcome of six or more ADHD symptoms vs. five symptoms or less. Associations were analysed using log-binomial regression and linear mixed regression models with adjustment for covariates. RESULTS: The adjusted regression coefficients for the standardized ADHD offspring symptom score were 0.31 [95% confidence intervals (0.001, 0.62)] and 0.46 (0.15, 0.77) for maternal daily intake of ≥ 1 glasses of SCB, when the models included adjustments for total energy intake or energy intake from other sources than SCBs and sweet drinks, respectively. The corresponding adjusted relative risks were 1.16 (1.004, 1.34) and 1.21. (1.05, 1.39) for drinking ≥ 1 glasses daily. CONCLUSION: In a large pregnancy cohort with offspring followed until 8 years of age, we found an association between maternal daily intake of SCB and offspring ADHD symptoms. These results suggest a weak positive relationship between prenatal exposure to SCB and offspring ADHD.

Cesarean delivery in Norwegian nulliparous women with singleton cephalic term births, 1967-2020: a population-based study.

BACKGROUND: Nulliparous women contribute to increasing cesarean delivery in the Nordic countries and advanced maternal age has been suggested as responsible for rise in cesarean delivery rates in many developed countries. The aim was to describe changes in cesarean delivery rates among nulliparous women with singleton, cephalic, term births by change in sociodemographic factors across 50 years in Norway. METHODS: We used data from the Medical Birth Registry of Norway and included 1 067 356 women delivering their first, singleton, cephalic, term birth between 1967 and 2020. Cesarean delivery was described by maternal age (5-year groups), onset of labor (spontaneous, induced and pre-labor CD), and time periods: 1967-1982, 1983-1998 and 1999-2020. We combined women's age, onset of labor and time period into a compound variable, using women of 20-24 years, with spontaneous labor onset during 1967-1982 as reference. Multivariable regression models were used to estimate adjusted relative risk (ARR) of cesarean delivery with 95% confidence interval (CI). RESULTS: Overall cesarean delivery increased both in women with and without spontaneous onset of labor, with a slight decline in recent years. The increase was mainly found among women < 35 years while it was stable or decreased in women > = 35 years. In women with spontaneous onset of labor, the ARR of CD in women > = 40 years decreased from 14.2 (95% CI 12.4-16.3) in 1967-82 to 6.7 (95% CI 6.2-7.4) in 1999-2020 and from 7.0 (95% CI 6.4-7.8) to 5.0 (95% CI 4.7-5.2) in women aged 35-39 years, compared to the reference population. Despite the rise in induced onset of labor over time, the ARR of CD declined in induced women > = 40 years from 17.6 (95% CI 14.4-21.4) to 13.4 (95% CI 12.5-14.3) while it was stable in women 35-39 years. CONCLUSION: Despite growing number of Norwegian women having their first birth at a higher age, the increase in cesarean delivery was found among women < 35 years, while it was stable or decreased in older women. The increase in cesarean delivery cannot be solely explained by the shift to an older population of first-time mothers.

Sex differences in parent-offspring recurrence of attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison. METHODS: In a generation study linking data from several population-based registries, all Norwegians born 1967-2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex. RESULTS: The absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2-8.6 vs. RRpaternal 6.2, 6.0-6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5-21.7) vs. PDpaternal 14.8% (14.3-15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons. CONCLUSIONS: The intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex- and diagnosis-specific intergenerational recurrence risk in parents with ADHD.

Male to female ratios in autism spectrum disorders by age, intellectual disability and attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine the gender distribution in ASD in adults compared with children and the impact of comorbid intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) on the male to female ratio (MFR). METHODS: We estimated the MFR and the male prevalence ratio (PR) for ASD in adults and children using the Medical Birth Registry of Norway, including all individuals born during 1967-2011. We examined variation with age, comorbid ID and ADHD as defined by diagnoses in the Norwegian Patient Registry during 2008-2015 and/or a dispensed prescription for ADHD medication. RESULTS: The sample included 1,701,206 adults and 804,146 children, including 8,995 (0.5%) adults and 8,056 (1.0%) children with ASD, 53,822 (3.2%) adults and 26,967 (3.4%) children with ADHD and 9,178 (0.5%) adults and 5,038 (0.6%) children with ID. The MFR for ASD was 3.67 in children and 2.57 in adults, corresponding to a male PR in ASD of 1.54 (95% CI 1.53-1.56) and 1.41 (1.39-1.24), respectively. Comorbid ID decreased the MFR and the male PR in both adults and children, whereas comorbid ADHD significantly increased the male PR in children. The MFR and the population prevalence of ASD, ADHD and ID decreased from children to younger adults and yet further to older adults. CONCLUSION: We found a lower MFR and male PR in adults than in children. Findings suggest the strong male predominance seen in childhood/clinical studies of ASD diminishes in adult samples, possibly reflecting the influence of non-aetiological factors such as later diagnosis in females, diagnostic biases and diagnostic trends.