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1.  Pesticide Exposure and Self-Reported Gestational Diabetes Mellitus in the Agricultural Health Study 
Diabetes care  2007;30(3):529-534.
To examine the association between pesticide use during pregnancy and gestational diabetes mellitus (GDM) among wives of licensed pesticide applicators.
Using data from the Agricultural Health Study (AHS), we estimated the association between self-reported pesticide-related activities during the first trimester of the most recent pregnancy and GDM among 11,273 women whose pregnancy occurred within 25 years of enrollment.
A total of 506 (4.5%) women reported having had GDM. Women who reported agricultural pesticide exposure (mixing or applying pesticides to crops or repairing pesticide application equipment) during pregnancy were more likely to report GDM (odds ratio [OR] 2.2 [95% CI 1.5–3.3]). We saw no association between residential pesticide exposure (applying pesticides in the home and garden during pregnancy) and GDM (1.0 [0.8–1.3]). Among women who reported agricultural exposure during pregnancy, risk of GDM was associated with ever-use of four herbicides (2,4,5-T; 2,4,5-TP; atrazine; or butylate) and three insecticides (diazinon, phorate, or carbofuran).
These findings suggest that activities involving exposure to agricultural pesticides during the first trimester of pregnancy may increase the risk of GDM.
PMCID: PMC3902103  PMID: 17327316
2.  Postpartum Haemorrhage in Canada and France: A Population-Based Comparison 
PLoS ONE  2013;8(6):e66882.
Maternal mortality ratio due to postpartum haemorrhage (PPH) is higher in France than in Canada. We explored this difference by comparing PPH features between these two countries.
Using data between 2004 and 2006, we compared the incidence, risk factors, causes and use of second-line treatments, of PPH between France (N = 6,660 PPH) and Canada (N = 9,838 PPH). We assessed factors associated with PPH through multivariate logistic models.
PPH incidence, overall (4.8% (95% CI 4.7–4.9) in Canada and 4.5% (95% CI 4.4–4.7) in France), and after vaginal delivery (5.3% (95%CI 5.2–5.4) in Canada and 4.8 (95%CI 4.7–4.9) in France), were significantly higher in Canada than in France, but not after caesarean delivery. Women delivering without PPH were similar between the two populations, except for macrosomia (11% in Canada, 7% in France, p<0.001), caesarean delivery (27% in Canada, 18% in France, p<0.001), and episiotomy (17% in Canada, 34% in France, p<0.001). After vaginal delivery, factors strongly associated with PPH were multiple pregnancy, operative delivery and macrosomia in both populations, and episiotomy only in France (Odds Ratio 1.39 (95% CI 1.23–1.57)). The use of second-line treatments for PPH management was significantly more frequent in France than in Canada after both vaginal and caesarean delivery.
PPH incidence was not higher in France than in Canada and there was no substantial difference in PPH risk factors between the 2 countries. Greater use of second-line treatments in PPH management in France suggests a more frequent failure of first-line treatments and a higher rate of severe PPH, which may be involved in the higher maternal mortality ratio due to PPH.
PMCID: PMC3691240  PMID: 23826165
3.  Birthweight, preterm birth and perinatal mortality: A comparison of black babies in Tanzania and the USA 
Adverse conditions in Africa produce some of the highest rates of infant mortality in the world. Fetal growth restriction and preterm delivery are commonly regarded as major pathways through which conditions in the developing world affect infant survival. The aim of this article was to compare patterns of birthweight, preterm delivery, and perinatal mortality between black people in Tanzania and the USA.
Registry-based study.
Referral hospital data from North Eastern Tanzania and US Vital Statistics.
Consisted of 14 444 singleton babies from a hospital-based registry (1999–2006) and 3 530 335 black singletons from US vital statistics (1995–2000).
Main outcome measures
birthweight, gestational age and perinatal mortality.
Restricting to babies born with at least 500g, we compared birthweight, gestational age, and perinatal mortality (stillbirths and deaths in the first week) in the two study populations.
Perinatal mortality in the Tanzanian sample was 41/1000, compared with 10/100 among USA blacks. Tanzanian babies were slightly smaller on average (43g), but fewer were preterm (before 37 weeks) (10.0% vs 16.2%). Applying the USA weight-specific mortality rates to Tanzanian babies born at term suggested that birthweight does not play a role in their increased mortality relative to USA blacks.
Higher mortality independent of birthweight and preterm delivery for Tanzanian babies, suggests the need to address the contribution of other pathways that can further reduce the excess perinatal mortality.
PMCID: PMC3655527  PMID: 21615361
birthweight; developing country; fetal development; perinatal mortality; preterm birth
4.  Levels of hexachlorobenzene (HCB) in breast milk in relation to birth weight in a Norwegian cohort 
Environmental research  2009;109(5):559-566.
Hexachlorobenzene (HCB) is a ubiquitous environmental contaminant that, even at low doses, causes destruction of ovarian primordial germ cells in experimental studies. However, its potential for reproductive toxicity in humans exposed to background levels has not been fully evaluated. Here we examined the association between maternal levels of HCB and their infants’ birth weight.
HCB was measured in milk samples from a subset of women in the Norwegian Human Milk Study (HUMIS), 2003–2006. 300 subjects were randomly chosen from the cohort and 26 from all small for gestational age (SGA) children. Additional information was obtained through questionnaires and the Medical Birth Registry.
Overall, HCB was associated with birth weight (adjusted b=−90 g per eight μg/kg milk fat, 95 % CI −275 to 8) and with SGA (OR 1.8, 95 % CI 0.9–3.7 per eight μg/kg milk fat (difference between the 10th and the 90th percentile)). After stratification, however, the association was present only among smokers. For birth weight for past or current smokers: b=−282, CI −467 to −98; for never smokers: b=0.5, CI −149 to 150, p-value for interaction: 0.01. Similar results were observed for head circumference, crown-heel length, and SGA.
We saw a moderate association between HCB and markers of impaired fetal growth among past and current smokers. This finding may be non-causal and due to underlying genetic variants tied to both growth and breakdown of HCB or to confounding by unmeasured toxicants that coexist in exposure sources. It may, however, also result from HCB exposure.
PMCID: PMC3625060  PMID: 19410245
Hexachlorobenzene; small for gestational age; birth weight; ponderal index; POPs
5.  On the Pitfalls of Adjusting for Gestational Age at Birth 
American Journal of Epidemiology  2011;174(9):1062-1068.
Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified.
PMCID: PMC3243938  PMID: 21946386
adjustment; collider; directed acyclic graph; gestational age; infant mortality; mediating variable; premature birth; stratification
6.  Carbonated Beverages and Chronic Kidney Disease 
Epidemiology (Cambridge, Mass.)  2007;18(4):501-506.
Carbonated beverage consumption has been linked with diabetes, hypertension, and kidney stones, all risk factors for chronic kidney disease. Cola beverages, in particular, contain phosphoric acid and have been associated with urinary changes that promote kidney stones.
We examined the relationship between carbonated beverages (including cola) and chronic kidney disease, using data from 465 patients with newly diagnosed chronic kidney disease and 467 community controls recruited in North Carolina between 1980 and 1982.
Drinking 2 or more colas per day was associated with increased risk of chronic kidney disease (adjusted odds ratio = 2.3; 95% confidence interval = 1.4 –3.7). Results were the same for regular colas (2.1; 1.3–3.4) and artificially sweetened colas (2.1; 0.7–2.5). Noncola carbonated beverages were not associated with chronic kidney disease (0.94; 0.4 –2.2).
These preliminary results suggest that cola consumption may increase the risk of chronic kidney disease.
PMCID: PMC3433753  PMID: 17525693
7.  Might rare factors account for most of the mortality of preterm babies? 
Epidemiology (Cambridge, Mass.)  2011;22(3):320-327.
Preterm delivery has a variety of causes, with each of these presumably carrying its own mortality risk. To the extent that they add to the risk of mortality, the various pathologic factors triggering preterm delivery will confound the causal contribution of gestational age to mortality, inflating the observed rates of gestational-age-specific mortality. We have previously estimated that about half of the mortality of US preterm singletons may be due to unmeasured pathologies that increase mortality risk and also cause preterm birth. In this paper, we examine the impact that rare factors may have, at least in theory, on preterm mortality.
We constructed a simple model of gestational-age specific mortality, in which we arbitrarily selected a function to represent the mortality due to immaturity alone (“baseline” risk). We then added “unmeasured” confounding factors that cause mortality and also cause preterm birth. This construct allowed us to calculate, in simple scenarios, the proportion of preterm mortality that could be caused by unmeasured confounding.
We found that rare pathologies with moderate-to-strong effects can substantially contribute to preterm mortality. The presence of such rare factors can also produce an intersection of gestational-age-specific mortality curves when stratifying by known risk factors.
It is possible that a few relatively rare factors may account for a large fraction of preterm mortality. The search for such factors should be a primary focus of future research on preterm delivery.
PMCID: PMC3097041  PMID: 21372718
8.  Parental infertility and cerebral palsy in children 
Human Reproduction (Oxford, England)  2010;25(12):3142-3145.
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.
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.
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).
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.
PMCID: PMC2989872  PMID: 21045245
cerebral palsy; infertility; infertility treatment; time to pregnancy; Danish National Birth Cohort
9.  In utero exposure to tobacco smoke and subsequent reduced fertility in females 
Human Reproduction (Oxford, England)  2010;25(11):2901-2906.
Animal studies have shown that in utero exposure to chemicals in tobacco smoke reduces female fertility, but epidemiological findings have been inconsistent.
We examined the association between in utero exposure to tobacco smoke and female fertility among women in the Norwegian Mother and Child Cohort Study, enrolled from 1999 to 2007. Around the 17th week of pregnancy, participants reported how long they took to conceive (time to pregnancy), and whether their mother smoked while pregnant with the participant. This analysis included 48 319 planned pregnancies among women aged 15–44 years. We estimated fecundability odds ratios (FORs) using a discrete-time survival analysis, adjusting for age, education and adult tobacco smoking.
The adjusted FOR for in utero exposure to tobacco smoke among all subjects was 0.96 [95% confidence interval (CI): 0.93, 0.98], among subjects reporting no adult tobacco smoking or passive exposure it was 0.96 (95% CI: 0.93, 0.99) and among subjects reporting adult tobacco smoking or passive exposure it was 0.95 (95% CI: 0.91, 0.99). We performed a probabilistic sensitivity analysis to estimate the effect of exposure and outcome misclassification on the results, and, as expected, the association became more pronounced after taking misclassification into account.
This large cohort study supports a small-to-modest association between in utero exposure to tobacco smoke and reduced fertility.
PMCID: PMC2955556  PMID: 20817739
tobacco smoking; in utero exposure; fertility
10.  Mortality risk among preterm babies: Immaturity vs. underlying pathology 
Epidemiology (Cambridge, Mass.)  2010;21(4):521-527.
Deaths among preterm births are presumably due to both immaturity and the conditions that cause preterm birth. Their relative contributions are unknown.
Using US birth certificates (1995–2002), we estimated what portion of preterm neonatal mortality may be attributable to immaturity alone Twins have elevated mortality, yet they usually have lower mortality than singletons at most preterm weeks. Twinning itself is a cause of early birth. Thus, at any given preterm week, singletons are more likely than twins to have pathological causes of preterm delivery. If any such cause is associated with a mortality risk higher than that conferred by twinning, it is possible for singletons to have higher mortality than twins at some preterm weeks. Thus, mortality of twins at those weeks comes closer to describing the risk due to immaturity itself. To exclude high-risk babies, we focused on singletons and twins least likely to have suffered fetal growth disruptions (i.e. those with “optimal” birth weight). At each gestational week from 24 to 36, we identified (for twins and singletons separately) the 500-gram weight category with the lowest neonatal mortality, and selected the lower of the two mortality rates.
Using the above as our best estimates of mortality due to immaturity alone, we calculated that about half the mortality of singleton preterm babies was due to the pathologies that cause early delivery.
Factors that cause preterm birth apparently contribute a large proportion of preterm mortality. If so, the prevention of preterm mortality requires more than the postponement of delivery.
PMCID: PMC2967434  PMID: 20407380
11.  Mother’s age at menarche and offspring size 
An individual’s growth trajectory is, at least in part, inherited. Mother’s early age at menarche has been associated with taller offspring height and greater body mass index (BMI) at age 9 years, suggesting that mother’s age at menarche may be an intergenerational marker of growth. We examined the association between mother’s age at menarche and childhood size at birth, and at the ages 1, 3, 4, 7, and 8 years in the Collaborative Perinatal Project (CPP).
We examined 128,636 measurements from 31,474 Black and White children. We transformed the original measurements into z-scores. Child size was examined in mixed models, adjusted for center, child sex, race, socioeconomic index, child’s exact age at measurement (in months), mother's age at recruitment and, depending on which measure was the outcome in the specific model, mother's height, pre-pregnancy weight, or BMI.
Compared with children whose mother had menarche at age 15 or later, children whose mothers had age at menarche before age 12 were taller from age 1 and had higher BMI at ages 7 and 8 (0.17 and 0.19 z, respecively).
Mother’s age at menarche is a modest predictor of their children’s growth trajectory. The mechanism is likely to be heritable, although other explanations are possible.
PMCID: PMC3005766  PMID: 20548308
Age at menarche; Body Mass Index; Growth trajectory
12.  Parental infertility and developmental coordination disorder in children 
It has previously been reported that children born after infertility treatment had a slight delay in early motor milestones. In this study, we examined whether children of infertile couples with or without infertility treatment had a higher risk of developmental coordination disorder (DCD).
We used data on parental infertility and DCD among 23 167 singletons from the Danish National Birth Cohort (1996–2002). Data on time to pregnancy (TTP) and infertility treatment were collected early in pregnancy. Data on DCD in children were collected using the Developmental Coordination Disorder Questionnaire, filled in by the mothers during follow-up when the children were 7 years old. We used the recommended cut-off for the age group to classify children.
Compared with children born of fertile couples, children conceived after a waiting TTP of longer than 12 months had a slightly higher risk of DCD [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.03–1.77], but the estimated OR was not significant in children born after infertility treatment (OR 1.19, 95% CI 0.86–1.66). None of the individual treatment procedures was significantly associated with a higher risk of DCD. Children of parents who had not planned their pregnancy showed no elevated risk.
Our findings are overall reassuring, although it is possible that low fecundity may be associated with a modestly increased risk of DCD.
PMCID: PMC2839911  PMID: 20139428
assisted reproduction technologies; developmental coordination disorder; infertility
13.  Impact of Pregnancy-Induced Hypertension on Stillbirth and Neonatal Mortality in First and Higher Order Births: A Population-Based Study 
Epidemiology (Cambridge, Mass.)  2010;21(1):118-123.
Hypertensive disorders of pregnancy are more frequent in primiparous women, but may be more severe in multiparas. We examined trends in pregnancy-induced hypertension (PIH)-related stillbirth and neonatal mortality and explored whether mortality varied by parity and maternal race.
We carried out a population-based study of 57 million singleton live- and stillbirths (24-46 weeks) in the United States between 1990 and 2004. We estimated rates and adjusted odds ratio (OR) of stillbirth and neonatal death in relation to PIH, comparing births in 1990-91 with 2003-04.
PIH increased from 3.0% in 1990 to 3.9% in 2004. In both 1990-91 and 2003-04 periods, PIH was associated with an increased risk of stillbirth and neonatal death. We explored this in more detail in 2003-04, and observed that the increased risk of stillbirth was higher in women having their second or higher order births (OR=2.24, 95% confidence interval (CI)=2.11-2.37) compared with women having their first birth (OR=1.52, 95% CI=1.40-1.64). Patterns were similar for neonatal death (OR=1.30, 95% CI=1.18-1.43 in first and OR=1.64, 95% CI=1.51-1.78 in second or higher order births). Among multiparas, the association between PIH and stillbirth was stronger in Blacks (OR=2.93, 95% CI=2.66-3.22) than Whites (OR=1.98, 95% CI=1.83-2.14).
A substantial burden of stillbirth and neonatal mortality is associated with PIH, especially among multiparas women, which may be due to more severe disease women, or to a higher burden of underlying disease.
PMCID: PMC2841017  PMID: 20010214
14.  Infertility, infertility treatment, and mixed-handedness in children 
Early human development  2009;85(12):745-749.
Mixed-handedness, which may reflect atypical brain laterality, has been linked to a number of medical conditions as well as prenatal stress.
The aim of the study was to examine whether infertility or infertility treatment was associated with an increased risk of mixed-handedness in children.
Study design, subjects and outcome measures
We used data from three population-based birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984-1987), the Aarhus Birth Cohort (1990-1992) and the Danish National Birth Cohort (1996-2002) (N=7728, 5720 and 29486, respectively). Data on time to pregnancy and infertility treatment was collected during pregnancy. Handedness was reported in a follow-up questionnaire when the children were at least 7 years old. Children were categorized as mixed-handed if the mothers reported that they used both hands equally.
Children born after infertility treatment, particularly intrauterine insemination, had a higher risk of being mixed-handed compared to children of fertile couples with a time to pregnancy ≤12 months (odds ratio 1.41, 95% confidence interval 1.09-1.82). Children of couples with unplanned pregnancies, particularly after an oral contraceptives failure, were also more likely to be mixed-handed. There was no association between a long waiting time to pregnancy and mixed-handedness in children.
Children born after infertility treatment, particularly intrauterine insemination, and children exposed to oral contraceptives during early gestation may have a higher risk of being mixed-handed.
PMCID: PMC2788033  PMID: 19875254
Infertility; Infertility treatment; Mixed-handedness; Oral contraceptives; Time to pregnancy
15.  Maternal Pesticide Use and Birth Weight in the Agricultural Health Study 
Journal of agromedicine  2010;15(2):127-136.
Studies examining the association between maternal pesticide exposure and low birth weight yield conflicting results. We examined the association between maternal pesticide use and birth weight among women in the Agricultural Health Study, a large study of pesticide applicators and their spouses in Iowa and North Carolina.
We evaluated self-reported pesticide use of 27 individual pesticides in relation to birth weight among 2246 farm women whose most recent singleton birth occurred within 5 years of enrollment (1993–97). We used linear regression models adjusted for site, preterm birth, medical parity, maternal body mass index, height, and smoking.
Mean infant birth weight was 3586 g (±546 g), and 3% of the infants were low birth weight (<2500g). First-trimester pesticide-related tasks were not associated with birth weight. Ever use of the pesticide carbaryl was associated with decreased birth weight (−82 g, 95% CI = −132,−31).
This study provides limited evidence about pesticide use as a modulator of birth weight. Overall, we observed no associations between birth weight and pesticide-related activities during early pregnancy; however, we have no data on temporal specificity of individual pesticide exposures prior to or during pregnancy and therefore cannot draw conclusions related to these exposure windows. Given the widespread exposure to pesticide products, additional evaluation of maternal pregnancy exposures at specific time windows and subsequent birth outcomes is warranted.
PMCID: PMC2905891  PMID: 20407994
16.  Prepregnancy body mass index change between pregnancies and preterm birth in the following pregnancy 
Maternal prepregnancy body mass index (BMI) may affect the risk of preterm birth. However, it is unclear how changes in BMI between pregnancies modify the risk of preterm birth in the following pregnancy. We studied this effect in the Collaborative Perinatal Project, when obesity was uncommon and the prevalence of labor induction was low. This analysis included 1,892 nulliparous women whose first enrolled (index) pregnancy was a singleton live birth and the second enrolled (outcome) pregnancy was a consecutive singleton pregnancy (both pregnancy within 20-51 weeks of gestation). We used Cox regression model to calculate the hazard ratio (HR) of preterm birth at the outcome pregnancy as a function of reduced BMI (<25th percentile of change) and increased BMI (>75th percentile), compared to stable BMI (25th-75th percentile), adjusted for prepregnancy BMI at the index pregnancy and other covariates. BMI reduction was associated with a non-significant increased risk of preterm birth, adjusted HR 1.17 (95% confidence interval 0.90-1.53); BMI increase had effects close to null (adjusted HR 1.08 [0.83-1.41]). In the model with linear BMI change, each 1 kg/m2 increase was associated with an HR of 0.96 (0.89-1.03). The estimates associated with a BMI reduction were higher in women whose index pregnancy ended preterm (HR 1.49 [0.90-2.44]) and in those with BMI <25 kg/m2 at the index pregnancy (HR 1.30 [0.98-1.71]). This study involved mainly low-to-normal weight women with spontaneous deliveries, and might suffer from type II error due to small sample size. The effect of BMI change in overweight and obese women needs to be studied using contemporary data.
PMCID: PMC2790203  PMID: 19775382
17.  Intersecting Birth Weight-specific Mortality Curves: Solving the Riddle 
American Journal of Epidemiology  2009;169(7):787-797.
Small babies from a population with higher infant mortality often have better survival than small babies from a lower-risk population. This phenomenon can in principle be explained entirely by the presence of unmeasured confounding factors that increase mortality and decrease birth weight. Using a previously developed model for birth weight-specific mortality, the authors demonstrate specifically how strong unmeasured confounders can cause mortality curves stratified by known risk factors to intersect. In this model, the addition of a simple exposure (one that reduces birth weight and independently increases mortality) will produce the familiar reversal of risk among small babies. Furthermore, the model explicitly shows how the mix of high- and low-risk babies within a given stratum of birth weight produces lower mortality for high-risk babies at low birth weights. If unmeasured confounders are, in fact, responsible for the intersection of weight-specific mortality curves, then they must also (by virtue of being confounders) contribute to the strength of the observed gradient of mortality by birth weight. It follows that the true gradient of mortality with birth weight would be weaker than what is observed, if indeed there is any true gradient at all.
PMCID: PMC2727223  PMID: 19240224
birth weight; confounding factors (epidemiology); infant mortality; smoking
18.  Infertility, infertility treatment and psychomotor development: 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 ≤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.
PMCID: PMC2706001  PMID: 19159396
child development; infertility; assisted reproductive techniques
19.  Parental infertility and sexual maturation in children 
The reproductive health of children born of infertile couples may be affected by infertility treatment or factors associated with infertility. We examined sexual maturation in children of parents with infertility.
We used data from a follow-up of 3382 girls and 2810 boys born between 1984 and 1987 in the Aalborg–Odense Birth Cohort. We had mothers’ report of time to pregnancy (TTP) and infertility treatment (at the time, mostly hormonal) from the pregnancy questionnaire administered in 1984–1987, and the children’s report of their own sexual maturation from the follow-up questionnaire administered in 2005, when they were between 18 and 21 years old. Many reported age only in year when they had the events related to sexual maturation, and for each event, we imputed the month based on the median month at each year of age among those reporting both years and months.
In girls, the mean age at menarche was 13.3 years and, in boys, the mean age at appearance of acne, voice break, regular shaving and first nocturnal emission were 14.5, 14.5, 17.2 and 14.7 years, respectively. We saw no significant differences in age at these events among children born of either fertile (with TTP of 0–12 months and no treatment), untreated infertile (with TTP of more than 12 months and no treatment) or treated infertile couples (with a history of examination or treatment for infertility).
Our data suggest no significant association between parental infertility or hormonal treatment and timing of sexual maturation in the offspring.
PMCID: PMC2733842  PMID: 18840889
infertility; infertility treatment; puberty; time to pregnancy
20.  Handedness and time to pregnancy 
Non-right handedness, particularly mixed-handedness, has been associated with a number of medical conditions. We examined whether handedness was associated with fecundity, measured by time to pregnancy.
We used data on parental handedness and time to pregnancy from two regional birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984–1987) and the Aarhus Birth Cohort (1990–1992) (N=5808 and 3426, respectively). We applied discrete-time survival analysis to assess fecundity in relation to handedness.
In both cohorts, we saw a slightly lower fecundity in individuals who reported being mixed-handed. Left handedness was not significantly associated with fecundity.
Our data showed a modest association between mixed-handedness and subfecundity, which suggests that these traits may share a common prenatal etiology.
PMCID: PMC2662690  PMID: 19057386
handedness; fecundity; time to pregnancy
21.  Pesticide Exposure and Hypertensive Disorders During Pregnancy 
Environmental Health Perspectives  2009;117(9):1393-1396.
Hypertensive disorders of pregnancy, including pregnancy-induced hypertension (PIH) and preeclampsia (PE), complicate 2–8% of pregnancies. Few studies have examined environmental risk factors in relation to these conditions.
Our goal was to examine whether pesticide exposure during pregnancy was associated with hypertensive disorders of pregnancy.
We analyzed self-reported data from 11,274 wives of farmers enrolled in the Agricultural Health Study (AHS) between 1993 and 1997. Using logistic regression models, we estimated the adjusted odds ratios (AORs) for PIH and PE associated with pesticide-related activities during the first trimester of pregnancy.
First-trimester residential and agricultural activities with potential exposure to pesticides were associated with both PIH [residential AOR = 1.27; 95% confidence interval (CI), 1.02–1.60; agricultural AOR = 1.60; 95% CI, 1.05–2.45] and PE (residential AOR = 1.32; 95% CI, 1.02–1.70; agricultural AOR = 2.07; 95% CI, 1.34–3.21).
Exposure to pesticides during pregnancy may increase the risk of hypertensive disorders of pregnancy. Laboratory research may provide insights into relationships between pesticide exposure and hypertensive diseases of pregnancy.
PMCID: PMC2737015  PMID: 19750103
pesticide exposure; preeclampsia; pregnancy-induced hypertension
22.  Gestational Age, Birth Weight, Intrauterine Growth and Risk for Epilepsy 
American journal of epidemiology  2007;167(3):262-270.
The authors evaluated the association between gestational age, birth weight, intrauterine growth and epilepsy in a population-based cohort of 1.4 million singletons born in Denmark (1979-2002). A total of 14,334 individuals were registered with epilepsy in the Danish National Hospital Register as inpatients (1979-2002) and outpatients (1995-2002). Information on gestational age and birth weight was obtained from Danish Medical Birth Registry. Children small at birth were identified through two methods: 1) sex-, birth order-, and gestational-age-specific z-score, and 2) deviation from the expected birth weight estimated based on the birth weight of an older sibling. The incidence rates of epilepsy increased consistently with decreasing gestational age and birth weight. The incidence rate ratios (IRR) for epilepsy in the first year of life were more than five-fold in children born at 22-32 weeks compared with children born at 39-41 weeks, and in children with a birth weight <2,000 grams compared with children of 3,000-3,999 grams. The IRRs decreased with age, but remained elevated into early adulthood. Children identified as growth-restricted according to either of the two methods had increased IRRs for epilepsy, even among children with a ‘normal’ birth weight of 3,500-3,999 grams. Low gestational age at birth and low birth weight are associated with an increased risk of epilepsy throughout childhood and persisting into puberty. Intrauterine growth restriction is associated with an increased risk of epilepsy, even among children with a birth weight in a normal range.
PMCID: PMC2632964  PMID: 18042672
23.  Infertility, Infertility Treatment and Fetal Growth Restriction 
Obstetrics and gynecology  2007;110(6):1326-1334.
To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality.
From the Danish National Birth Cohort (1997–2003), we identified 51,041 singletons born of fertile couples (time to pregnancy ≤12 months), 5787 born of infertile couples conceiving naturally (time to pregnancy >12 months), and 4317 born after treatment. We defined SGA as the lowest 5% of birth weight by sex and gestational age.
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.
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.
PMCID: PMC2365892  PMID: 18055728
24.  Does low maternal blood pressure during pregnancy increase the risk of perinatal death? 
Epidemiology (Cambridge, Mass.)  2007;18(5):619-622.
The reported association between low maximum diastolic blood pressure (DBP) during pregnancy and perinatal death (stillbirth and death in the first week combined) may result from failure to account for gestational length, a strong predictor of perinatal death.
We studied 41,089 singleton pregnancies from the U.S. Collaborative Perinatal Project (1955–1966).
The association between low maximum DBP and elevated risk of perinatal death disappeared after accounting for reverse causation related to gestational length. At any given gestational week, women whose offspring ultimately experienced perinatal death did not have significantly lower maximum DBP than women whose offspring survived the perinatal period. When accounting for DBP trend during pregnancy through gestational-age-specific DBP standardized score, we saw no association between a mean low score and perinatal death.
Low maximum maternal DBP during pregnancy was a post hoc correlate of perinatal death in these data, but not a risk factor.
PMCID: PMC2225167  PMID: 17879438
25.  Infertility, infertility treatment and twinning: the Danish National Birth Cohort 
Human reproduction (Oxford, England)  2007;22(4):1086-1090.
We have previously observed that an increasing time to pregnancy (TTP) is associated with a reduced frequency of twin deliveries in couples not receiving infertility treatment. By using updated information, we assessed the frequencies of dizygotic and monozygotic twin deliveries as a function of infertility (TTP>12 months), as well as infertility treatment.
From the Danish National Birth Cohort (1997−2003), we identified 51730 fertile couples with TTP12 months, and 5163 infertile couples who conceived after treatment. Information on zygosity, available for part of the cohort (1997−2000), was based on standardized questions on the similarities between the twins at the age of 3−5 years.
Compared with fertile couples, the frequency of dizygotic twin deliveries was lower for infertile couples conceiving naturally (Odds ratio 0.4, 95% confidence interval 0.2−0.7) and was much higher for infertile couples conceiving after treatment (17.3, 14.4−20.7). The frequency of dizygotic twin deliveries decreased with TTP in untreated couples, while the frequency of monozygotic twin deliveries remained constant.
The frequency of dizygotic twin deliveries decreased with time to pregnancy and substantially increased with infertility treatment, whereas monozygotic twin deliveries remained substantially unchanged.
PMCID: PMC2077299  PMID: 17204529
infertility; infertility treatment; time to pregnancy; twinning; zygosity

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