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Aim: The aim of this study was to examine how fever during pregnancy is associated with motor development in the child., Method: This cohort study was based on data from females and their children, from the Danish National Birth Cohort, who took part in an 18-month and/or 7-year follow-up study. Information regarding fever (number of episodes, temperature, duration, and pregnancy week) was obtained around gestation week 12 and at the end of pregnancy. Assessments of motor development in early childhood were based on the ages at which the motor milestones 'sitting unsupported' (n=44,256) and 'walking unassisted' (n=53,959) were attained. The Developmental Coordination Disorder Questionnaire 2007 (DCDQ'07) was used to identify children with indication of developmental coordination disorder (DCD) at age 7 years (n=29,401). Any associations between the exposure to fever during pregnancy and motor development were estimated using Cox regression and logistic regression analyses., Results: Fever during pregnancy was reported by 15,234 (28.0%) participants in the 18-month follow-up and by 7965 (26.9%) participants in the 7-year follow-up. Adjusted analyses showed no association between prenatal exposure to fever and either 'sitting unsupported' or 'walking unassisted'. The proportion of children with indication of DCD was 3.1%. The odds ratio of indication of DCD if children were exposed to fever in utero was 1.29 (95% CI 1.12-1.49). However, no dose-response association was found., Interpretation: We found a significant association between maternal fever during pregnancy and DCD in children at age 7 years. The lack of a dose-response association might suggest that this association is explained by the underlying causes of the fever., (© 2015 Mac Keith Press.)

Cryptorchidism is thought to result from a disruption of the androgen-estrogen balance in utero. Alpha-fetoprotein (AFP) interacts with and may modulate fetal responses to estrogens. Using a cohort of boys born to women participating in a Danish maternal serum AFP screening program between 1980 and 1994, the authors explored whether AFP levels (as reflected by maternal serum AFP levels in gestational weeks 14-22) were associated with the risk of isolated cryptorchidism in male offspring. Cryptorchidism diagnoses and covariate information were obtained from Denmark's national health registries. Risk ratios for cryptorchidism by maternal serum AFP multiples of the median were estimated by use of log-linear binomial regression. Of 25,418 boys, 663 (2.6%) were diagnosed with cryptorchidism. After adjustment for confounders, boys with maternal serum AFP levels greater than or equal to 2.5 times the median had a 63% (95% confidence interval: -2, 172) greater risk of cryptorchidism than did boys with maternal serum AFP levels within 25% of the median. High fetal AFP levels may contribute directly to events producing cryptorchidism; alternatively, elevated maternal serum AFP levels may reflect placental dysfunction, some aspect of which contributes to cryptorchidism.

Background: Hyperthermia acts as a teratogen in some animals where it can induce resorption of the fetus and fetal death. Fever during pregnancy, especially in the period of embryogenesis, is also suspected as being a risk factor for fetal death in human beings. We did a large cohort study in Denmark to investigate this possibility., Methods: We interviewed 24040 women who were recruited in the first half of pregnancy to the Danish National Birth Cohort Study, and obtained information on the number of fever incidents during the first 16 weeks of pregnancy. For each fever episode, the highest measured body temperature, duration of incident, and gestational age were recorded. Outcomes of pregnancies were identified through linkage with the Civil Registration System and the National Discharge Registry. Cox's regression with time-dependent variables was used to estimate the relative risk of fetal death, taking delayed entry into account., Findings: 1145 pregnancies resulted in a miscarriage or stillbirth (4.8%). During the first 16 pregnancy weeks 18.5% of the women experienced at least one episode of fever. However, we found no association between fever in pregnancy and fetal death before or after adjustment for known risk factors of fetal death (relative risk 0.95 [95% CI 0.80-1.13]). This finding was consistent irrespective of measured maximum temperature, duration and number of fever incidents, or the gestational time of the fever incident, and was observed for fetal death in all three trimesters of pregnancy., Interpretation: We found no evidence that fever in the first 16 weeks of pregnancy is associated with the risk of fetal death in clinically recognised pregnancies.

Background: Previous research has suggested that some women are at increased risk of postpartum depression (PPD) because of an extra sensitivity to fluctuating hormones before and after parturition. This may particularly apply to women with endocrine disease, characterised by a less than optimal capability to self-regulate the hormonal feedback system. Aims: To investigate if women with endocrine disease history are at increased risk of developing PPD. Method: Based on information from Danish national registers, this nationwide cohort study included 888 989 deliveries (1995–2018). Endocrine disease history was defined as thyroid disease, pre-pregnancy diabetes, polycystic ovary syndrome and/or previous gestational diabetes within 10 years before pregnancy start. PPD was defined as use of antidepressants and/or hospital contact for depression within 6 months after childbirth. Results: Among 888 989 deliveries, 4.1% had a history of endocrine disease and 0.5% had a PPD episode. Overall, women with an endocrine disease history had a 42% (risk ratio 1.42, 95% CI 1.24–1.62) higher risk of PPD when compared with women with no endocrine disease. However, we also found the reverse association, whereby women with a PPD history had a 50% (hazard ratio 1.5, 95% CI 1.4–1.6) higher risk of endocrine disease when compared with women with no PPD history. Conclusions: Women with endocrine disease history had a 40% higher risk of PPD compared with women with no endocrine disease. More attention should be given to pregnant women with endocrine disease history to increase awareness of early signs of PPD. The bi-directionality of the association points to a common underlying factor. [ABSTRACT FROM AUTHOR]

Background: Peripartum cardiomyopathy (PPCM) is a serious cardiac disorder occurring late in pregnancy or early in the postpartum period. We examined associations between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and PPCM, accounting for other pregnancy-related risk factors for PPCM. Methods: Using nationwide Danish register data, we constructed a cohort of all women with ≥1 live birth or stillbirth in Denmark between 1978 and 2012. Using log-linear binomial regression and generalized estimating equations, we estimated risk ratios (RRs) for PPCM associated with HDP of varying severity. Results: In a cohort of 1,088,063 women with 2,078,822 eligible pregnancies, 126 women developed PPCM (39 in connection with an HDP-complicated pregnancy). The risks of PPCM were significantly higher in women with HDP-complicated pregnancies than in women with normotensive pregnancies (severe preeclampsia, RR 21.2, 95% confidence interval [CI] 12.0–37.4; moderate preeclampsia, RR 10.2, 95% CI 6.18–16.9; gestational hypertension, RR 5.16, 95% CI 2.11–12.6). The RRs for moderate preeclampsia and gestational hypertension were not significantly different from one another (p = 0.18); the RR for severe preeclampsia was significantly different from the RR for moderate preeclampsia and gestational hypertension combined (p = 0.02). Conclusions: Although 70% of PPCM occurred in women with normotensive pregnancies, HDPs were associated with substantial increases in PPCM risk that depended on HDP severity. The heart’s capacity to adapt to a normal pregnancy may be exceeded in some women already susceptible to cardiac insult, contributing to PPCM. HDPs, severe preeclampsia in particular, probably represent an additional cardiac stressor during pregnancy. [ABSTRACT FROM AUTHOR]

Background and Objectives: Existing data on pregnancy complications in inflammatory bowel disease (IBD) are inconsistent. To address these inconsistencies, we investigated potential associations between IBD, IBD-related medication use during pregnancy, and pregnancy loss, pre-eclampsia, preterm delivery, Apgar score, and congenital abnormalities. Methods: We conducted a cohort study in >85,000 Danish National Birth Cohort women who were pregnant in the period 1996-2002 and had information on IBD, IBD-related medication use (systemic or local corticosteroids, 5-aminosalicylates), pregnancy outcomes and potential confounders. We evaluated associations between IBD and adverse pregnancy/birth outcomes using Cox regression and log-linear binomial regression. Results: IBD was strongly and significantly associated with severe pre-eclampsia, preterm premature rupture of membranes and medically indicated preterm delivery in women using systemic corticosteroids during pregnancy (hazard ratios [HRs] >7). IBD was also associated with premature preterm rupture of membranes in women using local corticosteroid medications (HR 3.30, 95% confidence interval [CI] 1.33-8.20) and with medically indicated preterm delivery (HR 1.91, 95% CI 0.99-3.68) in non-medicated women. Furthermore, IBD was associated with low 5-minute Apgar score in term infants (risk ratio [RR] 2.19, 95% CI 1.03-4.66). Finally, Crohn’s disease (but not ulcerative colitis) was associated with major congenital abnormalities in the offspring (RR 1.85, 95% CI 1.06-3.21). No child with a congenital abnormality born to a woman with IBD was exposed to systemic corticosteroids in utero. Conclusion: Women with IBD are at increased risk of severe pre-eclampsia, medically indicated preterm delivery, preterm premature rupture of membranes, and delivering infants with low Apgar score and major congenital malformations. These associations are only partly explained by severe disease as reflected by systemic corticosteroid use. [ABSTRACT FROM AUTHOR]

Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations < 15 nmol/L, 15–24 nmol/L and 25–49 nmol/L, respectively, and 1.53 (CI: 1.04; 2.26) and 1.89 (CI: 1.06; 3.37) among women with vitamin D concentrations of 80–99 nmol/L and ≥ 100 nmol/L, respectively. In an additional analysis among women with sufficient vitamin D (≥ 50 nmol/L), we observed a significant positive association between vitamin D concentrations and PPD. Our results did not support an association between low maternal vitamin D concentrations during pregnancy and risk of PPD. Instead, an increased risk of PPD was found among women with the highest vitamin D concentrations. [ABSTRACT FROM AUTHOR]

Background Because parvovirus B19 infection in pregnancy has been associated with infant morbidity and mortality in case reports and after intrauterine transfusion, we tested the population-based association using serum and hospital data of high quality.Methods We established a cohort of 113 228 children born to women tested for parvovirus B19 infection during pregnancy in a major diagnostic laboratory in Denmark, from 1994 to 2009. Information on 20 selected morbidity diagnoses and on mortality was obtained from the Danish National Patient Register, the Danish Cancer Register and the Danish Civil Registration System. Incidence rate ratios (IRR) were estimated by log-linear Poisson regression with adjustment for age and sex of the child, maternal age and year of maternal parvovirus B19 test.Results A total of 1095 (1.0%) children were born to mothers who were infected with parvovirus B19 during pregnancy. During 1 million person-years of follow-up, 10 856 children experienced morbidity and 590 children died. Overall, maternal infection status was neither associated with morbidity during infancy (IRR 0.64; 95% CI: 0.40 to 1.02) or childhood (IRR 0.93; 95% CI: 0.77 to 1.14), nor with infant mortality (IRR 0.98; 95% CI: 0.44 to 2.20). Specifically, there was no association with 19 of 20 morbidities. An excess risk of cancer in the central nervous system was observed (IRR 5.88; 95% CI: 1.41 to 24.6); however, the number of exposed cases was very small (n = 2).Conclusions Parvovirus B19 infection during pregnancy was not associated with overall morbidity or mortality in infancy and childhood. [ABSTRACT FROM AUTHOR]

Because parvovirus B19 infection during pregnancy has been associated with increased risk of fetal loss in small or selected study populations, the authors evaluated the risk in a population-based study. A nested case-control study was conducted by using a population-based screening for syphilis in 3 regions in Denmark from 1992 to 1994. Cases of women with fetal loss were identified in the National Patient Register (n = 2,918), and control women with live-born children were identified in the Medical Birth Register (n = 8,429) by matching on age and sampling week. First-trimester serum samples were tested for parvovirus B19 immunoglobulin M positivity. Parvovirus B19 immunoglobulin M positivity was associated with a 71% increased risk of fetal loss (odds ratio = 1.71, 95% confidence interval: 1.02, 2.86). Adjustment for number of children or stratifying for gestational age at loss did not change the risk estimate. Assuming causality, only 0.1% of fetal losses were attributable to parvovirus B19 positivity, a proportion which could increase to approximately 1% during epidemic periods. In conclusion, acute parvovirus B19 infection during the first trimester of pregnancy was associated with an increased risk of fetal loss. However, the impact on the overall burden of fetal losses appeared small even during epidemics. [ABSTRACT FROM AUTHOR]

The role of breastfeeding in allergic diseases remains controversial. The authors studied the association between breastfeeding and development of atopic dermatitis during the first 18 months of life among children with and without a parental history of allergy. A cohort study of 15,430 mother-child pairs enrolled in The Danish National Birth Cohort was carried out between 1998 and 2000. Data on breastfeeding, atopic dermatitis, and potential confounders was obtained from telephone interviews conducted during pregnancy and when the children were 6 and 18 months of age. The cumulative incidence of atopic dermatitis was 11.5% at 18 months of age. Overall, current breastfeeding was not associated with atopic dermatitis (incidence rate ratio (IRR) = 0.91, 95% confidence interval (CI): 0.80, 1.04). Exclusive breastfeeding for at least 4 months was associated with an increased risk of atopic dermatitis in children with no parents with allergies (IRR = 1.29, 95% CI: 1.06, 1.55) but not for children with one (IRR = 1.11, 95% CI: 0.94, 1.31) or two (IRR = 0.88, 95% CI: 0.69, 1.13) parents with allergies (test for homogeneity, p = 0.03). The authors found no overall effects of exclusive or partial breastfeeding on the risk of atopic dermatitis. However, the effect of exclusive breastfeeding for 4 months or more depended on parental history of allergic diseases. [ABSTRACT FROM AUTHOR]

A pregnancy may lead to hormone-induced growth of breast tumors. The authors investigated whether women in the first years after childbirth had a higher incidence of breast cancer and, in particular, a higher incidence of late-stage tumors (i.e., a large tumor, nodal involvement, or histologic grading II + III). The study was based on a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1978 and 1994, 10,790 incident cases of breast cancer were identified in a nationwide cancer registry. Overall, uniparous and biparous mothers experienced a transient increased risk that did not appear to be attributable to delayed cancer diagnosis. The risk of being diagnosed with a tumor whose diameter was larger than 5 cm was, on average, 53% higher during the first 10 years after birth compared with later. The risk of tumors of less than 2 cm was not significantly associated with time since the latest birth. In conclusion, after a childbirth, mothers experience a transient increased risk of breast cancer and, in particular, a relatively high risk of late-stage disease. This finding suggests that pregnancy-related factors transiently induce a high growth rate in cells that are already malignant and stimulate new tumor growth. [ABSTRACT FROM PUBLISHER]

Background: A full-term pregnancy is associated with a reduced risk of breast cancer, but the underlying biologic mechanism has not been elucidated. During pregnancy, maternal serum levels of alpha-fetoprotein, an estradiol-binding protein, rise sharply. In culture, alpha-fetoprotein inhibits the growth of estrogen-sensitive cells, including estrogen-sensitive breast cancer cells. Thus, we investigated whether a high level of alpha-fetoprotein in maternal serum during pregnancy is associated with a reduced risk of breast cancer.Methods: From a population-based cohort of 42057 pregnant women in Denmark, enrolled in an alpha-fetoprotein-screening program from 1978 through 1996, we obtained a complete reproductive history, vital status, and a possible diagnosis of breast cancer (in 117 women) to the end of follow-up on September 1, 1998.Results: During pregnancy, women with an alpha-fetoprotein level greater than or equal to the median value had a 41% lower risk of breast cancer than women with an alpha-fetoprotein level below the median value (relative risk [RR] = 0.59; 95% confidence interval [CI] = 0.41-0. 85). RRs for breast cancer by mother's age at childbirth were as follows: 29 years or younger, RR = 0.21 (95% CI = 0.08-0.56); 30-34 years, RR = 0.61 (95% CI = 0.32-1.14); 35-37 years, RR = 0.96 (95% CI = 0.49-1.89); and 38 years or older, RR = 0.71 (95% CI = 0.29-1. 75) (P for trend =.02). Further analyses suggested that high levels of alpha-fetoprotein were associated with a reduced incidence of aggressive disease. The most striking finding was that women with high levels of serum alpha-fetoprotein, compared with women with low levels of serum alpha-fetoprotein, showed a particularly reduced incidence of large tumors (>2 cm; RR = 0.24 [95% CI = 0.11-0.50]).Conclusion: A high level of alpha-fetoprotein in maternal serum during any pregnancy is associated with a low overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer at diagnosis. This association appears particularly strong for a pregnancy occurring at a young age. [ABSTRACT FROM AUTHOR]

Background-Pregnancy losses and atherosclerotic disease may be etiologically linked through underlying pathology. We examined whether miscarriage and stillbirth increase later risk of myocardial infarction, cerebral infarction, and renovascular hypertension. Methods and Results-Among women pregnant at least once between 1977 and 2008, we identified a cohort of women with miscarriages, stillbirths, or live singleton births. These women were followed from the end of pregnancy for incident myocardial infarction, cerebral infarction, and renovascular hypertension. Using Poisson regression, we estimated incidence rate ratios for each of the outcomes by history of miscarriage and stillbirth. Among 1 031 279 women followed for >15928 900 person-years, we identified 2798 myocardial infarctions, 4053 cerebral infarctions, and 1269 instances of renovascular hypertension. Women with stillbirths had 2.69 (95% confidence interval, 2.06-3.50), 1.74 (1.32-2.28), and 2.42 (1.59-3.69) times the rates of myocardial infarction, cerebral infarction, and renovascular hypertension, respectively, as women with no stillbirths. Compared with women with no miscarriages, women with miscarriages had 1.13 (1.03-1.24), 1.16 (1.07-1.25), and 1.20 (1.05-1.38) times the rates of these same outcomes, respectively; these associations were dose dependent, with each additional miscarriage increasing the rates of myocardial and cerebral infarction and renovascular hypertension by 9% (3% to 16%), 13% (7% to 19%), and 19% (9% to 30%), respectively. Associations were strongest in younger women (<35 years). Conclusions-Pregnancy losses were associated with subsequent risks of myocardial infarction, cerebral infarction, and renovascular hypertension, consistent with either shared etiology or the initiation of pathological processes by a pregnancy loss leading to atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Both pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy often exhibit angiogenic imbalances, suggesting that the same mechanisms are involved in the pathogenesis of the former and the pathophysiology of the latter. We conducted a register-based cohort study to determine whether offspring congenital heart defects are associated with an increased risk of hypertensive disorders of pregnancy and whether the mechanisms driving any association are primarily maternal or fetal.Methods: Among singleton pregnancies without chromosomal abnormalities lasting ≥20 weeks in Denmark from 1978 to 2011 (n= 1 972 857), we identified pregnancies complicated by offspring congenital heart defects or early preterm preeclampsia, late preterm preeclampsia, term preeclampsia, and gestational hypertension. We used polytomous logistic regression to estimate odds ratios (ORs) for associations between offspring congenital heart defects and maternal hypertensive disorders of pregnancy overall and for specific heart defects.Results: Offspring congenital heart defects were strongly associated with early preterm preeclampsia (OR, 7.00; 95% confidence interval [CI], 6.11-8.03) and late preterm preeclampsia (OR, 2.82; 95% CI, 2.38-3.34) in the same pregnancy and weakly associated with term preeclampsia (OR, 1.16; 95% CI, 1.06-1.27), but they were not associated with gestational hypertension (OR, 1.07; 95% CI, 0.92-1.25). Association strengths were consistent across heart defect types. Offspring congenital heart defects in a previous pregnancy were also strongly associated with preterm preeclampsia in subsequent pregnancies (early preterm preeclampsia: OR, 2.37; 95% CI, 1.68-3.34; late preterm preeclampsia: OR, 2.04; 95% CI, 1.52-2.75) but were only modestly associated with term preeclampsia and not associated with gestational hypertension. Similarly, preterm preeclampsia in a previous pregnancy, but not term preeclampsia or gestational hypertension, was associated with offspring congenital heart defects in later pregnancies (early preterm preeclampsia: OR, 7.91; 95% CI, 6.06-10.3; late preterm preeclampsia: OR, 2.83; 95% CI, 2.11-3.79; term preeclampsia: OR, 0.98; 95% CI, 0.88-1.10; gestational hypertension: OR, 1.13; 95% CI, 0.92-1.38).Conclusions: Linked pathophysiological mechanisms may be involved in some congenital heart defects and preterm preeclampsia. The strong associations across pregnancies support a predominantly maternal origin of effect. [ABSTRACT FROM AUTHOR]