Postpartum psychiatric disorders and subsequent live birth: a population-based cohort study in Denmark.

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.

Interpregnancy weight change and recurrence of gestational diabetes mellitus: a population-based cohort study.

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 (<25 and ≥25 kg/m2 ). MAIN OUTCOME MEASURE: GDM in second pregnancy. RESULTS: Among overweight/obese women (BMI ≥25), recurrence risk of GDM decreased in women who reduced their BMI by 1-2 units (relative risk [RR] 0.80, 95% CI 0.65-0.99) and >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 <25), risk of GDM recurrence increased if BMI increased by 2-4 units (RR 1.32, 95% CI 1.08-1.60) and ≥4 units (RR 1.61, 95% CI 1.28-2.02) compared with women with stable BMI. CONCLUSION: Interpregnancy weight loss reduced risk of GDM recurrence in overweight/obese women. Weight gain between pregnancies increased recurrence risk for GDM in both normal and overweight/obese women. Our findings highlight the importance of weight management in the interconception window in women with a history of GDM. TWEETABLE ABSTRACT: Interpregnancy weight loss reduces recurrence of gestational diabetes mellitus in overweight/obese women.

Offspring birthweight by gestational age and parental cardiovascular mortality: a population-based cohort study.

OBJECTIVE: To estimate risk of parental cardiovascular disease mortality by offspring birthweight. DESIGN: Population-based cohort study. SETTING AND POPULATION: Norwegian mothers and fathers with singleton births during 1967-2002 were followed until 2009 by linkage to the Norwegian cause of death registry. METHODS: Hazard ratios by offspring absolute birthweight in grams and birthweight adjusted for gestational age (z-score) were calculated using Cox regression and adjusted for parental age at delivery and year of first birth. Stratified analyses on preterm and term births were performed. MAIN OUTCOME MEASURES: Maternal and paternal cardiovascular mortality. RESULTS: We followed 711 726 mothers and 700 212 fathers and found a strong link between maternal cardiovascular mortality and offspring birthweight but only slight evidence of associations in fathers. Adjusting birthweight for gestational age (by z-score) uncovered an unexpected strong association of large birthweight (z-score > 2.5) with mothers' cardiovascular mortality (hazard ratio 3.0, 95% CI 2.0-4.6). This risk was apparently restricted to preterm births. In stratified analyses (preterm and term births) hazard ratios for maternal cardiovascular mortality were 1.5 (1.03-2.2) for large preterm babies and 0.9 (0.7-1.2) for large term babies (P-value for interaction = 0.02), using normal weight preterm and term, respectively, as references. CONCLUSION: Women having large preterm babies are at increased risk of both diabetes and cardiovascular mortality. The birth of a large preterm baby should increase clinical vigilance for onset of diabetes and other cardiovascular disease risk factors. TWEETABLE ABSTRACT: Birth of a large preterm baby should increase vigilance for cardiovascular-disease risk factors.

Gestational diabetes mellitus and interpregnancy weight change: A population-based cohort study.

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.

Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group.

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.

Trends in perinatal health after assisted reproduction: a Nordic study from the CoNARTaS group.

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.

Pre-eclampsia and assisted reproductive technologies: consequences of advanced maternal age, interbirth intervals, new partner and smoking habits.

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.

Ultrasound prediction of perinatal outcome: the unrecognised value of sibling data.

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 < 0.0001) and perinatal death (4-19 per thousand, Ptrend = 0.012). In contrast, if the first baby was not vSGA, small fetal size on ultrasound is uninformative. CONCLUSIONS: When the firstborn baby is vSGA, discrepancies between fetal size on ultrasound and LMP become highly predictive of risk of vSGA and perinatal mortality in the second-born infant. The value of combining these routinely collected clinical data has not previously been recognised.

Maternal age and emergency operative deliveries at term: a population-based registry study among low-risk primiparous women.

OBJECTIVE: To study the association between maternal age and emergency operative delivery. The roles of in-labour indications, and birthweight ≥ 4000 g, gestational age ≥ 42 weeks, induction of labour, and epidural use, according to maternal age were explored. DESIGN: Population-based study. SETTING: Medical Birth Registry of Norway and Statistics Norway. POPULATION: We studied 169 583 low-risk primiparous mothers with singleton, cephalic labours, at ≥37 weeks of gestation, from 1999 to 2009. METHODS: The associations between maternal age and mode of delivery were analysed using multinomial regression analyses, adjusting for sociodemographic factors. MAIN OUTCOME MEASURES: Emergency caesarean section and operative vaginal delivery. RESULTS: Of women aged ≥40 years, 22% had emergency caesarean sections and 24% had operative vaginal deliveries, giving adjusted relative risk ratios (RRRs) of 6.60 (95% confidence interval, 95% CI 5.53-7.87) and 3.30 (95% CI 2.79-3.90), respectively, when compared with women aged 20-24 years. Adjustments for sociodemographic factors only slightly changed the estimates. Dystocia was the main indication, followed by fetal distress. All of the listed factors increased the level of emergency operative deliveries, mainly because of an increase in dystocia. The increase in risk for emergency caesarean section by all factors, and for operative vaginal deliveries by epidural, were greater in older than in younger women, but were significant for epidural only. CONCLUSIONS: We found a close association between maternal age and emergency operative delivery in low-risk primiparas. Contributory factors increased the risk for both emergency operative delivery and epidural more in older than in younger women.

Risk of stillbirth and infant deaths after assisted reproductive technology: a Nordic study from the CoNARTaS group.

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).

Degree of fetal growth restriction associated with schizophrenia risk in a national cohort.

BACKGROUND: Accumulating evidence suggests that fetal growth restriction may increase risk of later schizophrenia but this issue has not been addressed directly in previous studies. We examined whether the degree of fetal growth restriction was linearly related to risk of schizophrenia, and also whether maternal pre-eclampsia, associated with both placental dysfunction and poor fetal growth, was related to risk of schizophrenia. METHOD: A population-based cohort of single live births in the Medical Birth Registry of Norway (MBRN) between 1967 and 1982 was followed to adulthood (n=873 612). The outcome was schizophrenia (n=2207) registered in the National Insurance Scheme (NIS). The degree of growth restriction was assessed by computing sex-specific z scores (standard deviation units) of ' birth weight for gestational age' and ' birth length for gestational age'. Analyses were adjusted for potential confounders. Maternal pre-eclampsia was recorded in the Medical Birth Registry by midwives or obstetricians using strictly defined criteria. RESULTS: The odds ratio (OR) for schizophrenia increased linearly with decreasing birth weight for gestational age z scores (p value for trend=0.005). Compared with the reference group (z scores 0.01­1.00), the adjusted OR [95% confidence interval (CI)] for the lowest z-score category (

Fecundability among women with type 1 and type 2 diabetes in the Norwegian Mother and Child Cohort Study.

AIMS/HYPOTHESIS: We assessed the effects of type 1 diabetes and type 2 diabetes on fecundability (as manifest by increased time-to-pregnancy [TTP]) in a large cohort of pregnant women. METHODS: This study is based on the Norwegian Mother and Child Cohort Study. Members of this large cohort were enrolled early in pregnancy and asked about TTP and other factors. Among the 58,004 women included in the analysis, we identified 221 cases of type 1 diabetes and 88 cases of type 2 diabetes using the Medical Birth Registry of Norway. A logistic analogue of the proportional probability model, a Cox-like discrete-time model, was used to compute fecundability odds ratios (FORs) and 95% CI for type 1 diabetes and type 2 diabetes, adjusted for maternal age and prepregnancy BMI. RESULTS: Compared with non-diabetic women, the adjusted FOR for women with type 1 diabetes was 0.76 (95% CI 0.64-0.89) and the adjusted FOR for women with type 2 diabetes was 0.64 (95% CI 0.48-0.84). These FORs did not change substantively and remained statistically significant after excluding women with irregular menstrual cycles and accounting for cycle length. CONCLUSIONS/INTERPRETATION: The results from the present study provide evidence of substantially decreased fecundability for women with type 1 and type 2 diabetes, even among those with a normal menstrual cycle.

In utero exposure to maternal smoking and women's risk of fetal loss in the Norwegian Mother and Child Cohort (MoBa).

BACKGROUND: Whether in utero exposure to tobacco smoke increases a woman's risk of fetal loss later in life is unknown, though data on childhood exposure suggest an association may exist. This study evaluated the association between in utero exposure to tobacco smoke and fetal loss in the Norwegian Mother and Child Cohort Study (MoBa), which enrolled ∼40% of the pregnant women in Norway from 1999 to 2008. METHODS: Information on exposure to tobacco smoke in utero, the woman's own smoking behavior during pregnancy and other factors was obtained by a questionnaire completed at ∼17 weeks of gestation. Subsequent late miscarriage (fetal death <20 weeks) and stillbirth (fetal death ≥ 20 weeks) were ascertained from the Norwegian Medical Birth Registry. This analysis included 76 357 pregnancies (MoBa data set version 4.301) delivered by the end of 2008; 59 late miscarriages and 270 stillbirths occurred. Cox proportional hazards models were fit for each outcome and for all fetal deaths combined. RESULTS: The adjusted hazard ratio (HR) of late miscarriage was 1.23 [95% confidence interval (CI), 0.72-2.12] in women with exposure to maternal tobacco smoke in utero when compared with non-exposed women. The corresponding adjusted HR for stillbirths was 1.11 (95% CI, 0.85-1.44) and for all fetal deaths combined, it was 1.12 (95% CI, 0.89-1.43). CONCLUSIONS: The relatively wide CI around the HR for miscarriage reflected the limited power to detect an association, due to enrollment around 17 weeks of gestation. However, for in utero exposure to tobacco smoke and risk of stillbirth later in life, where the study power was adequate, our data provided little support for an association.

Recurrence of prolonged and post-term gestational age across generations: maternal and paternal contribution.

OBJECTIVE: To estimate intergenerational recurrence risk of prolonged and post-term gestational age. DESIGN: Population-based cohort study. SETTING: Norway, 1967-2006. POPULATION: Intergenerational data from the Medical Birth Registry of Norway of singleton mothers and fathers giving birth to singleton children: 478 627 mother-child units and 353 164 father-child units. A combined mother-father-child file including 295 455 trios was also used. METHODS: Relative risks were obtained from contingency tables and relative risk modelling. MAIN OUTCOME MEASURES: Gestational age ≥41 weeks (≥287 days), ≥42 weeks (≥294 days) and ≥43 weeks (≥301 days) of gestation in the second generation. RESULTS: A post-term mother (≥42 weeks) had a 49% increased risk of giving birth to a child at ≥42 weeks (relative risk [RR] 1.49, 95% CI 1.47-1.51) and a post-term father had a 23% increased risk of fathering a child at ≥42 weeks (RR 1.23, 95%CI 1.20-1.25). The RRs for delivery at ≥41 weeks were 1.29 (1.28-1.30) and 1.14 (1.13-1.16) for mother and father, respectively, and for ≥43 weeks 1.55 (1.50-1.59) and 1.22 (1.17-1.27). The RR of a pregnancy at ≥42 weeks in the second generation was 1.76 (1.68-1.84) if both mother and father were born post-term. Adjustment for maternal age in both generations, fetal sex in the second generation, parity, and maternal and paternal birthweight did not influence the risk estimates. CONCLUSIONS: There is a familial factor related to recurrence of prolonged pregnancy across generations and both mother and father seem to contribute.

Maternal birth characteristics and perinatal mortality in twin offspring. An intergenerational population-based study in Norway, 1967-2008.

OBJECTIVE: To investigate the relationship between maternal preterm birth and fetal growth in one generation and perinatal mortality of twin offspring in the next generation. DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway from 1967 to 2008. POPULATION: Linked generational data with 9426 mother-twin pair units. METHODS: Twin offspring were linked to their mothers by means of the unique national identification numbers. MAIN OUTCOME MEASURES: Perinatal mortality in twin offspring. RESULTS: The twin prevalence was not dependent on the mother's gestational age at birth, but increased with increasing birthweight in term mothers. Maternal gestational age was strongly and inversely associated with a risk of perinatal death in one or both of her twin offspring. Compared with term mothers, preterm mothers born at 27-31 and 32-34 weeks had relative risks (RRs) for perinatal loss of 3.83 [95% confidence interval (CI), 1.56-9.36] and 2.41 (95% CI, 1.29-4.50), respectively. This effect was even stronger after the use of assisted reproductive technologies (ART), with a significant interaction between maternal gestational age and ART (P = 0.03). Further, term mothers with birthweight-by-gestational age Z-scores of -2 or less had more than twice the risk of a perinatal loss in their twin offspring relative to mothers with the most favourable birthweight Z-scores (1-1.99) [RR, 2.42 (95% CI, 1.37-4.29)]. CONCLUSIONS: Women born preterm had an increased risk of perinatal mortality in their twin offspring, particularly after ART treatment. The same was true for women who were growth restricted at term. A twin pregnancy is a high-risk pregnancy in general, but even more so if the mother herself was born preterm or was growth restricted at birth.

Trends in incidence and mortality for triplets in Norway 1967-2006: the influence of assisted reproductive technologies.

OBJECTIVE: To assess changes in incidence rates and outcomes of triplets over 40 years with a particular focus on the influence of assisted reproductive technology (ART). DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway. POPULATION: 2.18 million pregnancies, including 448 sets of triplets and 27,575 twin pairs, covering the years 1967-2006. Since 1988, pregnancies from ART have been available through a separate registry and linked with the birth record. METHODS: Incidence rates and outcomes for triplets were analysed and compared with those for singletons and twins. Relative risks were estimated between time periods and between ART and non-ART pregnancies. MAIN OUTCOME MEASURES: Incidence rates, birthweight, gestational age and perinatal mortality. RESULTS: The total triplet rate per 10,000 pregnancies increased from 1.0 during 1967-71 to 3.5 during 1987-92, followed by a decline to 2.7 during 2002-06. After excluding ART pregnancies, the incidence was more than doubled at the end of the study period. The mean gestational age and birthweight of triplets were significantly lower during 1988-2006 than 1967-87, but similar for ART and non-ART triplets in the last period. The caesarean rate in triplets increased from 47 to 92%. The relative risk of perinatal death in triplets relative to singletons did not change after the introduction of ART [before: relative risk, 8.9 (95% confidence interval, 6.8-11.7); after: relative risk, 10.4 (95% confidence interval, 8.3-13.0)]. CONCLUSIONS: The triplet incidence rate in Norway has more than doubled during the last 40 years, even after excluding ART pregnancies. The risk of perinatal death in triplets is ten times higher relative to singletons and has not changed during this 40-year period, independent of the introduction of ART.

Parenthood probability and pregnancy outcome in patients with a cancer diagnosis during adolescence and young adulthood.

BACKGROUND: To compare first-time parenthood probability and pregnancy outcome between cancer patients and the general population. METHODS: Data from a hospital registry on cancer patients aged 15-35 years at diagnosis, including date/type of diagnosis, treatment and date of death, were merged with data from the Cancer Registry and the Medical Birth Registry, providing date of childbirth, IVF, pregnancy outcomes and demographics. RESULTS: The first-time parenthood probability at the age of 35 years was 63% in male patients (n = 463) and 64% in the male general population (n = 367 068). Figures in female patients were 66% (n = 284) compared with 79% in the female general population (n = 349 576) (P = 0.007). A total of 487 male and 251 female cancer patients were childless pre-diagnosis, and 130 male and 104 female cancer patients had one child before diagnosis and at least one birth post-diagnosis. Congenital anomalies were more frequent in first-borns to previously childless male patients [adjusted odds ratio (OR(adj)): 1.5; 95% confidence interval (CI): 1.1-2.3]. The risk of low birth weight and preterm delivery after cancer was increased in infants born to female patients, as was perinatal mortality (OR(adj) 2.3; 95% CI: 1.1-5.0) among post-diagnosis first births. CONCLUSIONS: The first-time parenthood probability in 35-year old cancer patients is approximately 60%, which in female patients is significantly reduced compared with the general population. Post-diagnosis pregnancies to female patients are high-risk pregnancies.

Is smoking an extra hazard in pregnant MS women? Findings from a population-based registry in Norway.

Multiple sclerosis (MS) in women leads to increased risk of operative delivery and reduced birth weight, which are presumably related to the neurological dysfunction in this patient group. Lifestyle factors may also contribute, and we therefore investigated smoking habits and relevant social factors in pregnant MS women. In total, 372,128 births were registered in the compulsory Medical Birth Registry of Norway from December 1, 1998 to October 6, 2005, and of them 250 by MS mothers. The MS births were compared with all the non-MS births. Smoking during pregnancy was not increased in the MS group compared with the non-MS references. From 1998 to 2005 the MS group had a larger reduction in smoking rate during pregnancy than the reference group. The differences in pregnancy and birth outcome between smokers and non-smokers were similar in the MS and the reference group. Those in the smoking MS group had no increase in birth complications, operative interventions or negative birth outcome compared with those in the smoking reference group. Smoking during pregnancy did not explain the birth weight reduction found for newborns of MS mothers.

Placenta weight percentile curves for singleton deliveries.

OBJECTIVE: To produce population-based, gender- and gestational-age-specific centile curves for placental weight. DESIGN: Population study. SETTING: Medical Birth Registry of Norway. POPULATION: All singleton live births in Norway from 1 January 1999 to 31 December 2002. METHODS: In a cohort of children born in Norway, placental weights and the ratio of the birthweight to the placental weight were analysed to produce percentile curves. MAIN OUTCOME MEASURES: Placental weight, birthweight-to-placental weight ratio. RESULTS: Tables and figures are presented for placental percentiles curves according to gestational age and gender. Also, tables and figures are presented for the ratio of birthweight to placental weight. CONCLUSIONS To our knowledge, this is the first time that population percentile curves have been produced for placental weights and hence for the ratio of birthweight to placental weight. These percentile curves may act as a reference for other populations as well until population-specific curves can be produced.

The spectrum of congenital anomalies of the VATER association: an international study.

The spectrum of the VATER association has been debated ever since its description more than two decades ago. To assess the spectrum of congenital anomalies associated with VATER while minimizing the distortions due to small samples and referral patterns typical of clinical series, we studied infants with VATER association reported to the combined registry of infants with multiple congenital anomalies from 17 birth defects registries worldwide that are part of the International Clearinghouse for Birth Defects Monitoring Systems (ICB-DMS). Among approximately 10 million infants born from 1983 through 1991, the ICB-DMS registered 2,295 infants with 3 or more of 25 unrelated major congenital anomalies of unknown cause. Of these infants, 286 had the VATER association, defined as at least three of the five VATER anomalies (vertebral defects, anal atresia, esophageal atresia, renal defects, and radial-ray limb deficiency), when we expected 219 (P<0.001). Of these 286 infants, 51 had at least four VATER anomalies, and 8 had all five anomalies. We found that preaxial but not other limb anomalies were significantly associated with any combination of the four nonlimb VATER anomalies (P<0.001). Of the 286 infants with VATER association, 214 (74.8%) had additional defects. Genital defects, cardiovascular anomalies, and small intestinal atresias were positively associated with VATER association (P<0.001). Infants with VATER association that included both renal anomalies and anorectal atresia were significantly more likely to have genital defects. Finally, a subset of infants with VATER association also had defects described in other associations, including diaphragmatic defects, oral clefts, bladder exstrophy, omphalocele, and neural tube defects. These results offer evidence for the specificity of the VATER association, suggest the existence of distinct subsets within the association, and raise the question of a common pathway for patterns of VATER and other types of defects in at least a subset of infants with multiple congenital anomalies.