We use duration models on a well-known historical data set of more than 15,000 families and 60,000 births in England for the period 1540–1850 to show that the sampled families adjusted the timing of their births in accordance with the economic conditions as well as their stock of dependent children. The effects were larger among the lower socioeconomic ranks. Our findings on the existence of parity-dependent as well as parity-independent birth spacing in England are consistent with the growing evidence that marital birth control was present in pre-transitional populations.The online version of this article (doi:10.1007/s13524-017-0556-4) contains supplementary material, which is available to authorized users. The existence of marital birth control before the fertility transition of the nineteenth century is a core question among historical demographers. Early statistical analyses have shown an overall absence of marital birth control in pre-transitional England Wilson  and in opreventive check or vice behavior  to show that parity-independent and parity-dependent birth spacing were practiced among the sampled families in the three centuries that preceded England’s historical fertility transition. Previous studies, which used variation in English vital statistics  from a sample of 404 parish registers . This restriction reduces the number of families to 80,198. Next, we require that the wife had at least two recorded births and that her age was known, between the ages of 15 and 45, at the time of her deliveries. The lower end of the age interval comes naturally: the Church of England did not allow women below the age of 15 to marry, and this is confirmed by the data. The rationale for the upper end is that the sampled women rarely conceived children after age 45 due to menopause. Moreover, the restriction mitigates the potential problem that births recorded as occurring after age 45 may be wrongly recorded.The sample is then further restricted to families for which wife’s age at marriage can be observed and dates of births (or baptisms) of all recorded family children exist. Prenuptially conceived children are included; however, birth intervals shorter than 40 weeks, which stem from either premature births or potential data entry errors, are excluded. These restrictions ultimately leave us with a total of 15,845 families and 62,223 birth events.The summary statistics are reported in Table In addition to the aforementioned demographic data, our analysis also uses statistics concerning national real wages, crude death rates, and temperatures. Our key explanatory variable when testing for the existence of preventive checks  is living standards measured by national real wages. The real wage series employed in the main analysis is provided by Clark . The wagPanel a of Fig. Any analysis that considers birth spacing as a measure of birth control has to address a number of confounding factors that are linked to biology. The key suspects are undernourishment and climatic conditions, both of which can influence the ability to conceive  marriage; (2) first conception (“starting”); (3) conception following the previous birth (“spacing”); and 4) last conception (“stopping”), for which the date of a conception is set 40 weeks prior to the date of a birth. last conOf note is that 90 % of our sampled birthdates are inferred from baptism dates. Previous studies have shown that most children were baptized within one month of birth . To capture the possibly nonlinear association between fecundity and age, we include a quadratic polynomial of maternal age that varies during the birth interval. We also account, again in a time-varying fashion, for the death of the previous child before the next conception. Finally, as is common in the literature, we include a binary variable for the last birth interval to capture a failed attempt to stop having children  is the baseline hazard function where t is time, measured in days;  are socioeconomic and demographic covariates; and W is the standardized (zero mean and unit standard deviation) time-varying (yearly) real wage . The estimates indicate a positive and statistically significant correlation between the real wage and the protogenesic interval. The magnitude of the effects on the events of marriage and starting are very similar: a 1 standard deviation increase in the real wage accelerates time to marriage and to first conception by 23 % and 25 %, respectively. This is consistent with the conventional view that marriage historically marked the onset of a family .The estimates in column 3 present evidence of pretransitional, parity-independent birth spacing, establishing that an increase in real wages accelerates the timing of the next conception. The magnitude of the impact of the real wage is also economically significant: a 1 standard deviation increase in the real wage accelerates the timing of the next conception by approximately 10 %.Turning to the stopping specification (column 4), we find no statistically significant impact of real wages on the hazard of the last conception. The effect remains statistically insignificant when we consider starting ages other than 15 for the event of stopping and when we split the sample by 50-year subperiods (not reported). These results are perhaps unsurprising: because real wages are largely nontrending across the period under observation, short-term variations in real wages are likely to cancel out over the course of a family life cycle, leaving little room for wages at any point in time to substantially affect the timing of the last birth.In summary, our analyses establish that falling living standards captured by lower real wages led not only to significantly later marriages but also to longer birth intervals within marriage. In our robustness analyses, we explore the impact of some key confounding factors to rule out the possibility that the spacing effects we observe are positive checks rather than preventive checks.To shed light on the role of socioeconomic factors in historical birth patterns, we subdivided our sampled families into income groups using a categorization proposed by Clark and Cummins . Clark aMore interestingly, looking at birth spacing, we find that poorer families had longer birth intervals on average than richer ones: column 3 shows that all six occupational groups included in the model have significantly shorter birth intervals (higher hazard ratios) compared with the reference group (laborers). In particular, we find that the coefficients for the richest groups  are statistically different from the coefficients of husbandmen and craftsmen; the difference between husbandmen and craftsmen is not statistically significant. Therefore, birth intervals appear to decrease with wealth.coitus interruptus may also explain the different patterns of birth spacing  and the attempt to replace the deceased child.Interestingly, socioeconomic differences also apply in the case of stopping. Column 4 establishes that, on average, laborers stopped later than their more-affluent counterparts and that the gentry were more likely to stop earlier. Husbandmen, craftsmen, traders, and merchants also stopped significantly earlier than laborers. These results are conditional on the mother’s age at marriage, her age at the last birth, and the family size. In fact, we find that a larger family size was associated with a later time of stopping. Therefore, differences in sterility associated with differences in the age at marriage or family size cannot explain the differences in stopping practice across occupational groups. The fact that the rich had more surviving offspring than the poor, as demonstrated by Clark and Hamilton  and BobeLiteracy among wives is also associated with shorter birth intervals and earlier stopping age, even after we control for socioeconomic status. Perhaps literate individuals from the lower socioeconomic ranks imitate the fertility patterns of their higher socioeconomic counterparts. Moreover, couples of low fecundity, captured by a relatively large protogenesic interval, had (as expected) significantly larger birth intervals than couples of high fecundity. Also, the group of couples that gave birth to children within 40 weeks of marriage (which includes couples that conceived their firstborn before marriage) had an overall lower hazard of subsequent births. The latter finding seemingly contradicts the suggestion made by Wrigley et al. :422 in tLast, as documented in previous studies, we find that the last birth interval was significantly larger, on average, than the previous intervals. This finding is consistent with the idea that the last birth was sometimes a failed stopping attempt.birth order. The coefficient for birth order  of the mother during the interval. Interestingly, we find that after we account for family heterogeneity, the impact of child death on the successive birth interval increases in size. This finding suggests that unobserved heterogeneity at family level is correlated with child death and estimates not accounting for family heterogeneity provide biased estimates.Column 2, instead, reports the results when we account for heterogeneity among the sampled couples, stratifying by family and quarter-century. We stratify also by quarter-century to allow the baseline hazard to vary over time.The impact of the real wage on the spacing of births remains highly significant also in the specifications including parity dummy variables. This leaves an important question: Does the effect of wages on births vary with parity? The underlying hypothesis here is that the decision to postpone a birth during hard times may be exacerbated by the presence of other dependent children. We test this hypothesis by interacting the real wage with the parity fixed effects. As shown in column 2 of Table It is also possible to quantify the effects of the real wage and of parities in terms of time. Consider the baseline estimate with parity fixed effects and stratification by family as in column 2 of Table Note that the mechanical association between parity and the mother’s age at conception could affect the parity fixed-effect estimates. Moreover, for high parities, parity might be positively correlated with fecundity , the estimated impact of the real wage on birth intervals remains highly significant both statistically and economically. Thus, the estimated effect of aggregate wages on the hazard of births within families cannot be attributed to secular variations across quarter-centuries. Overall, these specifications indicate that the qualitative results cannot be attributed to sample selection bias.permanent migration by including a dummy variable indicating those husbands and wives who had a missing birth or death date, and we account for temporary migration by excluding birth intervals lengthy enough to potentially conceal unobserved births. Furthermore, we also follow Ruggles  if the husband and wife both have missing birth/baptism dates but recorded death/burial dates. Furthermore, we define a couple as an emigrant couple  if the husband and wife both have missing death/burial dates but recorded birth/baptism dates. Table Low real wages may induce couples to temporarily leave their parish of residence in search of work. If they give birth and baptize a child while living outside their home-parish, these births will go unobserved in our data and instead appear as an extended birth spacing interval. We address this issue by excluding intervals that are comparatively long. In column 3 of Table Ruggles  pointed Is what we observe a biological mechanism rather than deliberate spacing behavior? Two potentially confounding biological factors are undernourishment and climatic conditions, as measured by air temperatures, both of which have been shown to impact fertility


Multiple regression analysis was used to identify independent maternal predictors of neonatal size, and the mediating role of neonatal head girth in these associations. Pelvic dimensions displaced maternal BMI as a predictor of birth weight, explaining 11.6% of the variance. Maternal conjugate and inter-spinous diameters predicted neonatal length, thorax girth and head girth, whereas inter-cristal diameter only predicted neonatal length. Associations of pelvic dimensions with birth length, but not birth weight, were mediated by neonatal head girth. Pelvic dimensions predicted neonatal size better than maternal BMI, and these associations were mostly independent of maternal height. Sensitivity of fetal growth to pelvic dimensions reduces the risk of cephalo-pelvic disproportion, potentially a strong selective pressure during secular trends in height. Selection on fetal adaptation to relatively inflexible components of maternal phenotype, rather than directly to external ecological conditions, may help explain high levels of growth plasticity during late fetal life and early infancy.Patterns of fetal growth predict non-communicable disease risk in adult life, but fetal growth variability appears to have a relatively weak association with maternal nutritional dynamics during pregnancy. This challenges the interpretation of fetal growth variability as ‘adaptation’. We hypothesized that associations of maternal size and nutritional status with neonatal size are mediated by the dimensions of the maternal pelvis. We analysed data on maternal height, body mass index (BMI) and pelvic dimensions  and neonatal gestational age, weight, length, thorax girth and head girth ( There is compelling evidence that growth patterns in early life predict diverse components of health or disease risk in later life, as summarized in the ‘developmental origins of adult health disease’ (DOHaD) hypothesis . Classicin utero to maternal famine during the Dutch Hunger Winter, in 1944–45 . Written consent was obtained from each individual, and ethical approval was granted by the IMIP Ethics Committee.+-born.Since previous work in this cohort has already shown that adolescent mothers have smaller pelvic dimensions , the inc2) calculated. In the newborn, anthropometric measurements of weight, length and girths of the thorax and head were obtained. All maternal and infant measurements were taken within 24 h of delivery.Clinic pelvimetry was carried out by two trained researchers using a Collin pelvimeter, with duplicate measurements taken. External pelvic measurements included the conjugate diameter (distance between pubic symphysis and spinous process of the 5th lumbar vertebra), the intercristal diameter (maximum width across iliac crests), and the interspinous diameter (distance between anterior superior iliac spines). Maternal weight and height were measured and BMI  or nutritional status (BMI) with neonatal size, and the extent to which such associations were mediated by maternal pelvic dimensions. Initial models included only single pelvic dimensions, while the final model included all three dimensions. Additional models tested whether associations between maternal pelvic dimensions and neonatal length or weight were mediated by neonatal head girth. All models were adjusted where relevant for birth order and offspring sex.2, ranging from 16 to 42 kg/m2 and average birth weight was 3150 g, ranging from 2000 to 4350 g. There were 116 male and 108 female offspring.A description of the sample of 224 mother-infant dyads is given in r = 0.06–0.21), while BMI showed higher correlations (r = 0.47–0.68). The pelvic dimensions were inter-correlated with coefficients of 0.49–0.67. Maternal height was correlated with birth length and weight, but not thorax or head girth, while maternal BMI was only correlated with birth weight. Among infants, birth size was positively correlated with gestational age and every component of birth size was correlated with all others (r = 0.56–0.75). There was no significant association by ANOVA of birth order with maternal height, BMI or pelvic dimensions, nor with any component of neonatal size. Second-born and third+-born offspring were 133 g (95% CI–68 335) and 97 g (95% CI–100 293) heavier, respectively, compared to first-born offspring. Offspring sex was not associated with any neonatal or maternal trait, and was not considered in subsequent regression models.+-born status was significant only in the birth weight model that included all three pelvic dimensions. Taking any such birth order associations into account, maternal BMI predicted birth weight, but this association disappeared if any pelvic dimension was added to the model. In the combined model, inter-spinous and inter-cristal diameters remained independent predictors of birth weight, and together they explained 11.6% of the variance in birth weight. For birth length, maternal BMI was negatively associated, but not significantly so. When pelvic dimensions were incorporated, each was an independent predictor of birth length, and the inverse association of maternal BMI was now significant or nearly so. In the combined model, no individual pelvic dimension predicted birth length, but the negative association with maternal BMI remained significant. For neonatal thorax and head girth, the conjugate and inter-spinous diameter were predictors in simple models, but in the combined model none was significant.Maternal BMI was strongly correlated with pelvic dimensions, whereas maternal height was more weakly associated with conjugate and inter-cristal diameters. Maternal height and BMI were each weak predictors of birth weight, but the only other neonatal outcome predicted by maternal size was length, predicted by maternal height. In contrast, maternal conjugate and inter-spinous diameters predicted all four components of neonatal size, while the inter-cristal diameter predicted birth weight and head girth. When these analyses were combined, pelvic dimensions displaced maternal BMI as a predictor of birth weight, explaining 11.6% of the variance and were associated with birth length independent of maternal height. Associations of pelvic dimensions with birth length or thorax girth were mediated by neonatal head girth, whereas for birth weight, pelvic dimensions remained predictors independent of head girth.These findings indicate that in this population (a) maternal pelvic dimensions account for associations of maternal BMI with neonatal weight and this is independent of maternal height, and (b) head girth and body weight appear to be the key components of neonatal size associated with maternal pelvic dimensions.In turn, these findings contribute to debate regarding the exact role of maternal/fetal nutrition in shaping long-term NCD risk, and the role of adaptation in this context. The finding that maternal BMI is strongly correlated with pelvic dimensions suggest that this component of maternal phenotype may not relate only to adiposity or lean mass, as widely assumed, but also to skeletal dimensions of relevance to fetal growth potential.Exactly how plasticity in growth might be adaptive in early life, and yet also contribute to non-adaptive outcomes such as NCDs in later life, has remained controversial. The ‘predictive adaptive response’ hypothesis assumes that fetal growth patterns represent an adaptation to external ecological conditions, allowing phenotype to be tailored adaptively in anticipation of similar ecological conditions in later life . An alteincrease in their sensitivity to maternal phenotype around the time of birth, as indicated by marked changes in the heritability of growth before and after birth. Fetal genes appear to ‘relax their control’ over growth before birth and then re-assert it after delivery  produce larger neonates if the father is European (larger body size) rather than Indian , indicatsuppressed–who have elevated NCD risk.Through constraint generated by her pelvic dimensions, therefore, as well as via other mechanisms, a mother whose growth was suppressed during her own development may constrain the growth of her offspring during pregnancy, even if that offspring has the potential to grow large in post-natal life. This generates two independent risk factors for NCDs–poorer fetal growth, and rapid post-natal catch-up among those whose fetal growth constraint was greater relative to their growth potential. Poor fetal growth constrains organ growth and metabolic capacity, whereas catch-up growth elevates metabolic load . NeitherThe magnitudes of effect we report are modest, and our findings require replication in other studies. Furthermore, in this population we have shown that pelvic dimensions mediate only the association of maternal BMI, and not that of maternal height, with neonatal size. In other studies, both higher , 43 and We have argued previously that in long-lived species such as humans, plasticity during fetal life may have less to do with ‘adapting’ to external ecological stresses than is often assumed , and morOnce such elevated plasticity in late fetal life has evolved, it cannot prevent external events such as maternal famine during pregnancy, or factors influencing growth in early infancy, also leaving a long-term imprint on phenotype. Therefore, the selective pressures that favoured the enhancement of fetal plasticity in the past need not necessarily be those acting most strongly on it in contemporary populations. The specific role of maternal pelvic dimensions in the developmental origins of adult disease still requires elucidation.threat of cephalo-pelvic disproportion may have selected for greater physiological sensitivity to maternal phenotype in late pregnancy, resulting in a developmental period characterized by high plasticity that is not driven primarily by benefits of adapting to external ecological conditions. Further work on this issue may benefit from cross-species comparisons, to understand whether the magnitude of offspring plasticity before and after birth differs according to whether delivery does or does not face the kind of constraint generated by maternal pelvic dimensions.More broadly, the key implication of our analysis is not that pelvic dimensions are necessarily strongly associated with fetal growth patterns in every mother-infant dyad; indeed populations appear to show substantial variability in the magnitude of this association, as discussed above. Rather, the important implication is that the Conflict of interest: None declared.


Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions , total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.DOI:http://dx.doi.org/10.7554/eLife.20320.001 Both meThe variance of adult height explained by additive genetic, shared environmental and unique environmental factors by birth-year cohorts is presented in Univariate quantitative genetic models for height were then conducted separately in the three geographic-cultural regions . The patThis very large twin study showed no clear pattern in the heritability of height across birth-year cohorts and thus does not support the hypothesis that the heritability of height is lower in populations with low living standards compared with affluent populations, nor that the heritability of height will increase within a population as living standards improve. Since infant mortality rates are higher in men than in women, both in singletons  and twinTotal and genetic variance of height generally increased across birth-year cohorts; gene-birth year interaction analysis showed that the genetic variance increase was only modest even when it was statistically significant in this very large twin cohort. However, part of the increase in total variance in some birth-year cohorts was also due to the increase in shared environmental variance. This suggests that both greater ethnic diversity and variation in living standards have contributed to the secular increase in height variation. The greatest total height variation in North America and Australia was due to both genetic and environmental factors and the pattern of variance components across the birth cohorts was less consistent than in Europe. A recent study across 14 European countries found that many independent loci contribute to population genetic differences in height and estimated that these differences account for 24% of the captured additive genetic variance . TherefoThe main strength of the present study is the very large sample size of our multinational database of twin cohorts, with adult height data from individuals born between year 1886 and 1994, allowing a more detailed investigation of the genetic and environmental contributions to individual differences in height across birth cohorts than in the previous studies. Important advantages of individual-based data are improved opportunities for statistical modeling and lack of publication bias. This type of analysis is difficult to perform by using literature-based meta-analyses because most of the published studies do not provide the needed statistics by birth-year cohorts. However, our study also has limitations. Countries and/or ethnic-cultural regions are not equally represented and the database is heavily weighted toward populations following Westernized lifestyles. In the classical twin design, parental phenotypic assortment increases dizygotic correlations and thus inflates the shared environmental component when not accounted for in the modeling. In our database, we do not have information on parental height and thus could not take into account assortative mating, which may thus explain part of the shared environmental variation. In addition, most of the height measures were self-reported , which mIn conclusion, although the genetic variance of height showed a slightly increasing trend with birth year, heritability estimates did not present any clear pattern of secular changes across birth-year cohorts from 1886 to 1994. Thus, our findings do not support the hypothesis that the heritability of height increases along with increasing living standards and diminishing rate of absolute poverty within populations.This study is based on the data from the Collaborative project of Development of Anthropometrical measures in Twins (CODATwins), which was intended to pool data from all twin projects in the world with information on height and weight measurements for MZ and DZ twins . For theFrom the initial 558,672 height measurements, we excluded those <145 or>210 cm in men and <135 or >195 cm in women (<0.1% of the measurements). Since individuals in longitudinal studies have more than one measurement over time, analyses were restricted to one observation per individual resulting in 323,491 individuals. After excluding unmatched pairs (without data on their co-twins), we had 286,780 twin individuals  born between year 1886 and 1994 (40% monozygotic (MZ), 41% same- sex dizygotic (SSDZ) and 19% opposite-sex dizygotic (OSDZ) twin pairs). The smaller proportion of OSDZ compared to SSDZ twins in this study is explained by the fact that some of the twin cohorts in our database have collected, by design, only SSDZ twins and thus do not have data on OSDZ twins. These individuals were categorized into nine consecutive birth year groups described in We first tested whether the means and variances of height differed between twin cohorts within each sex and birth-year group . Since tTo analyze genetic and environmental influences on the variation of height, we used classic twin modeling based on linear structural equations . MZ twinPrior to conducting the modeling, height values were adjusted for the year of birth and twin cohort within each birth year and sex groups using linear regressions, and the resulting residuals were used as input phenotypes. The ACE sex-limitation model was selected as a starting point of the univariate modeling based on the following criteria: (i) MZ within-pair correlations were clearly higher than DZ correlations consistent with the influence of genetic effects, (ii) the magnitude of the difference between MZ and DZ correlations (rDZ > 1/2 rMZ) indicated the presence of common environmental effects and (iii) the lower within-pair correlations for OSDZ than for SSDZ twins observed for most birth-year groups suggested the presence of sex-specific genetic effects (results not shown). Previous findings from this international database showed that both male and female DZ twins are slightly taller than MZ twins in these age groups , and thu In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.eLife. Your article has been favorably evaluated by Prabhat Jha (Senior Editor) and four reviewers, one of whom, Eduardo Franco, is a member of our Board of Reviewing Editors. The following individual involved in review of your submission has agreed to reveal their identity: Timothy Frayling.Thank you for submitting your article "Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994" for consideration by The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.Summary:This study tested the plausible hypothesis – grounded on economic theory – that the genetic influences on adult height may have increased over the last several decades as living standards improved, which would have decreased the environmental constraints from socioeconomic deprivation on attained height. The investigators could only test this hypothesis because of the opportunity to pool together via a massive consortium many twin cohorts across multiple continents. They concluded that the hypothesis could not be confirmed, as the heritability of height did not follow any clear secular trends, irrespective of population. This study addresses an interesting question using the power of almost all, if not all, the twin studies in the world – how has the genetic and environmental component to height altered over the last 100 years? Given all the studies included this can be regarded as as close to the definitive study as one can get.Essential revisions:The following are specific points summarized from the reviewers' critiques. They require your attention for us to consider a revised version of your paper.1) Could the relative proportion of MZ to DZ twins have changed over time and this affected the conclusions of this study? The entire set included 40% MZ, 41% same-sex DZ, and 19% opposite-sex DZ. Greater than average height and weight increases the likelihood of a pregnancy resulting in DZ twins. Age over 40 and prior history does the same. Average age at first pregnancy and numbers thereof are likely to have changed over time and represent variables that could be sensitive to era effects related to war and other determinants of deprivation. On the other hand, there are no known genetic correlates of MZ pregnancies and the rate is constant across populations. Another potential confounder related to the above is the improvements in obstetric care over time, which would have increased the survivability of MZ twins.2) As a sidebar to the above question: Shouldn't the proportion of opposite-sex DZ be higher than what the study found?3) I am intrigued by the apparent secular decreases in the proportion of variation due to the unique environment component. This happened for both men and women and were more noticeable for the European cohorts. It seems to me that this suggests that the original declining-deprivation hypothesis has some merit. The authors focused on the additive genetic component but did not discuss much what happened to the other components.4) It is worth considering presenting the results of both sexes together as well as split by sex. Whilst I can think of reasons why changes in the heritability of height may differ by sex, it is not clear why the authors have stratified their primary analysis by sex. If the main hypothesis is that secular changes will change the heritability of height, one would expect these to operate in the childhood growth of boys and girls. Perhaps girls will be less susceptible because they grow for a shorter period of their lives. But why reduce the power of the study by half? 5) Are the differences between men and women in the earliest time points significant? It is not clear. The authors speculate that there may have been stronger survival effects in men, but this will be unnecessary speculation if there is no evidence of a difference between sexes.6) It is not possible to prove the negative. Instead can the authors place some bounds on their conclusions? E.g., "we could exclude an increase of x% genetic variance per generation (25 years) with 95% confidence"? On a related note, there are no p values or effect sizes anywhere in the main text. This makes the reader take the results on faith . I realise these appear in the supplementary information, but I think it would help the reader to see the genetic variances across time with 95% CIs at least (and combined sexes would be most powerful).7) Can the authors comment more on the overall increase in variance observed? It is worth noting that the genetic variance appears to go up in line with the overall variance. The reasons for this are not testable I imagine, but presumably could be due to increased ethnic diversity, and greater variation in living standards, as the average increases. It is clear in 8)  […]Essential revisions:The following are specific points summarized from the reviewers' critiques. They require your attention for us to consider a revised version of your paper.1) Could the relative proportion of MZ to DZ twins have changed over time and this affected the conclusions of this study? The entire set included 40% MZ, 41% same-sex DZ, and 19% opposite-sex DZ. Greater than average height and weight increases the likelihood of a pregnancy resulting in DZ twins. Age over 40 and prior history does the same. Average age at first pregnancy and numbers thereof are likely to have changed over time and represent variables that could be sensitive to era effects related to war and other determinants of deprivation. On the other hand, there are no known genetic correlates of MZ pregnancies and the rate is constant across populations. Another potential confounder related to the above is the improvements in obstetric care over time, which would have increased the survivability of MZ twins.As mentioned by the reviewer, changes in twinning rates are largely attributable to dizygotic (DZ) twinning. Monozygotic (MZ) twinning is considered an essentially random event with fairly constant rates worldwide, but a significant increase from 1960 has been reported for some countries . This increasing MZ twinning rate could be explained by the improvements in obstetric care over time increasing the survivability of MZ twins but it has also been associated with increasing use of oral contraceptives . in vitro fertilization (IVF) also causes MZ twinning occasionally . Changes in DZ twinning rates are influenced by maternal age, ethnicity, family history, and height and weight. The higher DZ twinning rate since the 1980s have been attributed to the widespread use of IVF and other fertility treatments in most industrialized countries . Therefore, after the introduction of fertility drugs and IVF, variations in the DZ twinning were not only due to biological factors, but also depended on the popularity of fertility drugs and IVF in each country.In this sample, the proportion of MZ to DZ twins across the studied birth-year cohorts (from 1886-1909 to 1980-1994) is as follows: 37%, 39%, 41%, 35%, 33%, 38%, 43%, 48%, 50%. This shows that the proportion of MZ to DZ twins is quite similar from 1886-1909 to 1950-1959 (33-41%) and starts to increase from 1960, which does not reflect the rise in DZ twins seen in developed countries during the past three decades. In a previous study on this database, we showed that there was no zygosity difference in height variance, neither in childhood nor in adulthood . Therefore, there is no reason to think that changes in the proportion of MZ to DZ twins would affect variance components estimates. This has now been discussed in limitations.2) As a sidebar to the above question: Shouldn't the proportion of opposite-sex DZ be higher than what the study found?The reviewer is right in that the proportion of same sex (SSDZ) and opposite sex (OSDZ) dizygotic twins should be the same. The considerably smaller proportion of OSDZ compared to SSDZ twins in this study is explained by the fact that some of the twin cohorts in our database have collected, by design, only SSDZ twins and thus do not have data on OSDZ twins. This has now been mentioned in the manuscript.3) I am intrigued by the apparent secular decreases in the proportion of variation due to the unique environment component. This happened for both men and women and were more noticeable for the European cohorts. It seems to me that this suggests that the original declining-deprivation hypothesis has some merit. The authors focused on the additive genetic component but did not discuss much what happened to the other components.A decreasing trend in the proportion of variation due to unique environmental factors (E) across birth-year cohorts was observed only for the four earliest birth cohorts, and was more noticeable in Europe and in women. That is, this trend was not observed in East Asia or North America and Australia , nor in Europe from 1940 onwards. Moreover, in men, the decrease in relative E variance was not associated with a parallel increase in relative A variance (because relative C variance increased), which does not support the declining-deprivation hypothesis. That is, since height is influenced by environmental factors during the whole growth period (particularly in infancy and puberty), we expect that some of these environmental factors are shared by co-twins; therefore, and according to the hypothesis, this should have been seen as a decrease in C variance, which was not observed. In fact, in several cases a decrease in relative E variance was associated with an increase in relative C variance. If we look at the raw variances, the decreasing trend in E variance in the earliest birth cohorts is noticeable for women but not clear for men.greater influence of unique environmental factors in the earliest birth cohorts in womenmight be explained byshrinkage in old age. Finally, since shared environmental factors did not show any pattern across birth-years cohorts, we described the results but not discussed them in the Discussion.In summary, the parallel decrease in relative E variance and increase in relative A variance was observed only in European women for the four earliest birth-year cohorts; in fact, the heritability estimate decreased again in the two latest birth cohorts. Therefore, we alternatively speculated that the 4) It is worth considering presenting the results of both sexes together as well as split by sex. Whilst I can think of reasons why changes in the heritability of height may differ by sex, it is not clear why the authors have stratified their primary analysis by sex. If the main hypothesis is that secular changes will change the heritability of height, one would expect these to operate in the childhood growth of boys and girls. Perhaps girls will be less susceptible because they grow for a shorter period of their lives. But why reduce the power of the study by half? We presented the results separately in men and women because the model fit statistics showed that the variance components differed between sexes in all birth-year cohorts, and the relative contribution of the genetic and environmental variance components differ in the three earliest and two latest birth-year cohorts  Are the differences between men and women in the earliest time points significant? It is not clear. The authors speculate that there may have been stronger survival effects in men, but this will be unnecessary speculation if there is no evidence of a difference between sexes.The variance components differed between sexes in all birth-year cohorts, and the relative contribution of the genetic and environmental variance components differed in the three earliest and two latest birth-year cohorts (Table 2 in 6) It is not possible to prove the negative. Instead can the authors place some bounds on their conclusions? E.g., "we could exclude an increase of x% genetic variance per generation (25 years) with 95% confidence"? On a related note, there are no p values or effect sizes anywhere in the main text. This makes the reader take the results on faith . I realise these appear in the supplementary information, but I think it would help the reader to see the genetic variances across time with 95% CIs at least (and combined sexes would be most powerful).As suggested by the reviewer, we have quantified the increase in genetic variance per generation by using G-E interaction analyses. The results showed that genetic variance increased 1.37 (95% CI 0.50-2.27) and 1.07 (95% CI 0.46-1.79) per 25 years in men and women, respectively, which information is now given in the main text. The 95% CIs thus shows that the increase of genetic variance is statistically significant but the increasing effect in variance is still quite modest. As suggested by the reviewer, we have now also included in the main text the table showing the proportion of height variance explained by A, C and E factors. As previously explained in comment 4, we finally decided to present in the main text the results separately in men and women (and combined results in supplementary table) because variance components differed between sexes and thus we think that, even if less powerful, results are more correct.7) Can the authors comment more on the overall increase in variance observed? It is worth noting that the genetic variance appears to go up in line with the overall variance. The reasons for this are not testable I imagine, but presumably could be due to increased ethnic diversity, and greater variation in living standards, as the average increases. It is clear in Although there is a general trend to increasing total and genetic variance across birth cohorts, genetic variance does not always go up with total variance. For example, in men, the greatest increase in total variance was observed from birth cohort 1940-1949 to 1960-1969 and although genetic variance also increased during this period it increased especially in the two latest birth-year cohorts (1970-1979 and 1980-1994). In women, although total variance also started to increase from birth cohort 1940-1949, genetic variance showed the greatest increase from 1886-1900 to 1940-1949. As can be seen in 8) Supplementary Table 2 is now part the main text as


In the US, growing up with parents with a low socio-economic status (SES) has been shown to increase the chance of having a birth outside marriage. However, less is known about the influence of parental SES in other Western countries. The current paper examines the association between parental educational attainment with the partnership context at first birth in 16 European and North American countries, by differentiating births within marriage, within cohabitation, or while being single. Moreover, we test whether the association between parental education and partnership context at childbirth changes over cohorts and whether its influence changes when controlling for own educational attainment. Data from the Generations and Gender Programme were used, as well as data from the American National Survey of Family Growth, the Canadian General Social Survey, and the Dutch Survey on Family Formation. The results show that in North American and East European countries, but not in West European countries, lower parental education increases the risk of having a birth within cohabitation. Moreover, in North American countries and half of the West and East European countries, lower parental education increases the risk of having a birth while being single. The association of parental education with the partnership context at birth tends to change furthermore over cohorts, although no clear pattern could be observed between countries. The study suggests that the intergenerational transmission of education is an important mechanism in explaining the influence of parental education, although other mechanisms also appear to be at work. Over the past decades, the percentage of children born outside marriage  in Western societies has increased strongly. Within the European Union, the percentage of all births to unmarried women increased from 9 per cent in 1980 to 40 per cent in 2011 Eurostat , 2015, aIn the US, growing up with parents with a low socio-economic status (SES) has been shown to increase the chance of having a birth outside marriage Aassve ; Wu 1996Some cross-national studies have looked at the influence of own education on the partnership context at birth . We study union status at first birth, because starting a family is an important event in people’s lives which often triggers changes in partnership relations , improving living standards, weakening normative regulations, and increasing female autonomy resulted in an increasing need for self-development and individualism  retrospective information on the occurrence and timing of cohabiting and marital partnerships, as well as fertility. For this paper, we were able to use data of four West and nine East European countries. Insufficient information on fertility history, partnership history, or parental educational attainment was available for Australia, Italy, Japan, and the Netherlands. Investigation of retrospective data of various countries of the GGS has suggested that there are issues with the quality of the fertility history of the German dataset  coding system, with scores ranging between 0 and 100. The ISLED-coding system was recently developed by Schröder and Ganzeboom  and has Respondent’s own educational attainment is included as a time-varying covariate by using information on the highest educational level (in ISLED) attained by the respondent in combination with information on the year and month in which this highest level was reached, thereby assuming that respondents remained enrolled in school continuously after finishing primary education.Cohort is a continuous variable reflecting the year of birth of the respondent. Only for the descriptive results showing the changes in partnership context at birth over different cohorts, a categorical variable was constructed. This variable differentiates people born before 1955, between 1955 and 1975, and after 1975. Because of the younger age range for the data of Austria and the US, and because for the US only data collected in 2006–2008 was used, these countries lack a cohort with people born before 1955. For the interaction model testing the difference in the association of parental education over cohorts, cohort was centred around the year 1960, because the SDT assumes that in many countries changes in family behaviour started from the 1960s onwards .As control variables, A discrete-time competing risk model is estimated to test the association of the independent variables with the risk of having a first birth within cohabitation or while being single as compared to having a birth within marriage. This model examines the monthly risk of a respondent to experience one of the events, starting from the age of 15. The model is competing because as soon as a person has experienced an event, he or she is no longer at risk of experiencing any of the other events. The results of the multinomial logistic regressions are reported in relative risk ratios. A relative risk ratio greater than one indicates that an increase in the independent variable increases the risk of becoming a cohabiting or single parent compared to becoming a married parent. A relative risk ratio smaller than one indicates that an increase in the independent variable decreases the risk of having a first child within cohabitation or while being single compared to having a first child within marriage. Since we are interested in how trends differ between countries and between gender, all analyses are run separately by country and gender.In this section, we start with discussing the results of women. In subsections Table 2, and age3. The results of these models are presented in Table To answer the first research question on the association of parental education and partnership context at birth, we estimated a model including parental educational attainment, cohort, and the control variables age, agePanel 1 shows that in the North American countries, most of the East European countries (except Poland), and in Norway, women with parents with a lower educational level have a higher risk to have a first birth within cohabitation compared to a birth within marriage, than women with higher educated parents. In the Netherlands, women with lower educated parents instead have a lower risk of having a birth within cohabitation, compared to women with higher educated parents. In Austria, Belgium, and Poland, parental education is positively associated and in France negatively associated with the outcome variable, but in these countries the associations do not reach statistical significance. In all countries, the risk to have a first birth within cohabitation rather than within marriage increases across cohorts.Panel 2 of Model 1 shows that in all countries, except Georgia, parental education is negatively associated with the risk of having a birth while being single compared to a birth within marriage, indicating that overall women with lower educated parents have a higher risk of having a birth while being single. The coefficients reach statistical significance in the North American, half of the West European , and half of the East European countries .In order to examine whether the association of parental educational attainment and union status at childbirth differs across cohorts (research question 2), we re-estimated the previous model and included an interaction term between parental education and cohort. The main effect of cohort represents the association of cohort for women with an average level of parental education. The main effect of parental education can be interpreted as the estimated association of parental education for women born in 1960. The results are presented in Table The results of the main effect of parental education on the risk to have a birth in cohabitation (Panel 1) and the interaction effect with cohort show that in Canada and Norway the negative association of parental education is more negative for younger cohorts. In Austria, Estonia, Georgia, and Russia, the negative association instead becomes less negative with consecutive cohorts . The opposite is found in the Netherlands, in this country the positive association becomes less positive with consecutive cohorts (in Belgium this association does not reach significance). In France, the positive association for older cohorts changes into a negative association for more recent cohorts.For the model comparing the risk of having a birth while being single versus within marriage (Panel 2), only for a few countries significant interaction effects are found. In Canada, the negative association of parental education is more negative for consecutive cohorts, while in Austria and Russia the negative association become less negative. In Poland, the negative association for older cohorts changes into a positive association for younger cohorts.To examine to what extent the association of parental education with the partnership context at birth changes by including own educational attainment, a model was estimated including both variables.When comparing Panel 1 of Tables For the models comparing the association of the independent variables with the risk to have a first birth while being single versus within marriage for women .The association of parental education with the risk of having a birth within cohabitation versus within marriage is fairly similar for men and women in most countries. Only in the Czech Republic, Lithuania, and Russia, a negative association is found for women, while for men no significant difference between the higher and lower educated is found, however, note that in the Czech Republic the association almost reaches significance for men .p-value is .045 for French men). In Estonia, we find a similar negative coefficient of parental education for men and women, however, for men this coefficient does not reach significance, although both p-values balance around the .05 level .For the model including a respondent’s own educational attainment, we only find different results for men as compared to women in three countries. In France and the Netherlands, a positive and significant association is found for men and no significant differences are found for women  are more likely to have non-marital births , this negative association coincides with a negative association between parental education and the risk of having a birth within cohabitation. Births to cohabiting couples in these East European countries thus appear to be part of a pattern of disadvantage together with births to single mothers, something previous research also observed in the US . There also did not appear to be clear patterns between the different groups of countries. This low level of consistency in the pattern between and within countries complicates the identification of societal changes that can explain the results. We therefore have to leave it to future research to further explore changes over time.Lastly, we wanted to know to what extent the association of parental education changes when a person’s own educational attainment is included in the model. In most countries, the initial negative coefficient of parental education on the risk of having a first birth within cohabitation or while being single became smaller after including information on respondents’ own educational attainment. For births within cohabitation, the negative associations of parental education, however, remained statistically significant in the North American countries, Norway, and half of the Eastern European countries. For women who had a birth while being single, this was less often the case, as after including own educational attainment, the initial negative association only remained statistically significant in the US, Austria, and Norway. Our expectation was that including own educational attainment in the model could reduce the association of parental education because US research has shown that part of the association between parental SES and family structure can be explained by the intergenerational transmission of SES  education and cohort. In view of other possible mechanism linking parental SES and partnership at first birth, additional insight into the topic could be gained by including additional childhood indicators .Most fertility research has focused on women. One additional objective of this paper was to examine whether the patterns for men and women are comparable across and within countries. In fact, the association of parental education was remarkably similar for men and women. The model including own educational attainment also did not differ much between men and women. This supports the idea that in most instances the mechanisms explaining partnership context at birth are fairly similar for men and women. We therefore recommend to study data of men in addition to that of women more often in fertility research, as it can serve as a test of the robustness of one’s findings in a certain context. In the few cases where statistical gender differences were found, the overall association of parental education was more negative for women than for men. This is in line with previous research suggesting that the mechanism of socialization and role modelling could potentially be stronger for daughters than for sons. Moreover, in quite some countries differences between men and women were found for the interaction model, indicating that the association of parental education changes differently across cohorts for men and women. This could be an interesting topic for further study. It could also be fruitful to expand analyses to higher-order births. In some countries, cohabiting parents are likely to get married after their first birth (Perelli-Harris et al.


Zika virus infection during pregnancy can cause serious brain abnormalities, but the full range of adverse outcomes is unknown  brain abnormalities or microcephaly  (The three birth defects surveillance programs identified 747 infants and fetuses during 2013 (North Carolina and Massachusetts) and 2013–2014 (Atlanta) with one or more defects that met the 2016 CDC Zika surveillance case definition  . Brain aIn general, the distribution by maternal age was similar across birth defect categories. Among 410 (55%) infants or fetuses with information on the earliest age a birth defect was recorded, 371 (90%) had evidence of a birth defect meeting the Zika definition before age 3 months. More than half of those with brain abnormalities or microcephaly or with neural tube defects and other early brain malformations had evidence of these defects noted prenatally .A congenital Zika syndrome phenotype has been described , and the prevalence of severe congenital microcephaly  was 4.2 per 10,000  (The findings in this report are subject to at least six limitations. First, population-based surveillance programs strive to ascertain the prevalence of birth defects among all members of a specified population. In contrast, the aim of USZPR is to estimate the proportion of birth defects among pregnancies with laboratory evidence of possible Zika virus infection, a specific subgroup of the general population (The birth defects surveillance data in this report were compiled from a period before introduction of Zika virus in the Americas, using the CDC surveillance case definition of birth defects potentially related to Zika virus infection; this is the same case definition adopted by USZPR. The higher proportion of these defects among pregnancies with laboratory evidence of Zika infection in USZPR supports the relationship between congenital Zika virus infection and these birth defects (Zika virus infection causes serious brain abnormalities; however, the birth defects observed are not unique to congenital Zika virus infection, and the full range of effects of congenital Zika infection is not known.CDC used data from population-based birth defects surveillance programs in Massachusetts, North Carolina, and Atlanta, Georgia, to retrospectively assess the prevalence of birth defects during 2013–2014 that met the surveillance case definition for birth defects potentially related to Zika virus infection, before introduction of Zika virus into the United States. After introduction of Zika virus, the proportion of infants and fetuses with birth defects born to mothers with laboratory evidence of possible Zika infection reported by the US Zika Pregnancy Registry during January 15–September 22, 2016, was approximately 20 times higher than the prevalence of potentially Zika-related birth defects among pregnancies during the pre-Zika years.Data on birth defects in the pre-Zika years serve as benchmarks to direct rapid ascertainment and reporting of birth defects potentially related to Zika virus infection. The higher proportion of these defects among pregnancies with laboratory evidence of possible Zika virus infection supports the relationship between congenital Zika virus infection and birth defects.


Introduction: Three recent systematic reviews suggested a relationship between noise exposure and adverse birth outcomes. The aim of this review was to evaluate the evidence for the World Health Organization (WHO) noise guidelines and conduct an updated systematic review of environmental noise, specifically aircraft and road traffic noise and birth outcomes, such as preterm birth, low birth weight, being small for gestational age and congenital malformations. Materials and methods: We reviewed again all the papers on environmental noise and birth outcomes included in the previous three systematic reviews and conducted a systematic search on noise and birth outcomes to update previous reviews. Web of Science, PubMed and Embase electronic databases were searched for papers published between June 2014 (end date of previous systematic review) and December 2016 using a list of specific search terms. Studies were also screened in the reference list of relevant reviews/articles. Further inclusion and exclusion criteria for the studies provided by the WHO expert group were applied. Risk of bias was assessed according to criteria from the Newcastle-Ottawa quality assessment scale for case-control and cohort studies. Finally, we applied the GRADE principles to our systematic review in a reproducible and appropriate way for judgment about quality of evidence. Results: In total, 14 studies are included in this review, six studies on aircraft noise and birth outcomes, five studies (two with more or less the same population) on road traffic noise and birth outcomes and three related studies on total ambient noise that is likely to be mostly traffic noise that met the criteria. The number of studies on environmental noise and birth outcomes is small and the quality of evidence generally ranges from very low to low, particularly in case of the older studies. The quality is better for the more recent traffic noise and birth outcomes studies. As there were too few studies, we did not conduct meta-analyses. Discussion: This systematic review is supported by previous systematic reviews and meta-analyses that suggested that there may be some suggestive evidence for an association between environmental noise exposure and birth outcomes, although they pointed more generally to a stronger role of occupational noise exposure, which tends to be higher and last longer. Very strict criteria for inclusion and exclusion of studies, performance of quality assessment for risk of bias, and finally applying GRADE principles for judgment of quality of evidence are the strengths of this review. Conclusions: We found evidence of very low quality for associations between aircraft noise and preterm birth, low birth weight and congenital anomalies, and low quality evidence for an association between road traffic noise and low birth weight, preterm birth and small for gestational age. Further high quality studies are required to establish such associations. Future studies are recommended to apply robust exposure assessment methods , disentangle associations for different sources of noise as well as daytime and nighttime noise, evaluate the impacts of noise evens (that stand out of the noise background), and control the analyses for confounding factors, such as socioeconomic status, lifestyle factors and other environmental factors, especially air pollution. Environmental noise is related to a range of adverse health outcomes, such as impaired cognitive function in children, sleep disturbance, and cardiovascular diseases . A numbeThe World Health Organization (WHO) defines PTB as a gestational age at birth of less than 37 completed gestational weeks, and LBW as birth weight of less than 2500 g irrespective of gestational age. LBW has been associated with not only poorer health and development in children, but also with adverse health outcomes in later life. It, for example, is a predictor infant mortality as well as impaired educational achievement and increased risk of enhanced risk of noncommunicable diseases (NCDs) such as of ischemic heart disease, chronic hypertension, and insulin resistance/metabolic syndrome in adults. The World Health Assembly has endorsed targets to reduce LBW prevalence by 30% by 2025 . SimilarEpidemiological studies have identified air pollution as an emerging potential risk factor for PTB and LBW, where inflammation has important role, through direct stimulation of inflammatory cells or mediated by oxidative stress . OccupatHohmann et al. 2013) conducted a systematic review to examine associations between chronic noise exposure during pregnancy or childhood and health outcomes in early and late childhood. They included 12 studies on pregnancy outcomes and rated evidence levels (3 to 2++) according to the Scottish Intercollegiate Guidelines Network and concluded that chronic noise exposure during pregnancy was not associated with birth weight, preterm birth, congenital malformations, perinatal and neonatal death based on six cohort, four case–control, and two cross-sectional studies (highest evidence level 2+). They also reported that the studies included in the systematic review showed a high variation in study design, outcome, exposure and confounder assessments [013 conduRistovska et al. (2014) conducted another systematic review of available evidence on the association between environmental noise exposure and pregnancy outcomes such as LBW, PTB, spontaneous abortion, and congenital malformations. They included nine studies in their review, encompassing four case-control, two surveys, one cross-sectional study, one prospective study and one population-based cohort study. Objective noise measurements were used in eight of these studies. Most studies examined aircraft noise exposure and its influence on low birth weight. According to their quality assessment score, six studies were assessed as providing strong evidence and three studies provided a moderate evidence score. They concluded that there is some suggestive evidence of adverse associations with noise from both occupational and epidemiological studies, especially for low birth weight .Dzhambov et al. 2014) conducted a systematic review and meta-analyses on 29 studies related to noise exposure and pregnancy complications and outcomes. They also assessed the quality of evidence and included both occupational and environmental studies of noise, but did not separate in the analyses the type of exposure, which is a limitation for this review. Women exposed to high noise levels (in most of the studies ≥80 dB) during pregnancy were at a significantly higher risk for having small-for-gestational-age newborn , gestational hypertension  and offspring with congenital malformations . The effects were not statistically significant for preeclampsia, perinatal death, spontaneous abortion and preterm birth [ conducteA change of approach is vital, moving from addressing individual risk factors of pregnant women to addressing co-occurring groups of factors with the whole family, household and community around the women most at risk. First priority goal of Health Strategy 2020 is investment in life course approach and empower people, especially for children to have good start in life, learn better and have more productive lives .The area of research on the association between noise exposure and birth outcomes is rapidly evolving. The translation of evidence in this area into policy, therefore, requires regular updates of the synthesized available evidence. Here we provide an update of the evidence for the WHO noise guidelines and conduct an updated systematic review of environmental noise, specifically aircraft and road traffic noise and birth outcomes.We reviewed again all the papers included in the three aforementioned systematic reviews and conducted a systematic search on noise and reproductive outcomes. After careful reading of full papers included in the previous reviews we found that only 8 papers satisfied inclusion criteria, developed for this review .Web of Science, PubMed and Embase electronic databases were searched for papers published between June 2014 (end date of previous systematic review) and December 2016. Studies were also screened in the reference list of relevant reviews/articles. In addition, hand searching was used for acoustical conference proceedings. No language restriction was applied. The following search terms were used: noise AND health AND perinatal OR prenatal OR labor OR birth OR malformation OR gestation OR preterm OR fetus OR pregnancy. We found 455 titles of the studies, but after careful reading of the abstracts and full papers we decided that only 6 studies met the inclusion criteria .Studies were included if: (a) noise exposure assessment was performed with noise measurements or noise mapping, (b) the source of noise was environmental , (c) the study investigated the following reproductive outcomes: birth weight/gestational length/preterm birth/prematurity/reproductive health/congenital malformations/fetal growth retardation/small-for-gestational-age infant/spontaneous abortion, (d) the above health outcomes occurred during pregnancy or delivery up to 4 weeks after birth and (e) the paper examined a relationship between the above health outcomes and noise exposure. Studies investigating health outcomes other than those listed in the inclusion criteria such as preeclampsia, hearing development, male reproductive function, or health outcomes that occurred after the 4th week of birth were not included in this review. Case studies or case reports, studies containing no original research and studies investigating different noise source such as neonatal intensive care unit (NICU) noise were excluded as were studies looking at distance from road only without other assessment of noise exposures.Publication type ,Study design ,Noise exposure assessment ,Assessment of the birth outcomes ,Confounding factors ,Statistics ,Bias .We used data extraction sheets designed for the following entries: author, year of publication, country, study design, sample size, exposure assessment (indicators and range of exposure), outcome, confounding factors, potential for bias, effect size and quality score following an earlier systematic review by Ristovska et al. (2014). We used a quality assessment (QA) for epidemiological studies based on criteria from the Newcastle-Ottawa quality assessment scale for case-control and cohort studies . The criBased on this scale, the maximum total score can be 14. Studies with a score of ≥10 were assessed as at low risk of bias, studies with a score from 6 to 9 were assessed as at unclear risk of bias, and studies with a score ≤5 were assessed as at high risk of bias.Finally, we applied the GRADE  principles to our systematic review in a reproducible and appropriate way for judgments about quality of evidence.In total, from the previous systematic reviews and new search we found 14 studies  includinAndo and Hattori (1973) reported that there was an increased incidence of low birth weight in babies from mothers exposed to aircraft noise. The mothers were divided into five subgroups of exposure in range of 74–90 dBA using the ECPNL  indicator. The relative low birth weight rate was 3% lower for in the noisy area (above 75 dBA) compared to neighboring quiet cities, which were not exposed to jet aircraft flights. The relative low birth weight rate increased further to over 5% for both males and females when the planes started to fly more regularly over the affected areas .p < 0.001). They also found a weak non-statistically significant negative correlations between noise exposure and male birth weight and gestational length and with female birth weight [In a small study involving 115 infant, s Schell (1981) examined the association between maternal exposure to aircraft noise and birth weight and gestational length. They performed a noise exposure assessment with measurements during airplane takeoff (range of 75–100 dBA). They collected birth weight and other data through personal interviews with the mothers. They reported a significant negative partial correlation between noise exposure and gestational length in female infants, after adjusting for maternal age, smoking, parity, socioeconomic status, and parental height and weight  compared the rate of low birth weight in 498 infants whose mother lived in a noisy area near the Amsterdam airport with that of 404 infants from less noisy areas. Eighteen percent of babies were of low birth weight in areas exposed to Ldn < 65 dBA and 23% in areas exposed to Ldn 65–70 dBA. They adjusted their analyses for parent’s income, mother’s age, birth order, twinship and sex of the infant (but not for mother’s smoking) and found that after adjustment for family income, there was only an association among female babies .In Japan, in a large study  Matsui et al. (2003) found a strong statistically significant dose-response relationship between aircraft noise exposure and low birth weight in the highest exposure group in the town of Kadena (adjusted odds ratio (OR) for low birth weight was 1.32, 95% confidence intervals (CI): 1.18, 1.48 and for preterm birth was 1.25, 95% CI: 1.09, 1.44, average noise levels 88 dB of WECPNL. They adjusted their analyses for the gender of the baby, maternal age, birth order, occupation of householder, but not for smoking of the mothers, which may have resulted in some residual confounding .p < 0.02). For white babies of mothers who lived near the airport, there was an increased incidence of anencephaly and spina bifida [Near Los Angeles airport using an ecological study design, Jones and Tauscher (1978) reported a greater incidence of all congenital malformations combined among black babies in areas where the noise exposure was >90 dBA compared to those babies who were not exposed to aircraft noise  reported on the incidence of congenital malformations combined (1745 cases) in two groups of infants whose mothers lived around the airport and were exposed to Ldn above 65 dB or below 65 dB. They did not report a statistically significant association .Based on the above evidence the GRADE quality scores are provided in the p = 0.24), traffic noise exposure and low birth weight (p = 0.17), and using personal listening musical devices and birth weight (p = 0.34) [Wu et al. (1996) conducted detailed noise assessments during pregnancy in a cohort of 200 pregnant women using personal noise dosimeter performing noise measurements for 24 h, noise maps for residential areas of the participants; and self-reported exposure to loud music and using personal listening devices. The mean level and standard deviation of individual exposure Leq 24 h was 67.9 dBA, (52.4 dBA–86.8 dBA). The birth weight was obtained from medical records. They reported no statistically significant associations between personal noise exposure measured and low birth weight ( = 0.34) .In Vancouver, Canada, Gehring et al. (2014) examined the association between modeled residential road traffic and all transportation noise exposure and birth outcomes in nearly 70,000 administrative birth records. They focused on road traffic noise as railways and airports were minor contributors to overall community noise in this region. They reported a statistically significant negative association between road traffic exposure and term birth weight with mean difference = −19 g (95% CI = −23 to −15) per 6 dBA after controlling for various factors including income and education. Adjustment for air pollution exposure did not change the results. They reported similar sized negative associations for combined road, aircraft and railway noise. They also reported a statistically significant increased risk for small for gestational age OR = 1.10 (1.06–1.13), but not for preterm or very preterm birth. In joint noise-air pollution models, they reported independent associations between noise and air pollution exposure and small for gestational age .In Barcelona, Spain (2001–2005), Dadvand et al. (2014) reported on a cohort study that was based on 6438 singleton term births. They obtained information on exposures to air pollution, noise, and heat using, temporally adjusted land-use regression models, annual averages of 24-h noise levels based on regulatory noise map of Barcelona, and average of satellite-derived land-surface temperature, respectively. They did not find any statistically significant association for noise, but did for air pollution and heat exposures .In Vancouver, British Columbia, Canada, in the same cohort as Gehring et al. (2014), Hystad et al. (2014)  reported2 and NOx) and road traffic noise was modeled at all addresses. Associations between exposures and indicators of newborn’s size at birth: birth weight, placental weight and head and abdominal circumference were analyzed by linear and logistic regression, and adjusted for potential confounders. In mutually adjusted models they found that exposure to residential road traffic noise was weakly associated with reduced head circumference, whereas none of the other newborn's size indicators were associated with noise, neither before nor after adjustment for air pollution. This study indicates that traffic noise seems not to affect newborn's size at birth [In Denmark, Hjortebjerg et al. 2016) investigated the associations between residential air pollution and traffic noise during pregnancy and newborn's size at birth. From a national birth cohort in Denmark they identified 75,166 live-born singletons born at term with information on the newborn’s size at birth. Residential address history from conception until birth was collected and air pollution , noise exposure, and ambient temperature on low birth weight and preterm birth in Madrid across the period 2001–2009. The mean Leqd value was 64.6 dB(A), with a daily maximum value of 69.0 dB(A), while the mean Leqn value was 59.4 dB(A), with a daily maximum value of 67.5 dB(A) noise values were exceeded on 45% of days and 100% of nights across the period analyzed. Regarding low birth weight, Leqd was the variable that had the most impact across the gestational period, displaying an association for exposure in weeks 3 (first trimester), 21 (second trimester) and 37 (third trimester) of pregnancy. Their results for preterm birth suggested that noise levels had an impact in two ways, namely: Leqd in week 21 (second trimester), midway through the pregnancy, coinciding with the explanatory lag for low birth weight; and Leqn, with a statistically significant association in week 36 (third trimester) of pregnancy. They concluded that special mention should be made of the effect of noise, not only because it acts continuously across the entire pregnancy, but also because it does so in an acute form in its role as a trigger of labor process. However, the study had serious limitations because they didn’t control confounding factors of mothers [Arroyo et al. (2016a) conducted a ecological time-series study to assess the impact of air pollution  conducted ecological time-series analysis on the same study sample as mentioned above and same model for noise exposure assessment to assess the short-term impact of daily mean concentrations of air pollutants, noise and heat waves on preterm birth, classified as very preterm births and extremely preterm births. For diurnal noise exposure Leqd (Lag 0), they found an increased risk (relative risk (RR) of 1.07, 95% CI: 1.04, 1.10) for very preterm birth associated with significant attributable risk of 6.89, and for extremely very PB  with an attributable risk of 22.23. Confounding factors from maternal lifestyle and socioeconomic status were not included in the analysis [2.5, NO2 and O3 concentrations, measured noise levels at monitoring stations, and temperatures on LBW among non-premature infants over the period 2001–2009 based on the same study sample and measures of exposure as the aforementioned studies by Arroyo et al. Their analysis extended to infants having birth weights of 1500 g to 2500 g classified as very low birth weight (VLBW) and less than 1500 g classified as extremely low birth weight (ELBW). Environmental variables were lagged until 37 weeks with respect to the date of birth, and cross-correlation functions were used to identify explaining lags. Results were quantified using Poisson regression models. The relative risk of Leqd on low birth weight was 1.09 (95 CI: 0.99–1.19) (p < 0.1). Leqd, however, displayed an appreciably higher AR than that of PM, i.e., around 8%, though this was exclusively for the variable, low birth weight, and this increase in risk was significant at only p < 0.1 [Diaz et al. (2016) conducted an ecological time-series study to assess the impact of PM p < 0.1 . No assoFor other noise exposures no evidence is available.We found that the number of studies on environmental noise and birth outcomes is small and many of these studies have serious limitations such as not properly addressing confounding factors ,22,23. EDzhambov et al. 2014) concluded in their meta-analyses that women exposed to noise levels above 80 dBA during pregnancy are at a significantly higher risk for having small-for-gestational-age newborn and infant with congenital malformations. They found a 19% risk for small-for-gestational-age if the mother has been exposed to ≥80 dBA during pregnancy. All studies used a cut point of approximately 80 dBA noise exposure assessed either by specific question about the acoustic environment at work or by quantification by industrial hygienists. That mean the risk was calculated mainly on evidence obtained with studies related to occupational noise exposure, which are not included in our review [ concludeRistovska et al. (2014) in their review concluded that a small number of available studies were generally supportive of an association between noise exposure and adverse effects on low birth weight, but publication bias cannot be ruled out and some studies had limitations in design. The two largest studies found associations with LBW. One study from Japan  found siVery strict criteria for inclusion and exclusion of studies, performance of quality assessment for risk of bias, and finally applying GRADE principles for judgment of quality of evidence are the strengths of this review. Some of the studies found significant risk for adverse birth outcomes, such as LBW, PTB or SGA, but according GRADE criteria for study limitations, inconsistency, directness, precision, publication bias, dose-response, magnitude of effect, confounding adjustment, they were assessed for quality of evidence as very low for aircraft noise exposure or quality of evidence as low for road traffic noise exposure .Although, the number of studies available on the impact of noise exposure on pregnancy outcomes is still small, the fact that we found six studies for the period from August 2014 to December 2016 could mean that this field of research is emerging. Investigation of combined effects of environmental factors is necessary, especially when the research is devoted to birth effects related to traffic pollution, or living in urban environment. Recently developed methods for exposure assessment based on traffic sources and modeling could provide great opportunity for further research work.Pregnancy is a physiological state characterized by increased hypothalamus-pituitary-adrenal (HPA) axis function and progressively increasing levels of serum concentrations of stress hormones including cortisol and adrenocorticotropic hormones (ACTH) after 12 weeks gestation. Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic–pituitary–adrenal axis, has been identified in most female reproductive tissues including the uterus, the placenta, and the ovary. Placental CRH has been proposed to directly modulate the endocrine function of placental trophoblasts, including the production of estrogen, ACTH, and prostaglandin, and is involved in the timing of parturition. Remarkably the trajectory of CRH increase during pregnancy has been described to differ by ethnicity and sociodemographic factors. Stress hormones have inhibitory effects on female reproductive organs are responsible for inadequate levels of progesterone during pregnancy, subsequently resulting in preterm birth ,4.The possible biological mechanism were recently discussed by Dzhambov et al. (2014) and include a general stress response mechanism leading to neuroendocrine secretion ,25,26 thAnnoyance and sleep disturbance are among the most prevalent community response in a population exposed to environmental noise. General stress model is behind this reactions, potential mechanisms are emotional stress reactions due to perceived discomfort (indirect pathway), and non-conscious physiological stress from interactions between the central auditory system and other regions of the CNS (direct pathway). But for sleep disturbance direct pathway is dominant mechanism even at low noise levels. These effects have additional burden on stress response of pregnant women and individual noise sensibility has very important role ,30.We prepared figure for pathway of possible biological mechanism for developing birth outcomes related to noise exposure .Further studies are urgently needed on noise from different sources and pregnancy outcomes, given the suggestion that noise may affect pregnancy outcomes and that the number of studies are still fairly small. Studies should be conducted in different settings to show consistency and focus on the whole range of pregnancy outcomes including miscarriage, fetal growth, length of gestation, and congenital malformations. Particularly, studies at lower levels of noise are needed, and the shape of the exposure response, including the possibility for thresholds should be evaluated.Special attention should be paid to the exposure assessment and potential confounders, especially socioeconomic status and air pollution. The exposure assessment should not only include modeled data, but also measurements, noise perception and take into account behavior, timing of exposure and building characteristics such as its acoustic properties , bedroom orientation (towards or away from road), floor, etc.). It is important to obtain information on potential confounders including other environmental data such as air pollution, which may occur often simultaneously in the case of traffic noise and can affect pregnancy outcomes. The accuracy level of assessment of confounders including air pollution should be at the same level of accuracy as the noise assessment to be able to make sensible comparisons of risk estimates. Furthermore, work is needed on the mechanisms explaining the possible relationships. New OMICs technologies provide great opportunities to provide new insights into the mechanisms underlying the effects of noise .We found evidence for associations between aircraft noise and preterm birth, low birth weight and congenital anomalies; however, the quality of this evidence could be considered as very low. We also found evidence for an association between road traffic noise and low birth weight, preterm birth and small for gestational age with the quality of evidence being low. Thus, there is a need for further studies with robust exposure assessment, including other confounding factors, such as socioeconomic status and air pollution, and evaluating role of potential modifiers such as noise sensitivity.


Prematurity is the single most important cause of mortality during the neonatal period. The early growth of these infants has been shown to be a predictor of their later growth and neurodevelopmental outcomes. The objective of this study was to establish the determinants of early growth in preterm infants after hospital discharge at the Kitui District Hospital, Kenya.A short longitudinal study design was adopted to execute the study. During the period of April and June 2014, all the preterm infants who were discharged from the Kitui District Hospital Newborn Unit were enrolled in the study by obtaining written informed consent from their guardians. The anthropometric measurements of these infants were taken at discharge and repeated two weeks later at the Pediatric Outpatient Clinic and the Maternal Child health Clinic. A questionnaire guided interview was held with the guardians to establish infant and maternal characteristics which influenced the infants' early growth.A total of 112 participants were enrolled for the study with 106 (94.4%) of them being available for reassessment after two weeks. Majority (72.6%) had deficit in growth by failing to attain the recommended WHO average weight gain of 15g/kg/day. Most of the mothers (63.4%) were between the ages of 20-29 years with half of them being first time mothers. Many of them (66.1%) had only attained primary education and were married (66.1%) to self-employed husbands (56%).Most of the preterm infants at discharge were females who were born between 33 and 36 weeks gestation. Growth deficit was present in the majority and gestational age at birth was a major determinant of the early growth in these preterm infants. Every year, an estimated 15 million babies are born prematurely. This translates to more than one baby in every 10 babies delivered and accounts for more than 1.1 million deaths annually . These iStudy setting: The study was carried out at the Kitui District Hospital, a public health facility in rural Kenya. This is the county referral hospital which serves the former Kitui and Mwingi districts. It has a bed capacity of 200 beds and 44 cots. It is also a teaching hospital for medical officer and nursing officer interns as well as the University of Nairobi and the Kenya Medical Training College students. The hospital newborn unit has a capacity of 15 infants but mostly it accommodates about 20 babies and offers excellent care.Study design: In this longitudinal observational study, a total of 112 preterm infants who were discharged from the hospital newborn unit between April and June 2014 were enrolled for the study. They were then followed two weeks post discharge. Any infant who had congenital anomaly which was likely to interfere with their growth or their guardians declined to participate in the study were excluded.Data collection: Data was obtained from the assessment of the infants' anthropometric measurements which included their body weight, body length and head circumference. A questionnaire guided interview was also held with the guardians to establish the infants' birth history, hospitalization and feeding history as well as the maternal demographics, pregnancy history, their socio-economic characteristics and knowledge and practice of the care of the small baby.Procedures: The infants had their body weight taken using an infant weighing scale to the nearest 50g, body length using an infant meter to the nearest 5 mm and head circumference by use of a tape measure to the nearest 1 mm. The same measurements were repeated again at two weeks post discharge at the Pediatric Outpatient Clinic or Maternal Child Health clinic. A 15-20 minutes questionnaire guided interview was held with the infants guardian at discharge and with the use of a code the infants road to health booklet was labelled for easy follow up.Data analysis: The sample size was calculated with the help of Cochrane's modification of Fishers et al formula. Data was entered using MS Excel and later exported to STATA version 10 Texas for analysis. Descriptive statistics was done using means, medians, ranges and proportions. Anthropometric measurements were analyzed using Mann Whitney's test. Bivariate regression was done by use of the Odd's ratio to test for any associations between the early growth and the infant and maternal characteristics.Ethical considerations: The study was approved by the Kenyatta National Hospital-University of Nairobi (KNH-UON) ethics and research committee and data collection was authorized by the Kitui District Hospital administration. Study participants gave informed consent after being given a detailed explanation about the purpose of the study as well as their right to withdraw any time during the study period. Participants were identified by use of codes and the data was analyzed and presented anonymously.Study limitations: The study period was three months which were too short for further follow up of the infants that could have enabled the researcher to establish the later growth or outcomes of the preterm infants.A total of 115 preterm infants were screened for the study. One was excluded because of congenital anomaly and two guardians declined to participate. Of the 112 participants enrolled in to the study at discharge from the Kitui District Hospital Newborn Unit, 106 (94.4%) of them were available for reassessment after two weeks. The six (5.6%) participants who were not reassessed at follow-up were due to two (1.8%) neonatal deaths and four (3.6 %) losses to follow-up. Majority of the infants were females (60%) born at gestational age of 33-36 weeks (54.5%). Most (83.9%) of these infants were born in a health facility through spontaneous vertex delivery (77%). They had an APGAR score of more than 7 in one minute (87.5%) and were not resuscitated at birth (74%). The infant length of hospital stay varied from two to 30 days with only 10% having had to stay for more than a month. Most of them were feeding on breast milk only (92.9%) and they had not suffered any illness post discharge (88.3%).Most of the mothers were between 20-29 years of age (73.9%) and were married (66.1%). Many of these mothers had only attained primary education (66.1%) and were housewives (35%) to self-employed spouses (56%). Majority of the mothers (88%) lived in the rural areas. The infants' body weight between NBU discharge and week 2 follow-up increased from median body weights of 1880 grams (IQR 1830-2270) and 2215 grams (IQR 1950-2500), respectively  . Their mContrary to what was expected, the preterm infants who were born between 33 - 36 weeks gestational age at birth were at more risk of developing growth deficit than those between 28 - 32 weeks. All the infants who were born less than 28 weeks gestation had optimal growth. This does not agree with a study that was carried in Brazil that showed that extremely low birth weight infants were at more risk of developing complications of prematurity. Infants born between 33 - 36 weeks have also been thought to require less support than those who are born at 32 weeks and below. Since the infants who were born less than 28 weeks gestation had longer hospital stay and better outcomes, it would be necessary to keep the late preterm infants for a longer period in the hospital before discharge. This will empower their guardians with the knowledge to care for the small babies by allowing more time with the health care providers. Follow up of the infants provided very important information in regards to their early growth which was often overlooked during their outpatient visits. Early detection of any deviation in their early growth would greatly assist in timely intervention for better future outcomes of these infants. In support to two studies which were carried out in Kenya and Uganda, most of the preterm infants did not attain the recommended daily weight gain. This could be associated with the many difficulties which were experienced by the guardians during the transition period from the health facility to their homes.Majority of the mothers were between the ages of 20-29 years (73.9%). This age group has been associated with better survival and outcomes of preterm babies which is a very positive maternal characteristic in this population. Optimal growth was demonstrated in infants whose mothers had any level of literacy in comparison to mothers who had not attained any formal education. Education always empowers the mothers in all aspects and should therefore be emphasized. Mothers who lack or have very low level of literacy should therefore be given extra support by either discharging their infants at a much higher weight or being given one week postnatal return date instead of two. Being married and staying home as a house wife was also shown to contribute positively towards the growth of the infants. A mother who receives family support from a spouse is more likely to be emotionally and psychologically stable which would in turn promote her parenting skills. Those mothers who were housewives could be able to offer their total attention to their infants and hence their better outcome.This study filled a gap which was identified in prior studies which stated that few studies were carried out in Africa during the postnatal periods of these infants. There was need for continued support of the preterm infants and especially during their immediate post discharge period in the community. This can be facilitated by linking them to level 2 and 3 facilities where their body weight, body length and head circumference can be monitored on weekly basis. However, the study did not follow the infants for a longer duration which would have established the later growth and developmental outcomes of these infants.Most of the preterm infants at discharge were females who were born between 33 and 36 weeks gestation. Growth deficit was present in the majority and gestational age at birth was a major determinant of the early growth in these preterm infants. There's need for further research in order to establish the later outcomes of preterm infants after hospital discharge at the Kitui District Hospital.Early growth in preterm infants is a predictor of their later growth and developmental outcomes;The extremely preterm infants are at increased risk of developing complications of prematurity such as deficit in growth;The growth of preterm infants is influenced by different infant and maternal characteristics.This study described the early growth of the preterm infants during their immediate postnatal period which is usually a difficult transition period for both the infant and the guardian;It also identified the infant and maternal characteristics that influenced their growth.