Collaborative Perinatal Project Research Articles

Cesarean delivery, labor duration, and mothers’ mortality risk over 50 years of follow-up

BackgroundPregnancy complications have been recognized as a window to future health. Though cesarean delivery is common, it is unknown whether labor duration and mode of delivery are associated with maternal long-term mortality. ObjectiveTo examine whether labor duration and mode of delivery were associated with all-cause and cause-specific mortality. Study DesignParticipants were mothers from the multisite Collaborative Perinatal Project (CPP) cohort (1959–1966; n=43,646, limited to last CPP delivery). We ascertained all-cause and specific causes of death as of 2016 via linkage to the National Death Index and Social Security Death Master File. Hazard ratios (HR) testing mode of delivery and labor duration were estimated using Cox proportional hazards models adjusted for demographic and clinical characteristics. We further stratified analyses by parity. ResultsAmong participants with a recorded delivery mode, 5.9% (2486/42,335) had a cesarean delivery. Participants who had a cesarean were older (26.9 vs 24.3 years), with higher body mass index (24.0 vs 22.7 kg/m2), were less likely to be nulliparous (21% vs 30%), and more likely to have a household income of at least $6000 (22% vs 17%), to smoke ≥1 pack/d (18% vs 15%), to have diabetes mellitus (12% vs 1%) and to have a prior medical condition (47% vs 34%), compared to participants with a vaginal delivery. Delivery mode was similar by race/ethnicity, marital status, and education. Median labor duration was 395 minutes among participants who had an intrapartum cesarean delivery and 350 minutes among participants delivered vaginally. By 2016, 52.2% of participants with a cesarean delivery and 38.5% of participants with a vaginal delivery had died. Cesarean vs vaginal delivery was significantly associated with increased risk for all-cause mortality (HR=1.16 (95% confidence interval [CI]: 1.09, 1.23); in nulliparas, HR=1.27 (95% CI: 1.09, 1.47); in multiparas, HR=1.13 (95% CI: 1.06, 1.21) as well as increased risk of death from cardiovascular disease, diabetes, respiratory disease, infection, and kidney disease. Associations with death from cardiovascular disease, infection, and kidney disease were stronger for multiparas than nulliparas, though the association with death from diabetes was stronger among nulliparas. Labor duration was not significantly related to overall mortality. ConclusionIn a historic United States cohort with a low cesarean delivery rate, cesarean delivery was an indicator for subsequent increased mortality risk, particularly related to cardiovascular disease and diabetes. Future studies with long-term follow-up are warranted given the current high prevalence of cesarean delivery.

In utero aspirin exposure and child neurocognitive development: A propensity score-matched analysis.

To evaluate the association between a short-period, high-dose in utero aspirin exposure and child neurocognitive development. A propensity score-matched analysis of a multicentre prospective cohort study. The US Collaborative Perinatal Project (1959-1976). A total of 50 565 singleton live births with maternal information. We performed a propensity score matching to balance maternal characteristics between women with and without aspirin exposure. Inverse probability-weighted marginal structural models were used to estimate associations between aspirin exposure and child neurocognitive assessments. Child neurocognitive development was assessed using the Bayley Scales at 8 months, the Stanford Binet Intelligence Scale at 4 years, and the Wechsler Intelligence Scale and Wide-Range Achievement Test (WRAT) at 7 years. Children exposed to aspirin in utero were associated with an 8%-16% reduced risk of having suspect/abnormal or below-average scores in most neurocognitive assessments. A trend of lower risks of having suspect/abnormal or below-average scores was further observed in children with in utero aspirin exposure for more than 7 days, particularly on Bayley Mental (relative risk [RR] 0.82, 95% CI 0.74-0.92), WRAT Reading (RR 0.88, 95% CI 0.78-0.98) and WRAT Arithmetic tests (RR 0.76, 95% CI 0.66-0.86). This association was mainly observed in the second trimester of pregnancy. In utero aspirin exposure was associated with improved child neurocognitive development in a prospective cohort study. Further studies are warranted to evaluate the impact of long-period and low-dose in utero aspirin exposure on child short- and long-term neurodevelopment.

Patterns of Adverse Childhood Experiences and Neurocognitive Development

Early life adversity is associated with higher risk of many adult health problems, including mental illness, substance abuse, suicide attempt, and chronic diseases. Many previous studies investigated adversities one at a time or investigated the health toll associated with the cumulative number of adversities. To examine the co-occurrence of adversities among children and how specific patterns of adversities are associated with neurocognitive development. This cohort study used data from the Collaborative Perinatal Project (CPP), which enrolled a national sample of women during pregnancy and followed their offspring to ages 7 to 8 years, between 1959 and 1974. The CPP was a community-based study conducted in 12 US medical centers. The CPP sample was ascertained through prenatal clinics and is diverse with respect to race and socioeconomic status. Data analysis was performed from August 2023 to March 2024. A latent class analysis was conducted of 12 adverse childhood experiences that occurred between birth and 7 years to identify common patterns of childhood adversities. Five neurocognitive tests were used to measure children's visual-motor, sensory-motor, auditory-vocal, intelligence quotient, and academic skills. The analysis sample included 49 853 offspring (25 226 boys [50.6%]); 24 436 children (49.0%) had low probability of experiencing any adversity, whereas the remaining half were classified into 5 groups reflecting distinct patterns of childhood adversities: parental harshness and neglect, 1625 children (3.3%); parental separation and poverty, 8731 children (17.5%); family instability, 3655 children (7.3%); family loss, instability, and poverty, 1505 children (3.0%); and crowded housing and poverty, 9901 children (19.9%). Children in 4 of these groups had lower neurocognitive scores than children with a low probability of experiencing adversity, with standardized mean differences ranging from -0.07 (95% CI, -0.11 to -0.03) to -0.86 (95% CI, -1.06 to -0.65). These findings suggest that adverse childhood experiences are associated with deficits in children's neurocognitive functions. It is important to understand the complexity in children's exposure to adversity and the resulting developmental consequences, as well as the underlying mechanisms, to help support children exposed to adversity and foster healthier and resilient trajectories of development.

Involuntary tobacco smoke exposures from conception to 18 years increase midlife cardiometabolic disease risk: a 40-year longitudinal study.

Few population studies have sufficient follow-up period to examine early-life exposures with later life diseases. A critical question is whether involuntary exposure to tobacco smoke from conception to adulthood increases the risk of cardiometabolic diseases (CMD) in midlife. In the Collaborative Perinatal Project, serum-validated maternal smoking during pregnancy (MSP) was assessed in the 1960s. At a mean age of 39 years, 1623 offspring were followed-up for the age at first physician-diagnoses of any CMDs, including diabetes, heart disease, hypertension, or hyperlipidemia. Detailed information on their exposure to environmental tobacco smoke (ETS) in childhood and adolescence was collected with a validated questionnaire. Cox regression was used to examine associations of in utero exposure to MSP and exposure to ETS from birth to 18 years with lifetime incidence of CMD, adjusting for potential confounders. We calculated midlife cumulative incidences of hyperlipidemia (25.2%), hypertension (14.9%), diabetes (3.9%), and heart disease (1.5%). Lifetime risk of hypertension increased by the 2nd -trimester exposure to MSP (adjusted hazard ratio: 1.29, 95% confidence interval: 1.01-1.65), ETS in childhood (1.11, 0.99-1.23) and adolescence (1.22, 1.04-1.44). Lifetime risk of diabetes increased by joint exposures to MSP and ETS in childhood (1.23, 1.01-1.50) or adolescence (1.47, 1.02-2.10). These associations were stronger in males than females, in never-daily smokers than lifetime ever smokers. In conclusion, early-life involuntary exposure to tobacco smoke increases midlife risk of hypertension and diabetes in midlife.

History of multifetal gestation and long-term maternal mortality.

Multifetal gestation could be associated with higher long-term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk. We examined whether spontaneously conceived multifetal versus singleton gestation was associated with long-term maternal mortality in a racially diverse U.S. We ascertained vital status as of 2016 via linkage to the National Death Index and Social Security Death Master File of 44,174 mothers from the Collaborative Perinatal Project (CPP; 1959-1966). Cox proportional hazards models with maternal age as the time scale assessed associations between history of spontaneous multifetal gestation (in the last CPP observed pregnancy or prior pregnancy) and all-cause and cardiovascular mortality, adjusted for demographics, smoking status, and preexisting medical conditions. We calculated hazard ratios (HR) for all-cause and cause-specific mortality over the study period and until age 50, 60, and 70 years (premature mortality). Of eligible participants, 1672 (3.8%) had a history of multifetal gestation. Participants with versus without a history of multifetal gestation were older, more likely to have a preexisting condition, and more likely to smoke. By 2016, 51% of participants with and 38% of participants without a history of multifetal gestation had died (unadjusted all-cause HR 1.14, 95% confidence interval [CI] 1.07, 1.23). After adjustment for smoking and preexisting conditions, a history of multifetal gestation was not associated with all-cause (adjusted HR 1.00, 95% CI 0.93, 1.08) or cardiovascular mortality (adjusted HR 0.99, 95% CI 0.87, 1.11) over the study period. However, history of multifetal gestation was associated with an 11% lower risk of premature all-cause mortality (adjusted HR 0.89, 95% CI 0.82, 0.96). In a cohort with over 50 years of follow-up, history of multifetal gestation was not associated with all-cause mortality, but may be associated with a lower risk of premature mortality.

Gestational weight change in a diverse pregnancy cohort and mortality over 50 years: a prospective observational cohort study

High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later. The Collaborative Perinatal Project (CPP) was a prospective US pregnancy cohort (1959-65). The CPP Mortality Linkage Study linked CPP participants to the National Death Index and Social Security Death Master File for vital status to 2016. Adjusted hazard ratios (HRs) with 95% CIs estimated associations between gestational weight gain and loss according to the 2009 National Academy of Medicine recommendations and mortality by pre-pregnancy BMI. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular and diabetes underlying causes of mortality. Among 46 042 participants, 20 839 (45·3%) self-identified as Black and 21 287 (46·2%) as White. Median follow-up time was 52 years (IQR 45-54) and 17 901 (38·9%) participants died. For those who were underweight before pregnancy (BMI <18·5 kg/m2; 3809 [9·4%] of 40 689 before imputation for missing data]), weight change above recommendations was associated with increased cardiovascular mortality (HR 1·84 [95% CI 1·08-3·12]) but not all-cause mortality (1·14 [0·86-1·51]) or diabetes-related mortality (0·90 [0·13-6·35]). For those with a normal pre-pregnancy weight (BMI 18·5-24·9 kg/m2; 27 921 [68·6%]), weight change above recommendations was associated with increased all-cause (HR 1·09 [1·01-1·18]) and cardiovascular (1·20 [1·04-1·37]) mortality, but not diabetes-related mortality (0·95 [0·61-1·47]). For those who were overweight pre-pregnancy (BMI 25·0-29·9 kg/m2; 6251 [15·4%]), weight change above recommendations was associated with elevated all-cause (1·12 [1·01-1·24]) and diabetes-related (1·77 [1·23-2·54]) mortality, but not cardiovascular (1·12 [0·94-1·33]) mortality. For those with pre-pregnancy obesity (≥30·0 kg/m2; 2708 [6·7%]), all associations between gestational weight change and mortality had wide CIs and no meaningful relationships could be drawn. Weight change below recommended levels was associated only with a reduced diabetes-related mortality (0·62 [0·48-0·79]) in people with normal pre-pregnancy weight. This study's novel findings support the importance of achieving healthy gestational weight gain within recommendations, adding that the implications might extend beyond the pregnancy window to long-term health, including cardiovascular and diabetes-related mortality. National Institutes of Health.

Adverse birth outcomes related to concentrations of per- and polyfluoroalkyl substances (PFAS) in maternal blood collected from pregnant women in 1960–1966

BackgroundPrior animal and epidemiological studies suggest that per- and polyfluoroalkyl substances (PFAS) exposure may be associated with reduced birth weight. However, results from prior studies evaluated a relatively small set of PFAS. ObjectivesDetermine associations of gestational PFAS concentrations in maternal serum samples banked for 60 years with birth outcomes. MethodsWe used data from 97 pregnant women from Boston and Providence that enrolled in the Collaborative Perinatal Project (CPP) study (1960–1966). We quantified concentrations of 27 PFAS in maternal serum in pregnancy and measured infant weight, height and ponderal index at birth. Covariate-adjusted associations between 11 PFAS concentrations (>75% detection limits) and birth outcomes were estimated using linear regression methods. ResultsMedian concentrations of PFOA, PFNA, PFHxS, and PFOS were 6.189, 0.330, 14.432, and 38.170 ng/mL, respectively. We found that elevated PFAS concentrations during pregnancy were significantly associated with lower birth weight and ponderal index at birth, but no significant associations were found with birth length. Specifically, infants born to women with PFAS concentrations ≥ median levels had significantly lower birth weight (PFOS: β = −0.323, P = 0.006; PFHxS: β = −0.292, P = 0.015; PFOA: β = −0.233, P = 0.03; PFHpS: β = −0.239, P = 0.023; PFNA: β = −0.239, P = 0.017). Similarly, women with PFAS concentrations ≥ median levels had significantly lower ponderal index (PFHxS: β = −0.168, P = 0.020; PFHxA: β = −0.148, P = 0.018). ConclusionsUsing data from this US-based cohort study, we found that 1) maternal PFAS levels from the 1960s exceeded values in contemporaneous populations and 2) that gestational concentrations of certain PFAS were associated with lower birth weight and infant ponderal index. Additional studies with larger sample size are needed to further examine the associations of gestational exposure to individual PFAS and their mixtures with adverse birth outcomes.

Association of the Severity of Hypertensive Disorders in Pregnancy with Birthweight, Childhood Obesity, and Blood Pressure at Age 7.

We aimed to examine the effects of various severities of hypertensive disorders in pregnancy on birthweight, blood pressure (BP), and body mass index in offspring at age 7. In the China Labor and Delivery Survey and the United States Collaborative Perinatal Project (CPP), the relationship of the severity of hypertensive disorders and nutritional and cardiovascular outcomes in offspring was assessed using a multivariable logistic and general linear regression model. In both datasets, those with gestational hypertension were more likely to deliver large for gestational age (LGA) and macrosomia (adjusted odds ratios (aOR) ranged from 1.29 to 1.91), as well as low birth weight (LBW) neonates (aOR ranged from 1.23 to 3.56), compared with normotensive mothers. In the CPP, when gestational hypertension was further stratified into mild and severe, only those with mild gestational hypertension (the mild group) were more likely to deliver macrosomia and LGA (aOR ranged from 1.25 to 1.32). Others (severe gestational hypertension and preeclampsia/eclampsia) were closely related to LBW and small for gestational age (aOR ranged from 1.27 to 2.77). Moreover, children of mothers in the mild group tended to be overweight/obese and had elevated diastolic BP. We concluded that the severity of hypertensive disorders had different effects on birthweight, childhood overweight, and BP.

Children's cognitive performance and suicide risk through middle adulthood.

Longitudinal studies show that lower cognitive performance in adolescence and early adulthood is associated with higher risk of suicide death throughout adulthood. However, it is unclear whether this cognitive vulnerability originates earlier in childhood since studies conducted in children are scarce and have inconsistent results. Vital status of 49,853 individuals born between 1959 and 1966 to participants in the Collaborative Perinatal Project cohort was determined by a probabilistic linkage to the National Death Index, covering all US deaths occurring from 1979 through 2016. Cox proportional hazard models were used to examine associations of general, verbal, and non-verbal intelligence at ages 4 and 7, and academic skills at age 7 with suicide death coded according to ICD-9/10 criteria, while accounting for sociodemographic and pregnancy factors previously associated with suicide in this sample. By the end of 2016, 288 cohort members had died by suicide. Cognitive performance at 7 years on tests with verbal components was associated with suicide risk (average vs. high verbal intelligence, HR = 1.97, 95% CI 1.05-3.71; low vs. high spelling skills, HR = 2.02, 95% CI 1.16-3.51; low vs. high reading skills, HR = 2.01, 95% CI 1.27-3.17). Associations were still evident, especially for verbal intelligence and reading skills, but hazard ratios were attenuated after adjusting for prenatal and sociodemographic factors at birth (verbal intelligence, HR = 1.97, 95% CI 1.03-3.78; spelling, HR = 1.61, 95% CI 0.90-2.88; reading, HR = 1.67, 95% CI 1.02-2.72). Childhood neurocognitive performance is associated with vulnerability to suicide mortality through middle-adulthood, suggesting that there might be a cognitive diathesis for suicide originating in early childhood. Future studies should examine how multiple domains of childhood cognitive performance contribute to vulnerability to suicide risk, including by increasing risk for social and environmental factors that are associated not only with suicide but also with many types of psychiatric disorders.

Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.

Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants. The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959-1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants' vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year. Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45-54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03-1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05-1.44]); preterm induced labor (aHR, 1.31 [1.03-1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75-2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97-1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99-1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20-1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00-1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10-2.46]) compared with White (aHR, 1.29 [0.97-1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90-2.90]) compared with Black (aHR, 1.40 [1.00-1.96]) participants. In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

Infant sex at birth and long-term maternal mortality.

Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain. The objective of the study was to examine whether male infants increase the risk of maternal mortality. This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project (CPP). Collaborative Perinatal Project records were linked to the National Death Index and the Social Security Master Death File to ascertain deaths until 2016. Foetal sex was determined by infant sex at birth, defined as the total number of male or female infants in pregnancies prior to or during enrolment in the CPP. In secondary analyses, exposure was defined as infant sex at the last CPP delivery. Outcomes included all-cause and underlying causes of mortality. We used Cox proportional hazards models weighted by the number of prior live births and stratified our models by parity and race/ethnicity. Among 48,188 women, 50.8% had a male infant at their last registered CPP pregnancy and 39.0% had a recorded death after a mean follow-up of 47.8 years (SD 10.5 years). No linear association was found between the number of liveborn males and all-cause mortality (primipara women: HR 1.02, 95% CI 0.95, 1.09, multipara women, 1 prior live birth: HR 0.96, 95% CI 0.89, 1.03, multipara women, ≥2 prior live births: HR 0.97, 95% CI 0.85, 1.11). A similar trend was noted for cardiovascular- and cancer-related mortality. At the last delivery, women with a male infant did not have an increased risk of all-cause or cause-specific mortality compared to women with a female infant. These findings were consistent across racial/ethnic groups. Women who give birth to male infants, regardless of number, are not at increased risk of all-cause and cause-specific mortality. These findings suggest that giving birth to male infants may not independently influence the long-term health of women.

Etiological subgroups of term small-for-gestational-age and childhood health outcomes.

Small-for-gestational-age (SGA) has a heterogeneous etiology. Our study aimed to examine the childhood health outcomes of etiology-distinct term SGA subgroups. Data from the Collaborative Perinatal Project were used. The etiological factors of SGA were categorized into five groups: maternal, fetal, placental, environmental and physiological factors. Primary child outcomes included low IQ and growth restriction. A total of 8417 term infants were eligible. Compared with AGA, SGA children due to fetal factors had the highest risk of low IQ (aOR = 1.94, 95% CI: 1.45-2.59). SGA infants due to physiological factors had the highest risk of growth restriction (aOR = 6.04, 95% CI: 3.93-9.27). SGA children had a higher risk of growth restriction with the aOR ranging from 3.05 (95% CI: 2.36-3.96) to 5.77 (95% CI: 4.29-7.75) for the number of risk factors that the SGA infants had from 1 to 5. SGA children with any risk factor were associated with a higher risk of lower IQ with the aOR ranging from 1.59 (95% CI: 1.31-1.94) to 1.96 (95% CI: 1.50-2.55). SGA without the five types of etiologies was not associated with adverse child outcomes except for growth restriction (aOR = 3.82, 95% CI: 2.62-5.55). Term SGA of different etiologies may lead to different child health outcomes. Our study found that SGA of different etiologies may lead to different child health outcomes. Compared with AGA, SGA children due to fetal factors had the highest risk of low IQ. SGA infants due to physiological factors had the highest risk of growth restriction. SGA babies should not be treated the same. In the era of precision medicine, our findings may help pediatricians and parents better manage SGA babies according to different etiologies and the number of risk factors.

Association of Maternal Caffeine Consumption During Pregnancy With Child Growth

Greater caffeine consumption in pregnancy is associated with reduced birth size, but potential associations with childhood growth are unclear. To evaluate the associations of pregnancy caffeine and paraxanthine measures with child growth in a contemporary cohort with low caffeine consumption and a historical cohort with high caffeine consumption. The Environmental Influences on Child Health Outcomes cohort of the National Institute of Child Health and Human Development Fetal Growth Studies (ECHO-FGS; 10 sites, 2009-2013) was a pregnancy cohort with 1 child measurement between ages 4 and 8 years (follow-up in 2017-2019). The Collaborative Perinatal Project (CPP) was a pregnancy cohort (12 sites, 1959-1965) with child follow-up through 8 years (1960-1974). The current secondary analysis was conducted in 2021 and 2022. Concentrations of caffeine and its primary metabolite, paraxanthine, were quantified from plasma (ECHO-FGS) and serum (CPP) collected in the first trimester. Cut points for analyses were defined by quartiles in ECHO-FGS and quintiles in CPP. Child z scores for body mass index, weight, and height were evaluated, as well as fat mass index and percentage and obesity risk measured at 1 time between age 4 and 8 years in ECHO-FGS. In a secondary analysis of the CPP cohort, child z scores and obesity risk longitudinally through age 8 years were evaluated. In ECHO-FGS (median caffeine intake <50 mg/d), 788 children (mean [SD] age, 6.8 [1.0] years; 411 boys [52.2%]) of women in the fourth vs first quartile of plasma caffeine concentrations had lower height z scores (β = -0.21; 95% CI, -0.41 to -0.02), but differences in weight z scores were only observed in the third quartile (β = -0.27; 95% CI, -0.47 to -0.07). In CPP, beginning at age 4 years, 1622 children (805 boys [49.7%]) of women in the highest caffeine quintile group had lower height z scores than their peers from the lowest group, with the gap widening with each successive year of age (β = -0.16 [95% CI, -0.31 to -0.01] at 4 years; β = -0.37 [95% CI, -0.57 to -0.16] at 8 years). There were slight reductions in weight at ages 5 to 8 years for children in the third vs first caffeine quintile (β = -0.16 to -0.22). Results were consistent for paraxanthine concentrations in both cohorts. Intrauterine exposure to increasing levels of caffeine and paraxanthine, even in low amounts, was associated with shorter stature in early childhood. The clinical implication of reductions in height and weight is unclear; however, the reductions were apparent even with levels of caffeine consumption below clinically recommended guidelines of less than 200 mg per day.

Adverse childhood experiences and premature mortality through mid-adulthood: A five-decade prospective study

Adverse childhood experiences (ACEs) can have lasting effects on adult health and survival. In this study, we aimed to examine how the cumulative number and clustering patterns of ACEs were related to premature mortality. Participants (N=46 129; 45% White, 48% Black; 49·5% females) were offspring (born in 1959-1966) of participants enrolled in the Collaborative Perinatal Project (CPP). We conducted latent class analysis to examine the clustering patterns of ACEs assessed between children's birth and age seven. We also calculated the cumulative ACE scores of 13 individual ACEs. Cox regression models were used to examine the associations of ACE clusters and scores with risk of premature mortality from adolescence to mid-adulthood. At the start of the follow-up for mortality in 1979, participants were 12-20 years old (Mean=15·99 years), and within the 38-year follow-up through 2016, 3 344 deaths were observed among the 46 129 CPP offspring. Five latent classes of ACEs were identified. Compared to children with Low Adversity (48% of the sample), children in Family Instability (9%, HR=1·28, 95%CI 1·07-1·53), Poverty & Crowded Housing (21%, HR=1·41, 95%CI 1·24-1·62), and Poverty & Parental Separation (19%, HR=1·50, 95%CI 1·33-1·68) classes had higher hazards of premature mortality. In addition, children with 2 (HR=1·27, 95%CI 1·14-1·41), 3 (HR=1·29, 95%CI 1·15-1·45), and 4+ (HR=1·45, 95%CI 1·30-1·61) ACEs had higher hazards of mortality than those with no ACE. The clusters of Poverty & Crowded Housing (HR=1·28, 95%CI 1·10-1·49) and Poverty & Parental Separation (HR=1·23, 95%CI 1·02-1·48) remained associated with higher risk of premature mortality, beyond the cumulative risk of higher number of ACEs (HR=1·05, 95%CI 1·01-1·08). About half of the CPP cohort experienced early life adversities that clustered into four distinct patterns, which were associated with different risk of premature mortality. It is important to deepen our understanding of how specific clusters of childhood adversities affect health and premature mortality to better inform approaches to prevention and interventions.

Associations between maternal exposure to surgery or pregnancy exposure to fluorinated anesthetics and children's cognitive development and educational outcomes.

A transgenerational, epigenetic effect of anesthesia, particularly fluorinated agents, has been examined in rat models, but translation to humans is unclear. This study examined associations of maternal lifetime exposure to anesthesia and pregnancy exposure to fluorinated anesthetics with child cognitive and educational outcomes. Women in the US Collaborative Perinatal Project (1959-1963) reported lifetime history of surgeries, and the obstetric record captured pregnancy exposure to anesthetics. Children were followed to age 7 for global cognitive ability and educational outcomes (n=47,977). Logistic and linear regressions were adjusted for maternal and child birth years, race and ethnicity, smoking, education, parity, study site. Many outcomes were not associated with exposure to maternal surgery that occurred at various life stages. However, maternal surgery in early childhood was associated both with being in a special school or not in school (adj OR=1.42; 95% CI 1.02, 1.98) and with slightly better cognitive ability across childhood (e.g., WISC IQ (adj β=0.59; CI 0.13, 1.04) (especially among boys)). Maternal surgery in puberty was associated with slightly lower IQ (adj β= -0.42; CI -0.79, -0.05) and poorer spelling at age 7. Children's prenatal exposure to fluorinated anesthetics was associated with slightly better spelling ability (adj β = 1.20; CI 0.02, 2.38) but lower performance IQ at age 7 (only among boys, adj β=-1.97; CI -3.88, -0.06). This study shows inconsistent evidence of effects of maternal exposure to surgery or prenatal exposure to fluorinated agents on child developmental and educational outcomes Residual confounding by indication and socioeconomic status may explain observed associations.

High-risk Growth Trajectory Related to Childhood Overweight/Obesity and Its Predictive Model at Birth.

Childhood obesity increases the risk of chronic disease in adulthood. To construct an early predictive model for a growth trajectory that is highly related to childhood overweight/obesity. Prospective cohort study. Shanghai Birth Cohort (SBC) and US Collaborative Perinatal Project (CPP). A total of 848 mother-child pairs in the SBC (2013-2016) and 22 691 pairs in the CPP (1959-1965) with 2- and 7-year follow-up, respectively. A high-risk postnatal growth trajectory intimately associated with childhood overweight/obesity and its predictive model. We demonstrated that the shifts of postnatal body mass index (BMI) percentile had been completed around 1 year of age and identified a high-risk growth trajectory that was closely related to overweight/obesity [odds ratio 6.5 (95% CI 5.9, 7.2)] at 7 years old. Children with this trajectory presented with a consistent BMI around the 85th percentile after the age of 1 year. It could be recognized early after birth using a predictive model with 4 metabolites (tyrosine, glycine, octenoylcarnitine, and stearoylcarnitine), combined with sex, birth weight, and maternal prepregnancy BMI. The model had an area under the receiver operating characteristic curve of 0.869 (95% CI 0.779, 0.932), a sensitivity of 83.3% (95% CI 51.6%, 97.9%), and a specificity of 81.1% (95% CI 70.3%, 89.3%) in the validation data set. Children with postnatal high-risk growth trajectories were significantly associated with subsequent overweight/obesity at 7 years old. Metabolite profiles at birth combined with clinical measures were able to predict at-risk children before overweight/obesity occurrence.

Maternal Underweight and Obesity Are Associated with Placental Pathologies in Human Pregnancy.

Maternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies. Data from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro- and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex. Pregnancies complicated by maternalobesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriately mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term. Maternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.

Long-Term Mortality Implications of Maternal Weight Change in Pregnancy

ObjectivesHigh pregnancy weight gain is associated with greater postpartum weight retention; yet the long-term implications remain unknown. We examined associations of pregnancy weight change with mortality after ∼50 years of follow-up.MethodsThe Collaborative Perinatal Project (CPP) Mortality Linkage Study linked maternal participants in the CPP, a prospective pregnancy cohort (1959–1965), to the National Death Index and Social Security Death Master File for vital status through 2016 (n = 46,042). Total gestational weight change (gain or loss) in the index pregnancy (last CPP singleton pregnancy) was the difference in recorded delivery weight and self-reported pre-pregnancy weight. All-cause and cause-specific mortality associations with quintiles of gestational weight change were estimated using Cox regression adjusting for index pregnancy age, pre-pregnancy body mass index (BMI), race, parity, smoking, marital status, income, education, site, study year, prior chronic conditions, and gestational week at delivery.ResultsMajority of women (69%) had a healthy pre-pregnancy BMI and 46% were White and 45% were Black. Median (interquartile range) total gestational weight change was 9.5 kg (6.4–12.2), respectively; 2.5% lost weight in pregnancy. Over a median follow-up of 52 years (IQR 45–54), 38.9% of women died. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for mortality across quintiles 1 to 5 were 1.07 (95% CI 1.01–1.12), 1.03 (0.98–1.09), 1.00 (Reference), 1.01 (0.96–1.07), and 1.09 (1.03- 1.14), respectively. Compared to the middle quintile, HRs for the top four causes of death, cancer, cardiovascular disease, respiratory disease, and diabetes for the first quintile were 1.20 (0.99–1.46), 1.05 (0.96–1.15), 1.14 (0.96–1.37), and 0.92 (0.72–1.17), respectively; HRs for the fifth quintile were 1.19 (0.98–1.45), 1.14 (1.03–1.27), 0.95 (0.78–1.14), and 1.52 (1.20–1.92) respectively.ConclusionsThis study's novel findings extend the importance of healthy pregnancy weight gain beyond the pregnancy window to women's long mortality risk, particularly from cancer, cardiovascular disease, and diabetes.Funding SourcesThis work was funded by the Intramural Research Program of the NICHD.

Are there sex differences in fetal growth strategies and in the long-term effects of pregnancy complications on cognitive functioning?

Males and females have been proposed to have different prenatal growth strategies, whereby males invest more in fetal growth and less in placental development, leaving them more susceptible to early-life adversity. We tested predictions of this hypothesis using data from the National Collaborative Perinatal Project. Male newborns were heavier than females, but there was no difference in placental weight, adjusting for birthweight. Among infants born prior to 33 weeks, the difference in birthweight between males and females was greater among those who did not survive than among those who did, potentially reflecting a strategy whereby males maintained growth in the face of prenatal insults, while females adjusted growth. However, there was no significant difference in mortality between the sexes. Being born small-for-gestational age or very preterm (prior to 33 weeks) was associated with significantly reduced performance for most of the cognitive traits examined at 7 years, although maternal preeclampsia was associated with reduced performance in fewer traits. Generally, these effects of early-life adversity (poor fetal growth, prematurity, and preeclampsia) did not differ between the sexes. However, analyzing the sexes separately (rather than testing the interaction between sex and adversity) resulted in numerous spurious sex-specific effects, whereby the effect of early-life adversity appeared to be significant in one sex but not the other. Overall, we found little support for the hypothesis that males prioritize growth more than females, and that this makes them more susceptible to early-life adversity. Furthermore, our results show that analyzing the sexes separately, rather than testing the adversity by sex interaction, can be highly misleading.

Moving up but not getting ahead: Family socioeconomic position in pregnancy, social mobility, and child cognitive development in the first seven years of life

ObjectivesUnderstanding when and how socioeconomic position (SEP) influences cognitive development is key to reducing population inequalities in health and achievement. The objective of this study was to determine the unique association between prenatal family SEP and child cognitive development, and to determine whether marked postnatal social mobility was associated with improvements in child cognitive performance to age 7. MethodsData were from children enrolled in the US National Collaborative Perinatal Project (NCPP) (n = 28,761) during 1959–1965, a dataset large enough to observe marked mobility, which remains uncommon. Multivariable linear regression was used to examine the relationship between SEP (i.e., parental income, education, occupation) during gestation and cognitive performance at 8 months (Bayley Scales of Infant Development Mental Development Index) and at 7 years (Wechsler Intelligence Scale for Children). ResultsHolding demographic and perinatal factors constant, family SEP during gestation was not associated with cognitive performance at 8 months (B = −0.03, 95% CI: −0.07–0.01) but was positively associated with performance at 7 years even after accounting for SEP at 7 years (B = 1.28, 95% CI: 1.11–1.45). Children whose families experienced the most extreme upward mobility (from the lowest to highest income quartile) showed a 12 percentile increase in cognitive performance in the first 7 years of life. Those with the most extreme downward mobility (from the highest to lowest income quartile) still experienced an 8 percentile increase in cognitive performance in this interval. ConclusionsThe proportion of children in poverty today is similar to 1965 and intergenerational mobility has declined markedly. Prenatal SEP may contribute to inequalities in child cognitive performance that even extraordinary social mobility cannot erase. To optimize cognitive development across generations, current means-tested programs to support families with young children should be supplemented by universal approaches to ensure access to opportunity before young people become parents.