Effect of maternal and infant covariates on sibship correlation in birth weight

Birth weight on 12,644 singleton infants from 6,196 sibships born in Maryland between 1980 and 1984 were used to estimate the effects of nine maternal and infant covariates on the sibship correlation in birth weight. Assuming a homogeneous correlation across all families, the estimated intraclass correlation was 0.4664 (+/- 0.0099). This high sibship correlation makes it possible to predict, with reasonable accuracy, the birth weight of a child given information on previous sibs, as well as covariates on the mother and/or infant pertinent to a given pregnancy. The reduction in variance associated with incorporating information on the nine covariates used here was approximately equal to that obtained by conditioning on a single previous sib. Testing for heterogeneity in correlation among different groups of families showed that a crude measure of parity (first live birth vs. other), time between births, mother's marital status, and maternal age at the birth of the last child significantly influenced the sibship correlation in birth weight.     

Predicting intrauterine growth retardation in sibships while considering maternal and infant covariates

Data on 6,210 full-term sibships (gestational age greater than 36 weeks) reconstructed from birth certificates registered in Maryland between 1980 and 1984 were used to study sibship aggregation and recurrence risk of intrauterine growth retardation (IUGR) while considering maternal and infant covariates. In this study, IUGR was defined as being below the 10th percentile for race-, sex-, and gestational-age-specific birth weight based on all births registered in Maryland during 1984. Maternal factors (race, age at delivery, marital status, amount of prenatal care, concurrent illnesses, and complications during pregnancy) and infant factors (congenital malformations and first born child or not) were used as covariates in a modified logistic regression model which allowed correlation among sibs. First-time mothers who were under age 30 years, unmarried, received too little prenatal care, or had any reported pregnancy complications were at high risk of delivering an infant with IUGR. Even given the effects of these risk factors, however, there was a significant correlation in risk among full sibs (r = .237 +/- .028), which, combined with information on risk factors, can be used to estimate sibling recurrence risk for IUGR.     

Contrasting effects of maternal fertility and birth rank on the occurrence of neural tube defects.

The relationships between the occurrence of anencephalus and spina bifida, sibship size and birth rank were examined, using linked records for births in British Columbia. Comparison of 414 sibships in which at least one infant had a neural tube defect with 1362 randomly chosen unaffected sibships showed that the affected sibships were larger. There were both more births than expected after the affected birth, and shorter intervals between births before the affected birth. Within sibships, the risk of anencephalus or spina bifida decreased strongly with increasing birth rank. No associations were seen with maternal age at first birth.     

Likelihood-ratio affected sib-pair tests applied to multiply affected sibships: issues of power and type I error rate

"All-pairs" likelihood-ratio analyses, such as those performed by MAPMAKER/SIBS [Kruglyak and Lander, 1995], require that a sibship containing N affected siblings be split into N(N - 1)/2 sibships, each containing a different pair of affected sibs, before analysis. Each of these N(N - 1)/2 sibships may also contain the other affected sibs from the original sibship, coded as unaffected, to infer missing parental genotypes, as is done automatically in MAPMAKER/SIBS. Then, the use of the same individuals both as affecteds to test for linkage and, elsewhere, as unaffecteds to infer missing parental genotypes leads to negative correlations in the estimated identity by descent sharing among affected pairs from the same original multiplex sibship. This gives a conservative test of linkage, even when no downweighting is applied. Conversely, if the other affected sibs from the original sibship are omitted, the correlations are positive and the linkage test is anticonservative in the absence of weighting. True type I error probability also depends on marker informativity, typed parents, number of affected sibs included in the analysis, and the weighting scheme. This suggests the use of simulation, rather than asymptotic theory, to assess significance levels. The power of multiplex sibships relative to affected pairs increases with increasing phenocopy percentage, but the presence of typed unaffected sibs improves the relative power of multiplex sibships greatly only when penetrance is high. It was found that the 2/N weighting proposed by Suarez and Hodge [1979] increased power over an unweighted analysis in many situations, provided significance levels were adjusted appropriately by simulation.     

Parity specific perinatal mortality. A longitudinal study based on sibships

Perinatal mortality in sibships has been examined using the Medical Birth Registry of Norway. Using linear logistic regression, parity specific perinatal mortality in the period 1967-1981 has been analysed, controlling simultaneously for maternal age, year of birth and survival of earlier births. The risk of a perinatal loss was increased by a factor of up to 6.0 following one earlier perinatal loss, and with three earlier losses the increase was 17.0. The general reduction in mortality between the different five year periods varied according to parity and maternal age. No secular reduction in risk, however, was demonstrated in sibships where the first birth died perinatally; for some subgroups of women the risk actually increased between the first and the second five year period. The effect of maternal age changed with parity, being strong in the first birth order, but of no effect either for the third or the fourth birth orders once the perinatal survival of earlier births was controlled for. This study shows the need to take heterogeneity of risk between women into account in studies of perinatal loss; the overall improvement in perinatal mortality does not apply to every woman. As care improves, perinatal losses become less and less random, demonstrated by increased risks of recurrence.     

Estimating familial aggregation while adjusting for covariates. Application to pulmonary function data from black and white sibships.

Although crude correlations are useful in family studies, some adjustment for effects of risk factors that vary both within and among families if often needed. A linear model for estimating sibship correlations while simultaneously considering height, age, race, sex, ascertainment, and smoking status was used on pulmonary function data on 1-second forced expiratory volume (FEV1) and the natural logarithm of the ratio of FEV1 to forced vital capacity (lnFEV%) from 402 adults in 152 white sibships and 172 adults in 59 black sibships. Crude correlations of .271 +/- .048 (FEV1) and .342 +/- .047 (lnFEV%) decreased significantly to .206 +/- .048 and .231 +/- .048, respectively, after adjustment. For black and white sibs, adjusted intraclass correlations, although not statistically different, were .153 +/- .089 and .225 +/- .055 (FEV1), respectively, and were .103 +/- .088 and .275 +/- .054 (lnFEV%), respectively, suggesting that pulmonary function may aggregate more strongly among whites. This analysis illustrates how risk factor adjustment can be readily incorporated into familial correlation studies.     

A generalized estimating equations approach to linkage analysis in sibships in relation to multiple markers and exposure factors

We describe a multiple regression approach to nonparametric linkage analysis in sibships incorporating multiple genetic loci, environmental covariates, and interactions. The covariance in trait residuals between sib pairs is treated as the dependent variable, regressed upon identical-by-descent sharing probabilities and interaction effects, using generalized estimating equations to allow for the correlations among multiple sib pairs within a sibship. Individual covariates can also be introduced in the model for the trait means. An application to the GAW11 simulated data revealed linkage with each of the four simulated loci, as well as gene x environment interactions of E1 with loci C and D and gene x gene interactions among the cluster of loci A, B, and D.     

Families with a perinatal death: is there an association between the loss and the birthweight of surviving siblings?

Our objective was to study birthweight among surviving siblings in families with and without a perinatal loss, and to evaluate whether different causes of death were associated with the results. Data were for 1967-98 from the Norwegian Medical Birth Registry. Births were organised with the mother as the observation unit through the personal identification number, providing sibship files. We analysed 550 930 sibships with at least two singletons, 208 586 sibships with at least three singletons and 45 675 sibships with at least four singleton births. We compared mean birthweight and gestational age between infants in sibships with and without a perinatal loss, total losses and the different causes of death. Surviving siblings in families with a perinatal loss had significantly lower mean birthweights than their counterparts in unaffected families, after adjusting for gestational age, interpregnancy interval, time period and marital status. An exception was found when cause of death was a birth defect, when growth retardation among surviving siblings was not found on average. We conclude that families who have lost an infant because of a birth defect do not appear to have an increased risk of adverse birth outcome associated with growth restriction.     

Differences in birth weight by sex using adjusted quantile distance functions

Herein, we report results from a study of birth weight distribution among boys and girls born in Norway in 2008. As our primary interest was to detect differences in the variability between the two sexes, we used the quantile distance function to describe the difference between two distribution functions. We used an adjusted version of the quantile function to look into the relation of sex differences in birth weight conditioned on maternal age, gestational age, preeclampsia, maternal diabetes type 1, maternal smoking status, and parity. At term (?37 weeks of gestation), boys showed a greater variability in birth weight than did girls, and these differences were maintained in the adjusted model. We also found that maternal age and maternal smoking habits influenced both sexes equally, whereas gestational age, preeclampsia, maternal diabetes type 1, and parity influenced one sex more than the other. The adjusted quantile distance function proved efficient in analyzing and demonstrating how covariates influence sex differences in birth weight. Copyright © 2013 John Wiley & Sons, Ltd.     

Families with birth defects: is birth weight of nonmalformed siblings affected?

Infants with congenital malformations have on average lower birth weight than do infants without malformations. Preterm delivery and low birth weight are known to recur in sibships. The aim of the study was to compare the birth weight of siblings to malformed infants with the birth weight of infants in families without malformed infants. Data were from the Medical Birth Registry in Norway from 1967 to 1998. Births were linked to their mothers through the unique personal identification number, providing sibship files with the mother as the observation unit. The study was based on 551,478 mothers with at least two singleton infants and 209,423 mothers with at least three singletons. The authors grouped the families according to whether and in which birth order an infant had a registered congenital malformation and compared birth weight and gestational age between infants of the same birth order in families with malformations and without. Overall, in families where one or two infants had a congenital malformation, the crude and adjusted mean birth weight of nonmalformed siblings did not differ from that of infants in unaffected families, whereas it was significantly reduced for the malformed infant itself. We conclude that reduced birth weight associated with congenital anomalies is specific to the affected pregnancy.     

Cesarean section and breastfeeding outcomes in an Indigenous Qom community with high breastfeeding support

Background and objectivesCesarean section may lead to suboptimal breastfeeding outcomes, though evidence has been mixed. Factors, such as premature birth, birth weight and maternal age may independently increase risk of cesarean and hinder breastfeeding initiation, while maternal preferences, support and sociostructural barriers may influence breastfeeding practices beyond the immediate postpartum period.MethodologyWe assessed impacts of cesarean section and gestational factors on breastfeeding duration among Indigenous Qom mothers in Argentina who have strong traditional breastfeeding support. We modeled transitions from exclusive breastfeeding to complementary feeding and from complementary feeding to full weaning in a Bayesian time-to-event framework with birth mode and gestational covariates (n = 89 infants).ResultsEstimated median time to full weaning was 30 months. Cesarean-delivered babies were weaned an average of 5 months later adjusting for gestational age, maternal parity and infant sex. No factors were associated with time-to-complementary feeding, and time-to-complementary feeding was not associated with time-to-full weaning.Conclusions and implicationsAmong Indigenous Qom mothers in Argentina, cesarean section was not associated with suboptimal breastfeeding outcomes. Although some Qom mothers do experience early breastfeeding problems, particularly following first birth, problems are not more frequent following cesarean delivery. Traditional postpartum kin and community support during prolonged postpartum periods may be instrumental in helping mothers to overcome early breastfeeding problems due to cesarean or other risk factors.     

The relationship between maternal skinfold thickness, smoking and birthweight in black and white women

Summary. A prospective study was conducted in a sample of 1491 multiparous women to ascertain whether the relationship between maternal tricep skinfold thickness and infant birthweight is modified by smoking status and whether the relationship is different in white and black infants. Maternal tricep skinfold thickness measured at midpregnancy was a significant predictor of infant birthweight in both white and black infants after adjusting for gestational age at birth, maternal height, maternal age, parity, alcohol consumption and sex of the infant. However, maternal tricep skinfold thickness was a better predictor of birthweight in smokers compared with nonsmokers. Both white and black women with tricep skinfold thickness below the sample mean had lower infant birthweight than women with tricep skinfold at or above the mean, after adjusting for gestational age at birth, but the difference was greater in smokers (198 g for white and 221 g for black infants) than in nonsmokers (124 g for white and 120 g for black infants). These results suggest that maternal subcutaneous fat measured by tricep skinfold thickness has a greater effect on infant birthweight in smokers compared with nonsmokers, with similar effects in white and black infants.     

Secondhand smoke exposure during pregnancy and infantile neurodevelopment

During prenatal development, the nervous system may be more susceptible to environmental toxicants, such as secondhand smoke. The authors assessed the effects of prenatal and postnatal secondhand smoke exposure on the neurodevelopment of 6-month infants. The subjects were 414 mother and infant pairs with no medical problems, taken from the Mothers' and Children's Environmental Health study. Prenatal and postnatal exposures to secondhand smoke were determined using maternal self-reports. Examiners, unaware of exposure history, assessed the infants at 6 months of age using the Bayley Scales of Infant Development. Bayley scores were compared for secondhand smoke exposed and unexposed groups after adjusting for potential confounders. Multiple logistic regression analysis was carried out to estimate the risk of developmental delay posed by SHS exposure. The multivariate model included residential area, maternal age, pre-pregnancy body mass index, education, income, infant sex, parity, birth weight, and type of feeding. After adjusting for covariates, secondhand smoke exposure during pregnancy was found to be related to a decrease in mental developmental index score, but not to a decrease in psychomotor developmental index score. In addition, secondhand smoke exposure during pregnancy was found to increase the risk of developmental delay (mental developmental index score ≤85) at 6 months. This study suggests that the infants of non-smoking women exposed to secondhand smoke are at risk of neurodevelopmental delay.     

Association between ambient air pollution and birth weight in São Paulo, Brazil

Objectives: Previous studies have implicated air pollution in increased mortality and morbidity, especially in the elderly population and children. More recently, associations with mortality in infants and with some reproductive outcomes have also been reported. The aim of this study is to explore the association between exposure to outdoor air pollution during pregnancy and birth weight. Design: Cross sectional study using data on all singleton full term live births during a one year period. For each individual birth, information on gestational age, type of delivery, birth weight, sex, maternal education, maternal age, place of residence, and parity was available. Daily mean levels of PM₁₀, sulphur dioxide, nitrogen dioxide, carbon monoxide, and ozone were also gathered. The association between birth weight and air pollution was assessed in regression models with exposure averaged over each trimester of pregnancy. Setting: São Paulo city, Brazil. Results: Birth weight was shown to be associated with length of gestation, maternal age and instruction, infant gender, number of antenatal care visits, parity, and type of delivery. On adjusting for these variables negative effects of exposure to PM₁₀ and carbon monoxide during the first trimester were observed. This effect seemed to be more robust for carbon monoxide. For a 1 ppm increase in mean exposure to carbon monoxide during the first trimester a reduction of 23 g in birth weight was estimated. Conclusions: The results are consistent in revealing that exposure to air pollution during pregnancy may interfere with weight gain in the fetus. Given the poorer outlook for low birthweight babies on a number of health outcomes, this finding is important from the public health perspective.     

The effect of birth interval on perinatal survival and birth weight

Although the effect of a short birth interval on the first child in a pair has received attention in the literature, the effect on the second child has received less. In this article the authors investigate the complex set of relationships between birth interval, maternal age and parity, and their effects on the birth weight and survival of the later-born child.The data consist of 12,995 singleton births to women of parity two or higher during1977 and 1978 in a single hospital. The outcome of the previous pregnancy is controlled by restricting the analysis to women whose previous pregnancy ended in a live infant who is still living at the time of the index birth.The effect of birth interval on birth weight and on survival is examined simultaneously(via logistic regression), with the effects of maternal age and parity. The risks of adverse outcomes as a function of birth interval are estimated by adjusted odds ratios.After adjusting for maternal age and parity, interval was found to be an important precursor of both perinatal mortality and low birth weight. At all levels of maternal age and parity, babies born during a 9- to 12-month birth interval are at greater risk of low birth weight and/or perinatal mortality than babies born after a longer birth interval.     

Efficient use of siblings in testing for linkage and association

Tests of linkage and association between a disease and either a candidate gene or marker allele can be based on sibships with at least one affected and one unaffected sibling. However, specialized techniques are required to account for within-sibship correlation if some sibships contain more than one affected or more than one unaffected sib. In this paper, we propose Within Sibship Paired Resampling (WSPR), a technique that is designed to test the null hypothesis of no linkage or no association, even when sibships contain variable numbers of sibs. One repeatedly generates data subsets based on randomly sampling one affected and one unaffected sibling from each sibship, and each subset is analyzed individually. Then, evidence is combined by averaging results across these resampled data sets, applying a variance expression that implicitly accounts for the correlation among siblings. While the general WSPR procedure allows for numerous testing strategies, we describe two in detail. Simulation results for scenarios with varying degrees of population stratification demonstrate good power for the WSPR testing methods compared to the sib TDT (S-TDT) and the sibship disequilibrium test (SDT).     

The Maximum-Likelihood-Binomial method revisited: a robust approach for model-free linkage analysis of quantitative traits in large sibships

Model‐free linkage analysis methods, based on identity‐by‐descent allele sharing, are commonly used for complex trait analysis. The Maximum‐Likelihood‐Binomial (MLB) approach, which is based on the hypothesis that parental alleles are binomially distributed among affected sibs, is particularly popular. An extension of this method to quantitative traits (QT) has been proposed (MLB‐QTL), based on the introduction of a latent binary variable capturing information about the linkage between the QT and the marker. Interestingly, the MLB‐QTL method does not require the decomposition of sibships into constituent sibpairs and requires no prior assumption about the distribution of the QT. We propose a new formulation of the MLB method for quantitative traits (nMLB‐QTL) that explicitly takes advantage of the independence of paternal and maternal allele transmission under the null hypothesis of no linkage. Simulation studies under H₀ showed that the nMLB‐QTL method generated very consistent type I errors. Furthermore, simulations under the alternative hypothesis showed that the nMLB‐QTL method was slightly, but systematically more powerful than the MLB‐QTL method, whatever the genetic model, residual correlation, ascertainment strategy and sibship size considered. Finally, the power of the nMLB‐QTL method is illustrated by a chromosome‐wide linkage scan for a quantitative endophenotype of leprosy infection. Overall, the nMLB‐QTL method is a robust, powerful, and flexible approach for detecting linkage with quantitative phenotypes, particularly in studies of non Gaussian phenotypes in large sibships. Genet. Epidemiol. 35:46–56, 2011. © 2010 Wiley‐Liss, Inc.     

Infant Mortality Among Arab-Americans: Findings from the Arab-American Birth Outcomes Study

Arab-Americans (AAs) have lower risk of preterm birth relative to Non-Arab Whites. This has been attributed to lower likelihood of birth out of wedlock, maternal tobacco use during pregnancy, and foreign maternal birthplace among AAs. We were interested in understanding the roles of these and other demographic factors in the etiology of infant mortality among this group. Using data about all live, singleton births between 1989 and 2005 in the state with the highest proportion of AAs in the US, we calculated infant mortality (death prior to 1 year of life) for AAs and Non-Arab Whites. To clarify the etiology of potential differences in infant mortality, we also assessed infant mortality sub-categories, including neonatal mortality (death prior to 28 days of life) and post-neonatal mortality (death between 28 and 365 days of life). We fit trivariable and multivariable logistic regression models adjusted for explanatory covariates to assess each covariate’s contributions to the relation between ethnicity and infant mortality. AAs had a lower infant mortality rate (4.7 per 1,000 live births) than non-Arab Whites (5.6 per 1,000 live births), overall (odds ratio = 0.84, 95 % confidence interval: 0.74–0.96). In trivariable models, adjusting for marital status, maternal tobacco consumption during pregnancy, and maternal birthplace each separately attenuated the bivariate ethnicity-mortality relation to non-significance. Our findings suggest that lower risk of infant mortality among AAs relative to non-Arab Whites may be explained by differences in demographic characteristics and parental behavioral practices between them.     

Total body iron in HIV-positive and HIV-negative Zimbabwean newborns strongly predicts anemia throughout infancy and is predicted by maternal hemoglobin concentration

One method of preventing postnatal iron deficiency is to ensure that the infant is born with a full endowment of iron. We calculated total body iron at birth (TBI) as the sum of hemoglobin iron (HbI) and body storage iron (BSI) in 2021 Zimbabwean newborns, and related TBI to subsequent anemia from 3 to 12 mo of age and to maternal and fetal characteristics. We estimated the mean +/- SD TBI to be 210 +/- 41 mg. There was an inverse dose-response association between TBI quartile and risk of anemia at all postnatal ages. The odds of anemia were >3 times higher in the lowest vs. highest TBI quartile (P < 0.001) at 6, 9 and 12 mo. Preterm birth and parity were not independently associated with TBI after controlling for birthweight. The predicted change in TBI per kilogram increase in birthweight was 68 mg (P < 0.001). After adjusting for birthweight, TBI increased by 25 mg with each 10-y decrement in maternal age (P = 0.033). Maternal hemoglobin was a strong linear predictor of TBI (P < 0.001). Maternal and infant HIV infection, especially among girls, was associated with apparently greater estimated TBI. We speculate that this is actually an artifact, explained by an inflammatory response, and that there was a sex difference in the response. We conclude that we can make satisfactory estimates of TBI and that the assumptions required for this approach are sufficiently robust to lead to an acceptable estimate of the prenatally acquired iron endowment. Babies born with low birthweight or to mothers with low hemoglobin are born with less TBI, which confers a substantially greater risk of anemia from 3 to 12 mo of age.     

Labor Epidural Anesthesia, Obstetric Factors and Breastfeeding Cessation

Breastfeeding benefits both infant and maternal health. Use of epidural anesthesia during labor is increasingly common and may interfere with breastfeeding. Studies analyzing epidural anesthesia’s association with breastfeeding outcomes show mixed results; many have methodological flaws. We analyzed potential associations between epidural anesthesia and overall breast-feeding cessation within 30 days postpartum while adjusting for standard and novel covariates and uniquely accounting for labor induction. A pooled analysis using Kaplan–Meier curves and modified Cox Proportional Hazard models included 772 breastfeeding mothers from upstate New York who had vaginal term births of healthy singleton infants. Subjects were drawn from two cohort studies (recruited postpartum between 2005 and 2008) and included maternal self-report and maternal and infant medical record data. Analyses of potential associations between epidural anesthesia and overall breastfeeding cessation within 1 month included additional covariates and uniquely accounted for labor induction. After adjusting for standard demographics and intrapartum factors, epidural anesthesia significantly predicted breastfeeding cessation (hazard ratio 1.26 [95 % confidence interval 1.10, 1.44], p < 0.01) as did hospital type, maternal age, income, education, planned breastfeeding goal, and breastfeeding confidence. In post hoc analyses stratified by Baby Friendly Hospital (BFH) status, epidural anesthesia significantly predicted breastfeeding cessation (BFH: 1.19 [1.01, 1.41], p < 0.04; non-BFH: 1.65 [1.31, 2.08], p < 0.01). A relationship between epidural anesthesia and breastfeeding was found but is complex and involves institutional, clinical, maternal and infant factors. These findings have implications for clinical care and hospital policies and point to the need for prospective studies.