Jin Liang Zhu

Infertility, infertility treatment, and congenital malformations: Danish national birth cohort

Abstract Objectives To examine whether infertile couples (with a time to pregnancy of > 12 months), who conceive naturally or after treatment, give birth to children with an increased prevalence of congenital malformations. Design Longitudinal study. Setting Danish national birth cohort. Participants Three groups of liveborn children and their mothers: 50 897 singletons and 1366 twins born of fertile couples (time to pregnancy ≤ 12 months), 5764 singletons and 100 twins born of infertile couples who conceived naturally (time to pregnancy > 12 months), and 4588 singletons and 1690 twins born after infertility treatment. Main outcome measures Prevalence of congenital malformations determined from hospital discharge diagnoses. Results Compared with singletons born of fertile couples, singletons born of infertile couples who conceived naturally or after treatment had a higher prevalence of congenital malformations—hazard ratios 1.20 (95% confidence interval 1.07 to 1.35) and 1.39 (1.23 to 1.57). The overall prevalence of congenital malformations increased with increasing time to pregnancy. When the analysis was restricted to singletons born of infertile couples, babies born after treatment had an increased prevalence of genital organ malformations (hazard ratio 2.32, 1.24 to 4.35) compared with babies conceived naturally. No significant differences existed in the overall prevalence of congenital malformations among twins. Conclusions Hormonal treatment for infertility may be related to the occurrence of malformations of genital organs, but our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants. The association between untreated infertility and congenital malformations warrants further examination.

Shift work, job stress, and late fetal loss: The National Birth Cohort in Denmark.

Objective: The Danish National Birth Cohort (DNBC) was used to examine whether shift work or job stress correlate with late fetal loss. Methods: We identified 33,694 pregnancies of daytime workers and 8,075 pregnancies of shift workers in women recruited to the DNBC between 1998 and 2001. Pregnancy outcomes were obtained by linkages to the national registers. Hazard ratios of fetal loss were calculated by using Cox regressions with left truncation. Results: Fixed night work was associated with fetal loss (hazard ratio = 1.85, 95% confidence interval = 1.00–3.42). No high risk of fetal loss was seen for other types of shift work. Job stress, as measured in our study, was not associated with fetal loss. Conclusions: Our results suggest that fixed night work during pregnancy increases the risk of late fetal loss.

Paternal age and preterm birth.

Background: There is growing evidence that advanced paternal age can be a reproductive hazard. Methods: We studied couples and their first children using nationwide registers in Denmark between 1980 and 1996. We restricted the analysis to mothers age 20–29 years. We estimated odds ratios (ORs) of preterm (<37 weeks gestation) and very preterm birth (<32 weeks) as a function of paternal age using logistic regression to adjust for potential confounding variables. Results: The risk of preterm birth increased with paternal age, almost entirely resulting from an association for very preterm birth. Compared with fathers age 20–24 years, ORs for very preterm birth were 1.3 (age 25–29), 1.4 (age 35–39), 1.7 (age 40–44), 1.6 (age 45–49), and 2.1 (age 50+) (test for trend: P = 0.01). Conclusions: Risk of very preterm birth increases among older fathers, perhaps as a result of a paternal placental effect.

Parental Smoking During Pregnancy and ADHD in Children: The Danish National Birth Cohort

BACKGROUND: Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. METHODS: We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. RESULTS: Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. CONCLUSIONS: Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.

Infertility, infertility treatment, and fetal growth restriction.

OBJECTIVE: To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality. METHODS: From the Danish National Birth Cohort (1997–2003), we identified 51,041 singletons born of fertile couples (time to pregnancy 12 months or less), 5,787 born of infertile couples conceiving naturally (time to pregnancy more than 12 months), and 4,317 born after treatment. We defined small for gestational age (SGA) as the lowest 5% of birth weight by sex and gestational age. RESULTS: Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index (1.32, 95% confidence interval [CI] 0.95–1.84 among untreated and 1.26, 95% CI 0.86–1.85 among treated couples). The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity, and smoking (OR 1.24, 95% CI 1.10–1.40 among untreated, and OR 1.40, 95% CI 1.23–1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution. CONCLUSION: The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small-to-moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases. LEVEL OF EVIDENCE: II

Infertility, infertility treatment and psychomotor development: the Danish National Birth Cohort

Babies born of infertile couples, regardless of treatment, have a higher risk of preterm birth and low birthweight, conditions associated with delayed development. We examined developmental milestones in singletons as a function of parental infertility [time to pregnancy (TTP) > 12 months] and infertility treatment. From the Danish National Birth Cohort (1997-2003), we identified 37 897 singletons born of fertile couples (TTP < or = 12 months), 4351 born of infertile couples conceiving naturally (TTP > 12 months), and 3309 born after infertility treatment. When the children were about 18 months old, mothers reported 12 developmental milestones by responding to structured questions. We defined a failure to achieve the assessed milestone or the minimal numbers of milestones in a summary (motor, or cognitive/language skills) as delay. Naturally conceived children born of infertile couples had a pattern of psychomotor development similar to that of children born of fertile couples, but increasing TTP correlated with a modest delay. When the analysis was restricted to infertile couples (treated and untreated), children born after treatment showed a slight delay in cognitive/language development (odds ratio 1.24, [95% confidence interval 1.01, 1.53]) for not meeting at least three out of six cognitive/language milestones); children born after intracytoplasmic sperm injection (ICSI) had the highest estimated relative risk of delay for most milestones, especially motor milestones. These results suggest that a long TTP may be associated with a modest developmental delay. Infertility treatment, especially ICSI, may be associated with a slight delay for some of these early milestones.

Time to Pregnancy among Women with Rheumatoid Arthritis

OBJECTIVE To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP). METHODS The study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables. RESULTS Overall, compared with women with no recorded RA (n=74,255), women with prevalent RA (onset prior to conception) (n=112) were slightly older (mean±SD age 30.8±4.3 years versus 29.7±4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken>12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0-2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy. CONCLUSION Women with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity.

Occupational exposure to pesticides and pregnancy outcomes in gardeners and farmers: a study within the Danish National Birth Cohort.

Objective: We conducted a follow-up study to examine whether exposure to pesticides during pregnancy had an adverse effect on pregnancy outcomes among Danish gardeners and farmers. Methods: Using data from the National Birth Cohort in Denmark, we identified 226 pregnancies of gardeners and 214 pregnancies of farmers during 1997 through 2003. Work activities and exposure to pesticides were reported in an interview (around 16 weeks of gestation). Totally, 62,164 other workers in the cohort served as a reference group. Pregnancy outcomes were obtained by linkage to the national registers. Cox regression was applied to analyze late fetal loss and congenital malformations, and logistic regression was used to analyze preterm birth and small for gestational age. Results: There were no significant differences in the studied pregnancy outcomes between gardeners or farmers and all other workers, except for an increased risk of very preterm birth for gardeners and a favorable birth weight for farmers. With the exception of biologic approach used in gardening, neither work activities nor exposure to pesticides showed a significant increased risk of adverse birth outcomes among gardeners or farmers. Conclusions: Our data suggest little effect of occupational exposures to pesticides on pregnancy outcomes among gardeners or farmers in Denmark. The results may not apply to other countries.

Survival among people with Down syndrome: a nationwide population-based study in Denmark.

Purpose:Several studies have shown substantially longer survival among persons with Down syndrome in recent decades. We examined survival patterns among Danish persons with Down syndrome by karyotype.Methods:A national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population were followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System.Results:Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% confidence interval 3.51–7.08), 8.94 (8.32–9.60), and 10.23 (7.50–13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects.Conclusion:Recent birth cohorts of persons with Down syndrome experienced declining mortality, likely due to treatment for congenital heart defects, and persons with mosaic trisomy 21 had better survival than persons with other Down syndrome karyotypes.Genet Med 2013:15(1):64–69

Parental infertility and cerebral palsy in children

BACKGROUND Children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have been reported to have a higher risk of cerebral palsy (CP), perhaps due to the higher frequency of preterm birth, multiple births or vanishing embryo in the pregnancies. However, it has been suggested that the underlying infertility may be part of the pathway. In this study, we examined whether untreated subfecundity (measured by time to pregnancy) or infertility treatment was associated with an increased risk of CP in the offspring. METHODS Using the Danish National Birth Cohort (1997-2003), we compared children born after 0-2 months of waiting time to pregnancy (n = 35 848) with those born after a time to pregnancy of 3-5 months (n = 15 361), 6-12 months (n = 11 528) and >12 months (n = 7387), as well as those born after IVF/ICSI (n = 3617), ovulation induction with or without intrauterine insemination (n = 3000), and unplanned pregnancies (n = 13 462). CP cases were identified through the Danish CP Register. RESULTS In total, 165 (0.18%) children were diagnosed with CP in the entire cohort. We found no significant association between time to pregnancy and the risk of CP in children conceived spontaneously. Children born after IVF/ICSI had an increased risk of CP, even after adjustment for preterm birth and multiplicity (hazard ratio 2.30, 95% confidence interval 1.12-4.73). CONCLUSIONS Subfecundity per se did not appear to be associated with the risk of CP in children, whereas being born after IVF/ICSI conferred an increased risk.