Abdominal obesity is becoming an increasingly serious public health challenge in children and adolescents, there remains controversial opinions on birth weight and risk of childhood abdominal obesity. This study aims to assess the association between birth weight and the risk of abdominal obesity in childhood, as well as to compare the associations among different sex and age groups.A total number of 30,486  participants aged 6–17 years old were included in this study. Participants were classified into five groups according to their birth weight. Waist-to-height ratio (WHtR) was used to define abdominal obesity. Fractional polynomial regression model was used to assess the association between birth weight and WHtR, and a multi-variable logistic regression model was applied to evaluate the risk of abdominal obesity in different birth weight groups.A J-shaped association was observed between birth weight and WHtR. Compared with birth weight of 2500–2999 g, high birth weight was associated with increased risk of abdominal obesity . No significant correlation was observed in children with birth weight ≤ 2499 g. Similar patterns were observed across different age groups. Abdominal obesity risk for high birth weight was particularly pronounced in boys compared to girls.Birth weight ≥ 3000 g, especially for boys, was associated with an elevated risk of abdominal obesity in childhood and may benefit from intervention to mitigate this risk. Childhood obesity is one of the most serious public health challenges worldwide . In ChinAlthough obesity had been typically defined using body mass index (BMI), it has been demonstrated that BMI has limited capacity in measuring fat distribution . Other aIt has been suggested that early development  can influence a person’s physiology and metabolic health status permanently , 15. BirIt has also been proposed that the correlations may vary by sex and age. A cross-sectional study in 7 to 8 year-old Japanese children  has demoData in this study comes from the baseline cross-sectional survey of a national multicenter cluster-controlled trial aimed to reduce the burden of obesity in children and adolescents (Registration number: NCT02343588). The survey was conducted in seven provinces or cities of China . Design and sampling procedure have been reported in detail elsewhere . Brieflyn = 234), weight (n = 1387), height (n = 1630), waist circumference (n = 1786), birthdate (n = 2780) or birth weight (n = 3902). The trial was approved by the Ethical Committee of Peking University (IRB0000105213034), and all participating children and their parents signed the informed consent forms for the physical examination and questionnaire survey.A total of 41,003 primary and middle school students aged 6–17 years old were enrolled in this study initially, of whom 30,486 remained in the analytical sample for the present work after excluding participants with missing records of urban/rural area  and height (cm) were measured. WC was measured at the midpoint between the iliac crest and lowest rib by Myotape scale  with 0.1 cm precision, and height was measured using the portable stadiometer  with 0.1 cm precision. Both WC and height were measured twice and the average of two records was used in data analysis. Waist-to-height ratio (WHtR) was calculated as WC divided by the height. The cut-off value of 0.5 was used for WHtR to classify abdominal obesity .Students’ questionnaire and parental questionnaire were used to collect the information from children and their parents, respectively.The students’ questionnaire was completed by themselves in children of grade 4 to 12 (with age range from 10 to 17 years old) and was completed under the assistance of their parents in children of grade 1 to 3 (with age range from 6 to 9 years old).The students’ questionnaire was used to collect information of dietary behavior, including the consumption of fruits, vegetables, total meat, and sugar-sweetened beverages (SSBs) over the past 7 days. A serving of fruit/vegetable was defined as the size of an adult fist (approximately 120 g) , a serviInformation of child’s physical activity was recorded by the International Physical Activity Questionnaire-Short (IPAQ-S) , which h2 was applied to define parental overweight/obesity. Parental educational level was classified into four categories . Parents were required to report their children’s early life information, including birth weight, gestational age and number of fetus  based on the birth certificate or health clinic record [The parental questionnaire was filled out by parents at home. Paternal and maternal height and weight were reported in the parental questionnaire and then used to calculate body mass index (BMI), a cut-off point of BMI ≥ 24 kg/mc record . If theyc record .n = 21,615). All analyses were conducted using SPSS 20.0  and Stata 14 software  and a two-sided P value of < 0.05 was considered statistically significant.Descriptive results were characterized as means ± standard deviations for continuous variables and percentages for categorical variables. One-way ANOVA, independent sample Student’s t-test and Chi-square test were used to compare the distribution of descriptive characteristics between boys and girls. The nonlinear association between birth weight and WHtR was performed by fractional polynomial regression model. Logistic regression models were performed to assess the odds ratios (ORs) and 95% confidence intervals (CIs) for abdominal obesity when participants with birth weight of 2500–2999 g were used as the reference group. The crude model was adjusted for sex , residence area, and age, while the adjusted model was further adjusted for gestational age, delivery mode, fetus number, feeding pattern, single-child status, paternal overweight/obesity, maternal overweight/obesity, paternal educational level, maternal educational level, daily fruit and vegetable consumption, daily meat consumption, daily SSBs consumption, and daily moderate to vigorous physical activity. Since about 25.6% of the original study sample had to be excluded for a variety of reasons, a sensitive analysis was conducted in the initial sample of 41,003 children. In addition, we have also done a sensitive analysis by extracting participants with original birth weight records (P<0.01). The prevalence of abdominal obesity was 16.4% in total participants with a higher rate in boys (20.5%) than that in girls (12.0%) (P<0.05).A total of 30,486 students aged 6–17 years were included in the analysis. As showed in Table The nonlinear relationship of birth weight and WHtR is shown in Fig. P = 0.692). When further adjusted for potential confounding factors, only minor changes were observed for these estimations. The birth weight (≥ 3000 g) was positively associated with higher risk of abdominal obesity . In addition, the ORs of abdominal obesity were higher in boys than those in girls in the same birth weight group. Participants had an evelated risk for those with a birth weight ≥ 3000 g in boys and ≥ 4000 g in girls. Based on the original sample  and original birth record sample , we have done two sensitive analyses and have come to similar results with the present study  and original birth record sample , we have done two sensitive analyses and have come to similar results with the present study.  , but higA J-shaped relationship was observed between birth weight and WHtR in this study. On the one hand, a positive association between birth weight and WHtR was found in children with birth weight > 3000 g, especially in boys. These findings were consistent with studies conducted by Schellong , Loaiza Additionally, the present study found that low birth weight (< 2500 g) was not significantly associated with risk of abdominal obesity regardless of sex and age. Studies from Frye , Yuan 3 and SingThe association between birth weight and abdominal obesity may be explained by intrauterine environmental condition, genetic and lifestyle factors. Birth weight is regarded as a reflection of the intrauterine environmental situation . On the Extending the findings of previous studies, we have further conducted an analysis by different age group. While high birth weight (> 4000 g) was significantly associated with abdominal obesity in all age groups, elevated risk of abdominal obesity was also observed in birth weight group of 3500–3999 g, but only in those of younger ages (6–9 years). A possible explanation for this is that the effects were influenced by other environmental factors which were not considered in this study, for example, it has been reported that younger children spend more time in doors than older children, and they are less sensitive to unhealthy food outside of the home than older children , and morThere are several limitations in this study. First, the birth weight information was obtained from parental questionnaire, rather than directly from the hospital birth records database, and nearly 30% children’s birth weight were obtained by parental recall. Second, this study was based on a cross-sectional study, and no causal relationship can be suggested. In addition, we did not have the information of parental nutritional status during pregnancy. It has been suggested that gestational weight gain could lead to fetal macrosomia and obesity after birth. Future study is needed to determine the relationship between birth weight and other health consequences in later life.In summary, this study examined the association between birth weight and risk of abdominal obesity in Chinese children and adolescents aged 6–17 years old. A J-shaped relationship was found between birth weight and WHtR, and children with high birth weight (> 3000 g) had higher risk of abdominal obesity than those with low birth weight, especially in boys. This study would contribute to a better understanding of the relationship between intrauterine growth and abdominal obesity in later life. Our findings could aid the clinical practitioners to identify youth at risk of abdominal obesity, and have a potential to improve intervention strategies aimed at reducing the burden of childhood obesity. Further study is needed to explore the mechanisms underlying this association.Additional file 1: Table S1. Risk of childhood abdominal obesity in boys and girls with different birth weights in Total participants . Table S2. Associations between birth weight and childhood abdominal obesity in different age groups. Table S3. Risk of childhood abdominal obesity in boys and girls with different birth weights in participants with original birth weight records. Table S4. Associations between birth weight and childhood abdominal obesity in participants with original birth weight records, stratified by age groups


Scientific Reports 10.1038/s41598-019-55324-2, published online 11 December 2019Correction to: This Article contains a typographical error in the Methods section under subheading ‘Participants’ where,“The following exclusions were applied: still births (n he59), multiple births (n 9)138), pregnancies resulting in the birth of children with congenital anomalies (n 38649), and women who had missing baseline questionnaire or birth outcome data (n 49831).”should read:“The following exclusions were applied: still births (n = 59), multiple births (n = 138), pregnancies resulting in the birth of children with congenital anomalies (n = 649), and women who had missing baseline questionnaire or birth outcome data (n = 831).”In addition there is a typographical error in the Methods section under subheading ‘Statistical Analysis’ where,“The shape of the BP trajectory across pregnancy was described by fitting restricted cubic splines using knot points which have been previously identified in the same dataset using linear splines , with two additional outer knots at the 5th and 9th percentiles of the data (14 and 40 weeks).”should read:“The shape of the BP trajectory across pregnancy was described by fitting restricted cubic splines using knot points which have been previously identified in the same dataset using linear splines , with two additional outer knots at the 5th and 95th percentiles of the data (14 and 40 weeks).”


Thanatophoric skeletal dysplasiais the most lethal, rare, sporadic birth defect due to de novo mutation in the fibroblast growth factor receptor-3. Clinically this is characterized by shortening of the limbs (micromelia), small conical thorax, flat vertebral bodies and macrocephaly at birth. We encountered a similar case with ultrasonographic findings suggestive of Thanatophoric Skeletal Dysplasia which resulted in the death of the baby within an hour of birth. Almost all cases of this condition have been reported to have died interuterinally or a few days after birth. All four limbs were small to corresponding gestation (micromelia) and Amniotic Fluid Index (AFI) 30 cm which is suggestive of Thanatophoric Skeletal Dysplasia .The emergency lower segment cesarean section (LSCS) was done at 39+6 WOG for fetal bradycardia and macrocephaly. A single, live, male with a birth weight of 3270 grams was born. The Apgar scorewas 4/10 in the first minute and 3/10 in the fifth minute. The baby did not cry immediately after birth despite rigorousstimulation and suctioning. We started bag and mask ventilation and still, there was no cry and heart rate was less than 60 beats per minute which were gradually decreasing. Meanwhile, the need for ventilator support and Neonatal Intensive Care Unit (NICU) care was counseled to the patient's family but they denied doing any lifesaving interventions and the baby died after an hour of birth.Examination revealedthe length of 36 cm (<5th centile for newborn boy),macrocephaly , frontal bossing, short neck, central and peripheral cyanosis, saddle nose, low set ears. The sutures were not separated. The thorax was narrow, cone-shaped with small rib cage and abdomen was protuberant with the abdominal girth of 33 cm. All the limbs were small with a deformed attitude . Thighs and legs were bowed. Deep creases were present in all limbs .There was small pit/dimpling over the sacral region, cryptorchidism and flat back and spine . However4 FGFR3 gene is located in chromosome 4p16.3, responsiblefor givinginstructions for making a protein that is involved in the development and maintenance of bone and brain tissue.4 The malformations due to bone growth seen in TSD are due to overactivation of FGFR3 gene.5 The examination findings, in this case, revealsmacrocephaly, narrow thorax associated with polyhydramnios, micromelia, bowed thigh, frontal bossing, saddle nose, low set ears, protruding abdomen and flattening of the spine. We found similar findings in the different reported case of type I TSD.2-7 The radiological and morphological features revealed in our report (4TSD is the most lethal, rare, sporadic birth defect due to de novo mutation in the FGFR3 gene.r report  confirms6 The reason being, no affected individuals are known to have had children.Therefore, the disorder has not been passed to the next generation. As presented in our case, TSD usually leads to death inutero or shortly after birth.10 The reason for mortality in TSD is either due to reduced thoracic capacity, hypoplastic lung or brainstem compression.8The inheritance pattern of TSD is autosomal dominant but virtually all cases of TSD occur in people with no family history of TSD.10Usually, the diagnosis of TSD is made by USG duringthe second trimester and further specific type is distinguished on later scans during the third trimester with the help of fetal skeletal morphology.10 Further diagnosis can be confirmed with autopsy and histopathology but unfortunately could not be done in the present case as consent was not given by the parents.The radiologic and morphologic features described in this report were compatible with TSD Type I. These findings helped us to correlate them with their pathogenesis and realize the reason why this disease usually has a poor prognosis. Proper counseling to the patient's family is crucial for management and should be advised to undergo anomalies screening in subsequent pregnancies.JNMA Case Report Consent Form was signed by the patient and the original article is attached with the patient's chart.None.


Help is directed towards kin in many cooperative species, but its nature and intensity can vary by context. Humans are one of few species in which grandmothers invest in grandchildren, and this may have served as an important driver of our unusual life history. But helping behaviour is hardly uniform, and insight into the importance of grandmothering in human evolution depends on understanding the contextual expression of helping benefits. Here, we use an eighteenth-nineteenth century pre-industrial genealogical dataset from Finland to investigate whether maternal or paternal grandmother presence  differentially affects two key fitness outcomes of descendants: fertility and survival. We found grandmother presence shortened spacing between births, particularly at younger mother ages and earlier birth orders. Maternal grandmother presence increased the likelihood of focal grandchild survival, regardless of whether grandmothers had grandchildren only through daughters, sons, or both. In contrast, paternal grandmother presence was not associated with descendants’ fertility or survival. We discuss these results in terms of current hypotheses for lineage differences in helping outcomes. Grandmothers are among a class of kin whose help is known to improve offspring outcomes, but this is taxonomically rare6 partly because few species have an extended post-reproductive life8—though post-reproductive life is not necessarily a prerequisite for grandmothering2—and partly due to dispersal patterns not facilitating grandmothering9. In humans, grandmothers routinely invest in their grandchildren11, which is associated with increased survival14, improved nutrition16, and also contributes to their well-being10. However, although most studies to-date have concentrated on grandchild outcomes, the fitness benefits of grandmothering are two-fold: not only do grandmothers increase the likelihood that their grandchildren will survive, they also relieve their children of substantial parental investment duties, which may allow them to shorten inter-birth intervals and ultimately produce more grandchildren17. These two types of beneficial effects form the basis of the grandmother hypothesis, which suggests grandmothering can lead to selection favouring longer post-reproductive lifespans15.One common explanation for helping behaviour is kin selection, whereby an individual gains fitness benefits by helping relatives20. For example, mothers generally provision more than fathers23, with paternal care more likely to rely on context 27. Dispersal patterns are crucial in determining the access of kin, and human dispersal in particular is flexible and diverse. As the strength of selection on post-reproductive lifespan can be affected by whether one or both lineages provide benefits, it is necessary to study lineage differences  in outcomes from grandmother presence in societies where both maternal and paternal kin have the opportunity to help.Even when potential helpers have the same degree of relatedness (i.e. kinship coefficient) to dependent offspring, the costs and benefits of help can vary between individuals, leading to differential levels of help33. In some societies, paternal grandmothers have even been found to be detrimental to the survival35 or physical development32 of their grandchildren. However, this is hardly universal: maternal grandmothers are not always beneficial to grandchildren36, and paternal grandmothers can both invest more than maternal grandmothers37 and are associated with increased grandchild survival39. Nor is there mutual exclusivity in being a maternal or paternal grandmother, because one can have grandchildren through both sons  and daughters . Might differences seen between the lineages be driven by preferential investment, when the choice is available? Alternatively, could grandmothers make a conscious effort to be ‘fair’ in their investment, and therefore be associated with better survival outcomes for paternal grandchildren only when they also have maternal grandchildren? To date, no work has explicitly investigated whether the presence of grandmothers with grandchildren from both sons and daughters leads to different outcomes compared to those with grandchildren from only one lineage.For survival outcomes, there is substantial evidence that maternal and paternal grandmothers do not always invest equally, with care typically exhibiting a matrilineal bias (i.e. the mother’s mother tends to invest more)11, and fewer still within the same models . Increased fertility resulting from (grand)mother presence is an important component of the grandmother hypothesis15, and should therefore be considered in a holistic package alongside survival effects to identify all the effects of grandmothers in both lineages, with the eventual aim of evaluating the strength of natural selection on the length of post-reproductive lifespan in women in different contexts.In contrast to grandchild survival outcomes, potential lineage differences in the effects of grandmother presence of the fertility of the next generation (i.e. daughters and daughters-in-law) are less well established, with relatively few studies distinguishing between the fertility impacts of (grand)mothers and (grand)mothers-in-law13, but these effects were not partitioned by lineage, and it remains unknown whether there are differential lineage effects in pre-industrial Finland. By distinguishing between all combinations of grandmothers , we can directly compare the effects of maternal and paternal grandmother presence (separately and in combination) versus the effects of not having any living grandmother. First, we test for fertility effects of (grand)mother/(grand)mother-in-law presence on i) the probability and timing of first birth and ii) probabilities of subsequent births of grandoffspring and birth spacing. We used time-event models, as these analyses take into account age-specific fertility, which can potentially confound studies of this nature: grandmothers are more likely to be alive when their offspring are younger. Second, we test for differences in grandchild survival between lineages during childhood. Because grandmother effects are known to differ by the age of grandchildren38, we investigate differences in grandmother effects across three distinct phases of childhood . Third, we investigate whether the effects of grandmothers are influenced by the type of grandchildren available. In other words, whether these effects differ between cases when both types of grandchildren  are alive and cases when only maternal or only paternal grandchildren are alive. This is important to consider because being a maternal grandmother does not preclude one from being a paternal grandmother, yet to our knowledge this has not been accounted for before. All these analyses allow direct comparisons between lineages, and aid in clarifying how grandmother lineage may be a key factor in the strength of selection from grandmothering on post-reproductive lifespan.Here, we analyse the differential effects of grandmother lineages  in a high fertility pre-industrial Finnish population on a) the fertility of their daughters and daughters-in-law, and b) the survival of their grandchildren. In this society, dispersal was such that both grandmothers typically resided nearby, with paternal grandmothers often co-resident. Previous studies on this population have established grandmother effects on both offspring fertility and grandchild survival41) for eight geographically-separated rural parishes in four regions of historical Finland  between 1731 and 1905. These registers—detailing births, deaths, children, occupations, and marriages—were maintained by the Lutheran Church, and were used to construct full life-histories of individuals and their descendants. Overall, Lutheranism was the prevalent religion, with 98% in the country still practicing in 190042. Orthodox Christianity was confined mostly to Karelia, but still at a low percentage.We investigated how mother fertility and grandchild survival were affected by grandmother presence using an extensive pre-industrial demographic dataset collected from population registers  for less than 10 years across the study period48. Residence was typically patrilocal, and migration was constrained such that both sets of grandparents typically lived nearby and marital partners came from the same or nearby villages. We categorised individuals as belonging to one of the two following social classes, which can capture important between-individual variation in mortality, marriage patterns, and birth rate49: landed  and landless . Social stratification was, however, less pronounced than elsewhere in Europe, and dispersal to urban areas (thus increasing geographic distances between generations) did not occur until the late nineteenth century50.Finnish society in the eighteenth and nineteenth centuries was agrarianHere, we included all individuals who were born between 1731 and 1890 and whose two grandmothers were both known , and their mothers, for the fertility analyses .51. Significance was defined at the level of α = 0.05. Model selection was done by removing each fixed term with the function drop1, and then comparing their Akaike information criterion (AIC) values to those of the full model. To avoid overfitting—see52 for further details—terms were not included in the final model if AIC decreased upon removal, or if it was within 2 units of the full model (more conservative than higher thresholds)52. We did not, however, remove mother/grandmother status or focal individual age, as the former was the main term of interest, and the latter is a necessary component in our modelling structure (see below for details).All analysis was conducted with R 3.5.153, with the logit link function. Statistical significance of interaction terms was assessed via likelihood ratio testing, implemented with the mixed function in R package afex 0.21–254.All analyses were discrete time-event analyses, which allowed us to analyse the effects of time-dependent variables on a yearly basis. These were implemented as binomial generalised linear mixed-effects models (GLMMs) using glmer from the R package lme455. Whilst women in this population did not co-reside pre-maritally with the paternal grandmother (their future mother-in-law), the paternal grandmother could still potentially accelerate the onset of reproduction by influencing who and when her son married. Therefore, we included women from the age of 16 (the end of childhood) until they gave birth or reached age 50 . In addition, we only included women who were ever married and had known information on their mother-in-law. As spousal death would disrupt reproductive scheduling, women were censored in the year their first spouse died.The age at which reproduction begins can be of greater importance for determining the length of an individual’s reproductive career than the less variable age of reproductive cessationThe response variable was whether the offspring had their first birth in that year . The main explanatory variable was the interaction of age (mean-centred) and mother/mother-in-law survival status , with ‘neither alive’ as the reference level, to test whether the presence of either mother or mother-in-law enhanced reproduction at age stage of the woman’s potential reproductive career. For any given single individual, mother/mother-in-law presence could change from year to year, depending on when the preceding generation died.48 (though running the model with this random term included did not affect the results). After model selection, we dropped the social class and region terms.We initially controlled for social class, region, birth order, quadratic (mean-centred) age, and number of living siblings, while entering mother ID as a random effect to account for shared family effects between siblings. We did not control for birth cohort in the final model, because age at first birth did not vary across time in this populationobservations = 25,161) starting from after their first child’s birth.Birth spacing is a crucial factor in determining an individual’s reproductive history. To analyse the effect of mother/mother-in-law presence both on probability of subsequent births and birth spacing in the middle generation, we restricted our analysis to a subset of women who had birthed more than one child  was entered as an additional random effect to account for an uneven spread of data and differences in conditions  across the period of study that may affect inter-birth intervals. Using the results of our model selection criteria (see above), we removed the birth order of the focal individual and number of living siblings terms.The response variable was whether the individual gave birth in a given year . We included two three-way interactions as explanatory variables. The first was between a time-varying mother/mother-in-law presence factor, time since last birth , and age (mean-centred), and the second between time-varying mother/mother-in-law presence variable, time since last birth, and birth order of the grandchild. Time since last birth was used instead of inter-birth interval, as the latter term is time invariant and inappropriate for this type of model. This birth order term was for the child born at the end of the interval , and was included as parity could affect desire to have more children. After the last birth, subsequent years had birth order coded as the next value . All two-way combinations from these interaction terms were also added to the model. We also included a two-way interaction of the survival status of the child born at the start of the interval  and the time since last birth, as this can affect the speed and probability of giving birth . Rather than removing observations in which the time since last birth exceeded 10 yearsIn the survival analyses, the response variable was whether the focal grandchild survived in a given year . Individuals without a recorded date of death and those with either grandmother disappearing from the records before they themselves reached the upper age limit (see below for details) or died were censored at the last date they were known to be alive. We excluded observation years for individuals from the analysis if the individual died within a week of the death of their mother , or if the mother and child were both censored in that year .57, so including grandmothers living in a different parish could mask the effects of nearby grandmothers.Grandmother presence was coded in a similar way to the fertility analyses above: as a 4-level factor with levels for both grandmothers alive, no living grandmother, only maternal grandmother alive, and only paternal grandmother alive. For a given individual, grandmother presence could change from year to year, depending on when their grandmothers died—this was only one directional e.g. once a maternal grandmother had died, the focal individual could not have ‘both alive’ or ‘maternal grandmother only’ as the value for grandmother presence. As precise housing information is unavailable, grandmother distance to a grandchild was considered at the parish level by comparing the last known parish of a grandmother to the birth parish of a grandchild. All grandmothers who were both coded as “alive” and included in the analysis needed to have lived in the same parish at the same time as the grandchild. Individuals with one or both grandmothers alive but living in a different parish were not included in the sample, as these grandmothers could not be treated as either present or as dead. Furthermore, grandmothering effects have been shown to decline with distanceobservations = 11,013), 2–5 , and 5–15 . These age intervals include the left border and exclude the right border, with the exception of 5–15, which included all individuals up to and including the age of 15.To investigate how maternal and paternal grandmother presence was associated with grandchild survival at different grandchild ages, we separated the data into three age classes: 0–2 , maternal survival status , childhood social class , whether the child was a twin, sex of grandchild, birth order, region of Finland, maternal age (continuous), and number of surviving siblings . Of these, grandmother presence, child age (linear and quadratic), maternal survival status, and number of living siblings were time-varying. Random terms included mother identity (ID) nested within maternal grandmother ID to account for variation between groups of siblings (from mother ID) and cousins (from grandmother ID), and birth cohort.Using the model selection procedure outlined above, quadratic age, birth order and mother age at birth were removed from all three models. Additionally, childhood social class, region, and sex were removed from 2 to 5 and 5 to 15 models, number of living siblings was removed from 0 to 2 and 2 to 5 models, and twin was removed from the 5–15 model. These new, more parsimonious models were run with the grandmother type ‘no living grandmother’ as the reference level, which provided the intercept values. Reference levels for other variables were as follows: ‘Southwest Finland’ for region, ‘mother alive’ for mother survival status, and ‘singleton’ for twin.observations = 11,013), 2–5 , and 5–15 . The grandmother type variable was updated to account for whether maternal grandmothers also had paternal grandchildren, and whether paternal grandmothers also had maternal grandchildren. The new variable therefore had six levels: both grandmothers alive , both grandmothers dead , maternal grandmother only , paternal grandmother only , maternal grandmother of the child but also a paternal grandmother , and paternal grandmother of the child but also a maternal grandmother . Due to separation issues (i.e. non-existence/exceedingly low sample size of certain combinations of variables), we were unable to account for whether grandmothers were maternal and paternal when both grandmothers were alive.To investigate whether the presence of grandmothers who have both maternal and paternal grandchildren are correlated with differing survival outcomes in maternal and paternal grandchildren compared to those with only maternal or only paternal grandchildren, we again ran GLMMs on grandchildren aged 0–2  are present in historical datasets such as ours.32 = 7.25, p = 0.06). In other words, age at first reproduction was not earlier in the presence of the preceding generation , and latest when both were deceased (26.75 ± 5.40). If only the mother was living, first reproduction of daughters was slightly earlier than if only the mother-in-law was alive (24.80 ± 4.75 vs. 25.26 ± 4.62). However, the mother/mother-in-law presence did not have a statistically significant effect on the probability of the first birth overall Table , or at dion Fig. .Figure 123 = 31.53, p < 0.001); when the mother was present, the probability of her daughter giving birth at shorter birth intervals was higher and the effect was stronger at younger ages  died during childhood, and an additional 7.2% (421) were censored before 15. To parse the age-specific effects of maternal or paternal grandmother presence on such grandchild mortality (i.e. how sensitive grandchildren were to grandmother presence at different stages of development), we investigated the influence of grandmothers for key grandchild age periods. Grandchild mortality was greatest early in life, with 53.1% of childhood deaths occurring in those younger than two, and 79.9% of deaths occurring in children younger than five.We found that grandmother effects varied between different age groups Fig. . BetweenWe then investigated whether lineage exclusivity of a grandmother  may have played a role in generating differences in grandchild outcomes by maternal and paternal grandmother presence. We found that there were no grandmother effects of any kind for infants (ages 0–2) or for older children (ages 5–15), whilst effects were found for ages 2–5 Fig. . SignifiWe found a matrilineal bias in grandmothering outcomes such that both higher offspring fertility and grandchild survival were associated with the presence of a maternal grandmother. In particular, maternal grandmothers were associated with an increased probability of birth after the first child and with shorter birth intervals of their daughters, and did this more when they were younger and earlier in their reproductive career (i.e. earlier births). Overall, this acceleration of reproductive scheduling in the presence of maternal grandmothers after the onset of reproduction supports the grandmother hypothesis. However, effects did not exist for all outcomes or contexts: for fertility, (grand)mother presence did not influence age at first birth, and survival effects on grandchildren were limited to the period after they had been weaned, with no detectable effects across the entirety of childhood. This may be due to the comparatively low mortality rates after age 5 (only ~20% of childhood deaths occurred after this age): the effect of maternal grandmothers is higher with toddlers, reiterating the importance of considering grandchild age when investigating the fitness outcomes of helping kin. Regardless, these fertility results show that both facets of the grandmother hypothesis can occur at the same time in the same population: maternal grandmothers could positively affect fertility of offspring and survival of grandoffspring.59. However, this interpretation cannot completely explain fertility differences, and is unlikely to explain the full effect of lineage differences in grandchild outcomes in this pre-industrial Finnish population. There are two elements of paternity uncertainty: psychological adaptations and a population parameter. The former invokes kin recognition and fidelity, which could reduce paternal grandparent attachment towards paternal grandchildren. In this population, these psychological adaptations are unlikely to explain lineage differences: monogamy was strictly adhered to in this population, with the church forbidding divorce and enforcing punishment for adultery60 . Indeed, historical extra-marital paternity rates in Europe are estimated to have been very low during this period (less than 1.5%)62. The population parameter of paternity uncertainty is an ancestral, taxon-wide parameter, but the impact this might have had on patrilineal grandmaternal behaviour is unknown and may be negligible. Furthermore, paternity uncertainty as an explanation often ignores societal differences63, is not universally supported65, and cannot be explicitly tested in historical societies without genotyping. Differential X-chromosome inheritance  has also been proposed as a possible mechanism for lineage differences in optimal grandmother investment strategies66, but this too has been found to be inapplicable to this population46. Similarly, whilst localised resource competition67 could explain differences in cases with negative effects of resident grandmothers on grandchild outcomes35 , they cannot explain differences when the co-resident lineage has no impact on survival, as is the case here. Perry and Daly68 raise the intriguing possibility that investment in the grandchildren is also a downstream investment in the mother’s ability to help others. Though this work outlines testable hypotheses, the authors themselves acknowledge the difficulties in addressing these without measures of alloparental contributions .Paternity uncertainty is frequently raised as a possible explanation for results showing differences between maternal and paternal grandmother investmentStudies into differential ‘helping’ outcomes  could be confounded by maternal grandmothers also being paternal (and vice versa). However, we found no evidence that lineage ‘exclusivity’ drives the difference in grandmother effect. Grandmothers with grandchildren from both daughters and sons were just as beneficial to their daughter’s children at grandchild ages 2–5 as grandmothers with grandchildren only through their daughters . Meanwhile, paternal grandmothers without grandchildren through their daughters did not improve the survival of grandchildren, which suggests that competition between daughters and sons was not a reason for the failure of paternal grandmothers to improve the fitness outcomes of their children. These results do not support preferential investment or any kind of ‘fair’ allocation of help, as paternal grandmothers remain unassociated with survival whether they have the option to invest in maternal grandchildren or not. Grandmother presence does not improve survival of their paternal grandchildren—something must be driving these clear lineage differences in survival outcomes, but we have not been able to identify it here.68). The effect of culture is difficult to empirically test, even accounting for dispersal and co-residence patterns, and makes it more challenging to determine the exact role of grandmothering in selection for post-reproductive lifespan as we delve further back into our evolutionary past. From an even broader perspective, however, one cannot look at any single factor as a key predictor of lineage-specific grandmothering. For example, though female-biased dispersal could predispose species to evolve extended post-reproductive lifespans and post-reproductive help15, it does not alone allow prediction of how grandmother effects are expressed. For example, even though pre-industrial Finland and rural Gambia share broad societal similarities—the populations are typically agrarian and tend towards patrilocal living—the fertility effects are reversed. In Gambia, it is the paternal grandmother (mother-in-law) that is associated with improved fertility in Gambia69, whereas in Finland the maternal grandmother increases it. Accounting for more societal and cultural elements reveals the populations are only superficially similar and differ in e.g. mating strategy and practised religion, emphasising the importance of considering multiple criteria for ‘defining’ societies.Regardless of the exact driver of lineage differences in grandmother effects, current hypotheses do not have to be mutually exclusive. Indeed, cultural practices and societal structure  may be the most important mediators of differential grandmaternal investment by altering the relative contributions of the various  mechanisms  grandmaternal lineages suggest that selection on post-reproductive lifespan from grandmothering may be weaker than once thought. As mechanisms currently hypothesised as drivers of lineage differences do not appear to produce the different effects found in this population, it may be that a suite of cultural practices mediate lineage biases in outcomes (and likely grandmother investment).Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Below is the link to the electronic supplementary material.


By Cox proportional hazard analysis, use of ritodrine in preterm birth was associated with significantly higher hazard of autism , after adjusting for confounding variables including maternal age, parity, cesarean section, preterm labor, steroid use, birth weight, gender, and preeclampsia. Thus, in utero exposure to ritodrine was associated with an increased risk of autism in their offspring.Beta-2 adrenergic receptor (B2AR) agonists, used as asthma treatments and tocolytics during pregnancy, have recently been reported to be associated with autism in their offspring. However, the particular link between autism and ritodrine, a common type of B2AR agonist used solely as tocolytics, has never been substantiated with any nationwide database. Thus, we aimed to examine the association between in utero exposure of ritodrine and the risk of autism in their offspring using a national database. This population-based cohort study was conducted by merging the Korea National Health Insurance claims database and National Health Screening Program for Infants and Children database. These databases included all women who had delivered singleton between January 2007 and December 2008 in Korea. Out of the total 770,016 mothers, 30,959 (4.02%) were exposed to ritodrine during pregnancy, and 5583 (0.73%) of their children were identified as having autism, defined until 8 years of age. According to our analysis, the overall cumulative incidence of autism up to 8 years was 1.37% in ritodrine exposure group and 0.70% in ritodrine non-exposure group ( The prevalence of preterm birth has been reported as 7.5% in the developed countries and 12.5% in developing countries2. Overall, it occurred in 11.1% births worldwide in 20103 and in nearly 7% of all births in Korea according to Korean National Statistics in 20164. Nowadays, a number of medical strategies for prevention and management of impending preterm births are implemented in obstetric practices, including tocolytics, progesterone, and antibiotics. However, there is a significant lack of data with regards to the long term effects of such medicines on childhood outcomes, when used for mothers during their antenatal period5.Preterm birth, a leading cause of neonatal mortality and morbidity, is one of the primary concerns among many obstetricians and pediatricians7. Such tocolytics include beta-2 adrenergic receptor (B2AR) agonist, calcium channel blocker, oxytocin antagonist, and magnesium sulfate, all prescribed for preventing preterm labor8.As a preventative measure for preterm birth, tocolytics therapy is usually recommended to secure time before the subsequent antenatal corticosteroid treatment. This therapy is known to be effective in delaying gestational age at delivery up to 48 h or 7 days, but its ability to improve neonatal outcomes has not been confirmed14. For instance, supply of ritodrine was voluntarily withdrawn from the United States market by the manufacturer in 1998 due to severe maternal side effects such as cardiovascular complication and death16. In addition, in 2011, the United States Food and Drug Administration restricted the prolonged use of terbutaline as tocolytics10. In 2013, European Medicines Agency also restricted the use of oral and suppository forms of short acting beta-agonists due to cardiovascular side effects11, and consequently, the National Institute for Health and Care Excellence guideline in 2015 prohibited the use of beta-mimetics for tocolytic purposes12.Among these tocolytics, a long-term usage of B2AR agonists has been discouraged by many recent guidelines due to its potential side effects17 and neonatal hypoglycemia18. In addition to these short-term side effects, deleterious behavioral effects in offspring after in utero exposure to various B2AR agonists in mothers have been recently reported. A study by Connors et al. in 2005 showed that prenatal exposure of terbutaline for 2 weeks or longer was associated with increased concordance rate for autism in dizygotic twins19. Another study from the Unites States in 2011 suggested that exposure of terbutaline during the third trimester may be associated with an increased risk of autism20. Later studies using Demark population registers also demonstrated that in utero exposure of B2AR agonists was associated with increased risk of autism and attention-deficit/hyperactivity disorders-risk22.It is well known that B2AR agonists may have maternal side effects including pulmonary edema, palpitation, and hypokalemia, along with various fetal-neonatal side effects such as fetal tachycardia25. Therefore, there is an urgent need to examine the link between in utero exposure of ritodrine and autism in their offspring using a nationwide birth database. Using a comprehensive database from the Korea National Health Insurance (KNHI) and National Health Screening Program for Infants and Children (NHSP-IC), we identified all women who delivered singleton between January 2007 and December 2008 . Then, based on International Classification of Diseases-10th Revision (ICD-10) codes, we examined the cumulative diagnosis of autism in their offspring until 2015.However, most studies above defined B2AR agonist exposure during pregnancy based on the outpatient prescriptions, and therefore included multiple types of B2AR agonists. In addition, since B2AR agonists are also commonly used in treatment of asthma, the association between in utero exposure of B2AR agonists and autism in their offspring demonstrated by the studies above may not specifically apply to situations in which B2AR agonists are used for tocolytic purpose only. Meanwhile, ritodrine is used solely as tocolytics unlike many other B2AR agonists and is still one of the most common tocolytics in clinical practice in many countries including Korea, Canada, JapanThis study was conducted by integrating the KNHI claims database and NHSP-IC database. The KNHI program covers 97% of the population; the Medical Aid Program is usually in charge of the remaining 3%. The KNHI claims database contains information on claims for approximately 50 million Koreans. Thus, nearly all information about the varied disease prevalence and treatments can be provided by this centralized database, with the exception of procedures not covered by insurance such as cosmetic surgery.The KNHI system provides an NHSP-IC for all neonates for seven consecutive health examinations based on age groups . The NHSP-IC consists of two components: a health interview with the parents and a health examination of offspring. NSHP-IC also offers screening for developmental delay, the Korean Ages and Stages Questionnaire (K-ASQ). Children suspected of a developmental delay on the K-ASQ questionnaire are transferred to specialized clinic. The study population was only composed of neonates who underwent NHSP-IC therefore these neonates were included in screening for developmental disorders.A flowchart of patient enrollment is shown in Fig. Using the KNHI claims database, autism was identified via primary or secondary diagnosis based on ICD-10 codes. Offspring were classified as having autism if they were diagnosed with autism (ICD-10 code F84.X) from birth to December 31, 2015.Maternal use of ritodrine during index pregnancy was identified using the KNHI claims database. Based on ICD-10 code, information about pregnancy outcomes including parity, cesarean delivery, preterm labor, steroid use, and preeclampsia were evaluated using the KNHI claims database. Information on neonatal outcomes including preterm birth, neonatal birth weight, and gender data were collected from the NHSP-IC database. Preterm birth was defined as gestational age < 37 weeks, low birth weight was defined as birth weight < 2500 g, and large for gestational age was defined as birth weight > 4000 g.p value of < 0.05 was considered statistically significant. Statistical analyses were performed using SAS for Windows, version 9.4 .Differences in continuous and categorical variables were analyzed using the t-test and Chi-square test, respectively. The cumulative incidence of autism was estimated using the Kaplan–Meier method and compared using the log-rank test. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the development of autism. A A total of 882,023 women delivered in South Korea from January 2007 to December 2008. Among these women, 112,007 were excluded from the study for the following reasons. As demonstrated in Fig. Among the 770,016 mothers, 30,959 (4.02%) were exposed to ritodrine during pregnancy.Table p < 0.05, log-rank test).Figure Table Since preterm birth itself is a significant risk factor for autism in their offspring, we also performed a subgroup analysis by dividing preterm and term delivery groups.p < 0.05, log-rank test).Figure Table Table Using a national database that encompasses nearly all infants born in Korea between 2007 and 2008, this study demonstrates that maternal in utero exposure of ritodrine during pregnancy is associated with an increased hazard of autism in their offspring until 8 years of age. By Cox proportional hazard analysis, the use of ritodrine during pregnancy is generally associated with higher hazard of autism, even after adjusting confounders such as maternal age, neonatal birth weight, preterm birth, preterm labor and steroid use . Moreover, the use of ritodrine in preterm birth was associated with significantly higher hazard of autism , after adjusting for confounding variables.26. The global prevalence of ASD was reported as 0.62% in a review published in 201227. In addition, its prevalence has increased in the United States from 0.67% in 2000 to 1.46% in 2012, according to the Autism and Developmental Disabilities Monitoring Network (ADDM) report28. A recent study using the total population of South Korean children aged 7–12 years revealed remarkably high ASD prevalence as 2.64%, accounting for 1/38 of the total sample29.Autism spectrum disorder (ASD) describes a wide range of symptoms, including difficulty with social interaction, lack of communication skills, and unusually repetitive behavior31. In addition, antiepileptic drugs such as valproate were reported to have seven times higher prevalence of ASD when exposed during pregnancy32. Recently, it was suggested that paracetamol (acetaminophen) may increase the risk of autism as well as hyperkinetic symptoms 33. Besides these medicines, many others introduced during pregnancy were also associated with increased risk of autism31.The reason for such increase in ASD is not entirely clear. Environmental effects such as use of medicines during fetal development as well as genetic factors are all suggested as a possible etiology of ASD. A number of studies have recently proposed a link between ASD and exposure to certain medicines, suggesting the importance of intrauterine environment in long-term fetal neurodevelopmental outcomes. For example, use of antidepressants during the second and/or third trimester was associated with an ASD risk 21. However, as this study did not specify the exact purpose of B2AR agonist prescriptions, it seems likely that these agonists were rather prescribed for the treatment of asthma, given that such B2ARs were chosen based on the outpatient prescriptions. Compared to these previous studies22, the difference in our study is that only the intravenous ritodrine, used only for tocolytic purposes and independently coded by the KNHI database, was included. Moreover, this is the largest cohort study so far, analyzing the association between B2AR and ASD risk using a nationwide database, collected from the Korea National Health Insurance Claims Database and Korea National Health Screening Examination for 2008–2015.Aside from these medicines, ritodrine, a particular type of B2AR agonist, was chosen for our analysis. Our study reveals an increased autism rate  with prenatal exposure of ritodrine, a result similar to a case–control study in 2016 based on Denmark population-based register. This previous study, which included 5200 cases with ASD and 52,000 controls without ASD, showed the increased odds of ASD  when exposed to B2AR agonists during pregnancy37. In fetal catecholamine system, norepinephrine binds to B2AR on the fetal rat CNS cell surface, activating adenylyl cyclase through G protein. This produces cyclic adenosine monophosphate and protein kinase A, which results in an activation or inhibition of mitogen-activated protein kinase pathways, ultimately leading to CNS cell growth, differentiation, and apoptosis38. Therefore, an overstimulation of B2AR by its ligand, such as terbutaline and ritodrine in immature rat fetal CNS cells, results in a disruption of synaptogenesis particularly in cerebellum39 and peripheral synaptic projections35. Such disruptions in neuro-inflammation patterns and structures are similar to the postmortem findings of children and adults with ASD36. Ritodrine has also been reported to pass through the placenta, according to animal experiments using pregnant baboon40 and a perfusion study of humans41.An insight into the mechanism behind ritodrine leading to ASD can be gained through several previous studies. Certain animal studies using rats have reported that an exposure to B2AR agonists during fetal period acts as a neurobehavioral teratogen for fetus and thus impairs the development of peripheral non-adrenergic projections20.21, we acknowledge that the validity of the diagnoses may be limited by either over-diagnosis or under-diagnosis. In addition, although the Korean Ages and Stages Questionnaire (K-ASQ) by NSHP-IC in our country provides to screen for developmental delays, it may not be perfect to exclude the diagnosis of ASD. Regardless of such limitations, however, the accuracy of the diagnostic codes tends to be higher for more severe conditions including ASD42, according to the health insurance system in Korea. Furthermore, the ASD cases in this study were diagnosed by physicians including psychiatric specialists, and the diagnosis were strictly reviewed by Health Insurance Review & Assessment Service in Korea.Despite such findings, however, there exist several limitations to our study. First, the diagnosis of ASD in this study was based on ICD-10 codes from insurance claims data, not on Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Although several epidemiologic studies on ASD used ICD based diagnosis like our study21. Another study by Croen et al. showed that terbutaline exposure for 2 days or more resulted in about fourfold increase in ASD risk , despite certain statistically imprecise effect estimates20. Particularly, terbutaline exposure for 1–2 days did not increase the risk for ASD  and exposure ≥ 2 weeks showed further increased risk . In addition, in a review by Witter et al., it was suggested that the duration of high-dose exposure to B2AR agonists was likely to be > 2 weeks43. Aside from ASD, the relation between dose-dependent risk of intravenous ritodrine and childhood asthma was also recently demonstrated in a Japanese study that used a hospital-based cohort44.Second, we could not analyze the dose response relationship between ritodrine and ASD. Instead, we could find two studies assessing the dose of general B2ARs in association with ASD. According to a study by Gidaya et al., longer exposure to B2ARs (defined as > 45 days) was associated with higher risk of ASD than shorter exposure (1–45 days)20, although it failed to reach statistical significance. In contrast, in a study by Gidaya et al., all trimesters manifested a similarly high increase risk of autism: first trimester , second trimester , and the third trimester 21. Considering that fetal brain development process varies on gestational age, it would have been meaningful to compare the effects of ritodrine exposure depending on gestational age. However, we did not have information on gestational age at ritodrine exposure and could not examine trimester-specific effect estimates of ritodrine.Furthermore, it still remains unclear as to which exact phase during pregnancy has the highest risk of autism when exposed to B2AR agonists. According to a study by Croen et al., third trimester exposure was suggested to have the highest risk for autism than the first and second trimesterIn addition, since we only analyzed clinical variables provided by KNHI and NHSP-IC database, we might have missed other confounding variables affecting the development of ASD. For example, these databases provided neonatal birth weight but not the exact gestational age at delivery, so our multivariable analysis used only neonatal birth weight. However, given the well-known multicollinearity of gestational age at delivery and neonatal birthweight, our analysis can be considered valid. Last limitation of our study is that we could not analyze the other well-known risk factors associated with childhood autism in our study such as paternal age, parental education, and socio-economic status etc., as this rather personal information was not available in our database system.45. Our data also revealed that male gender is significantly associated with autism development with an HR of 2.53 , which also agrees with previous studies46.This study also confirms several other important perinatal risk factors for autism, including maternal age and male gender as previously mentioned. For example, our analysis demonstrated that mothers aged 36–40 showed adjusted HR of 1.47  for autism in their child, compared to those aged 26–30. Such finding is in line with a recent meta-analysis, which showed that adjusted relative risk for autism in the offspring was 1.31  in mother above 35 years old, compared to mothers 25 to 29 years oldIn summary, the importance of our study lies on its use of a national scale data of a large population-based cohort, in proving the association between ritodrine and autism. Considering the possible long-term adverse outcomes of ritodrine, we reaffirm that the use of ritodrine should be limited to a short period of time, only to complete the corticosteroid for fetal lung maturation.


In Romania, in 2017, the infant mortality rate was eight per thousand; with 41,000 women who had no medical visits during pregnancy; 18,500 were teenagers.Our objective was to analyze how many teen pregnancies were in an Obstetrics and Gynaecology Hospital from Romania over a two-year period and underline the role that midwives have in preventing teenage pregnancies.A descriptive study of a group of 343 childbearing teenagers out of 7020 childbearing women who gave birth in 2017-2018 is presented. The teenagers were evaluated by age, the number of pregnancies, birth complications, way of delivery, and place of origin. The involvement of the midwife was highlighted.From the total of 7020 analyzed cases, 4.8% (n=343) were teen pregnancies. Within this group, 4.37%(n=15)were already at the third birth and 89.79 (n=308)were un-investigated during the entire pregnancy. Sixty-eight point fifty-one percent of the teenagers gave birth with the aid of a midwife while 4.66 (n=16) gave birth with no medical attendance and experienced homebirth. All the teenagers that gave birth at home were from rural areas and not married.High teenage pregnancy rates are determined in Romania by the low level of information about sexuality and family planning at young ages. The midwives have the ability to help to resolve these problems if they were more allowed to be involved in these programs, especially in rural areas. In the European Union, according to data published by EUROSTAT, Romania and Bulgaria have the highest proportion of teenage pregnancies . The MinIn 2017, in Romania, the infant mortality rate was eight per thousand, almost twice the average rate of the European Union, according to the National Institute of Statistics from Romania. At the same time, there were 41,000 women who had no medical visits during pregnancy, some due to poverty and others due to difficult access to doctors' offices. Another 18,500 mothers were teenagers .As a comparison, in the U.S., in 2017, a total of 194,377 babies were born in the 15-19 years age group, with a birth rate of 18.8 per 1,000 women for this age group. This is a drop of 7% from 2016 [Teen pregnancy at a very early age, less than 15 years old, may bring for most adolescents insecurity, problems, fear, and many questions. It means problems at home with the parents, but, at the same time, problems with the father of the child. A study published by Sriyasak et al. shows that teenage mothers struggled with unexpected changes in their lives and teenage fathers experienced changed role expectations and responsibility -9.The health hazards of the new-born from teen pregnancies may occur from the lack of a proper diet during pregnancy due to lack of health educational programs, especially in rural areas. In teenagers under 13 years old, many new-born health problems may occur due to the immaturity of the mother’s body. From a medical point of view, early adolescence is not anatomic-physiologically prepared to reproduce without risk. Romania holds first place in teen pregnancies in 2015 in Europe, according to a report published in 2018 .Recent studies showed that teen pregnancy is strongly influenced by childhood experiences in the family and social environment, especially those related to unstable parenting or early motherhood . Women wPregnancy and childbirth at an early age have major implications for the general and reproductive health of the teenager; these may either develop immediately after birth or after a certain period. In some cases, pregnancy at an early age is more complicated and involves certain risks, including during birth, which can affect the health of the mother or new-born. The experts paid attention to the psychological aspect of the phenomenon. As a teenager, the young girl does not have a coherent perception toward the new-born; they may not be responsible for him or take care of him properly. In many cases, childbearing teenagers neither have the necessary skills nor have they matured psychologically; the period of pregnancy and the one after the birth usually become strong psychological stress for these young childbearing women .There are several aspects that may contribute to placing Romania in the first place in Europe regarding the number of births registered among minors  such as In Romania, the Ministry of Health admits that these problems could be prevented with the help of midwives . CurrentThe World Health Organization (WHO) places the midwifery profession among the most important factors for the care of women of fertile age in good health .In Romania, there are currently only 1000 licensed midwives, but they cannot be integrated into the care system due to the lack of legislation. So they function along with nurses in Obstetrical and Gynaecology Hospitals. Although in other countries of the European Union, the assistance provided by the midwife is a natural practice, in Romania, there are still no rules of practice, guides, and professional protocols that clearly regulate this profession, by harmonizing with the European legislation. In rural areas, midwives could make a real difference in Romania. The role of midwife should not be neglected, as she has the knowledge and the competence to perform several practical and educational tasks .By this paper, the authors want to provide a general framework of teenage pregnancy and childbirth in the Hospital of Obstetrics and Gynaecology from Ploiesti, Romania, and to offer new data regarding teen pregnancy trends in Romania. Nowadays midwife practice is limited in Romania but midwives have the abilities that may help to decrease the number of teen pregnancies. We choose the Hospital of Obstetrics and Gynaecology from Ploiesti for our study. The hospital is in a country region that is around 60 km away from the capital of Romania, Bucharest, and is representative and similar to many other country hospitals from our country. The hospital serves not only the town of Ploiesti but also the rural surrounding area.The present study aims to analyze how many teen pregnancies were in Ploiesti Obstetrics and Gynaecology Hospital during 2017 and 2018 and to expose the social factors that favor early childbirth in Romania. The midwives may have a big role, as they may influence and improve the social protection of young mothers and they can help to prevent teenage pregnancies, especially in rural communities.We monitored all women who gave birth at Ploiești Obstetrics and Gynaecology Hospital over a two-year period (from January 2017 till December 2018). There were 7020 childbearing women who gave birth over the two-year period: 3580 in 2017 and 3440 in 2018. Our focus was on the 12-17 years old group. The age group was chosen according to the age at which a woman becomes officially an adult in Romania, which is 18 years old. The lower limit, 12 years of age, was given by the youngest teen pregnancy that occurred in our hospital. The teenagers were evaluated by age; number of pregnancies, birth complications, way of delivery, and place of origin.All women who came to give birth signed an informed consent form regarding the medical procedures involved and the personal data management. The women included in our study had given informed consent to participate in the study. For all childbearing teenagers, consent to be involved in the study was also provided by their parents or legal guardians. Our research was carried out with the approval and in accordance with the guidelines of the local Ethics Committee.The data were analyzed through the Microsoft Office package - Word and Excel . We calculated the p-value with the chi-square statistic test and considered a significant result when p <.05.There were 4.8% (n=343) teen pregnancies among the total of 7020 analyzed childbearing women. We analyzed them by year in order to be able to evaluate the trend of changes. In 2017, 3580 women of different ages gave birth in the Obstetrics and Gynaecology Hospital of Ploiesti. From them, 182 were between 12 and 17 years old. 49% (n=90) of pregnant women were 17 years old, 31% (n=58) were 16 years old, and 20% (n=34) of them were in the 12-15 age group . There were no women under 12 years old who gave birth in our hospital in 2017 , all teenagers had Romanian citizenship.We noticed that the majority of the teenagers that gave birth came from rural areas in 2017, as well as in 2018, with a total of 65.59% (n=224) for the two investigated years.A fact that was overwhelming was that some of the teenagers from the study gave birth to their second or even their third baby, p=.04 Table . In 2017The majority of teen pregnancies were not monitored during the pregnancy, the adolescents came to the hospital only to give birth, and they had no investigation at all during the entire pregnancy. So in 2017, there were 88% (n=160) un-investigated teen births and in 2018, there were 92% (n=148) un-investigated teen births.According to the way of delivery, we had three situations: the teenagers that presented themselves to the hospital and gave birth with the aid of a midwife; in 2017, there were 120 teenagers, and in 2018 there were 115.The second situation was delivery through a C-section performed by a gynecologist with the aid of a midwife. In this situation, the midwife was responsible for the new-born; she took the child from the gynecologist, dried him, stimulated him if needed, and then took care of the umbilical cord. There were 51 adolescents in 2017 that gave birth through C-section and 41 in 2018. The third situation was when the teenager gave birth at home. This was the most unfortunate situation. In Romania, the legislation does not allow women to give birth at home. Giving birth at home alone, without medical care, is dangerous and in all cases, this happens due to ignorance and lack of information about the pregnancy. In this situation, both the teenager and the new-born were facing potential complications and medical problems because they were not supported or helped in any way throughout the childbirth. After the childbirth, the teenagers were taken to the hospital by a hospital rescue car. At the hospital, a midwife evaluated them and the new-born. Because of the lack of a specialist during childbirth, the new-born could not receive an Apgar score. There were 11 teenagers that gave birth at home in 2017 and five in 2018. Out of them, only four were attending school, the rest had dropped out. There were no premature new-borns in 2017, and there were three premature new-born babies in 2018. In 2017, the median age of the teenagers that gave birth at home was 17 years old, with limits from 14 to 17 years old. In 2018, the median age was 16 years old, with limits between 15 and 16 years old.Surprisingly, in 2018, from the five teenagers that gave birth at home without medical care, three were at the second birth already, and they all were only 15 years old. So they had a history of teen pregnancies that may have been prevented, in our opinion, with the aid of the midwife if a legal frame for this would have existed.Although we are discussing the 12-17 age group, we noticed that almost a third of the teenagers that gave birth in the study presented diseases associated with pregnancy, previously undiagnosed and untreated: 59 in 2017 and another 63 in 2018.Some of the teenagers that gave birth in the hospital presented complications during childbirth, p=.012. The most frequent disturbing complication was lacerations of the birth canal; 28.86% of the teenagers (n=99) presented with it. Episiotomy was performed for 51.31% (n=176) of the teenagers. Another intervention was manual control for the removal of fragments of the placenta. All these interventions were performed by the midwife under the gynecologist's supervision. Three point seventy-nine percent (3.79%) (n=13) of the adolescents presented hematoma as a birth complication.Around the world, teenage pregnancies are more likely to occur in marginalized communities, commonly driven by lack of education, unemployment, gender inequality, lack of sexual and reproductive health services, and the low status of women and girls .The latest data published for Romania was in 2018 in the Complete End of Childhood Index 2018 where the adolescent birth rate  from 2015 was 34 per 1,000 birth.Comparing the two analyzed years from our study, we can see a slight decrease in the birth rate of teen pregnancies in 2018 from 50.83 per 1,000 births in 2017 to 46.80 per 1,000 births in 2018. But this data cannot be accounted as statistically significant for the country because the data come only from a single hospital. Nevertheless, the number of teen pregnancies from 1,000 births is higher than in the US, where, for example, in 2017, a birth rate of 18.8 per 1,000 women was published [A study of the WHO Global Health Observatory Data Repository from 2017 had shown that the girls that have poor social conditions have about three times as many births as the wealthiest [In our study, all teenagers had poor social conditions and poor education. Although 2018 was a year with fewer teen pregnancies in our hospital, the percentages of adolescents that gave birth for the second or even for the third time at such an early age was similar to the one encountered in 2017. In our study, there were 15 teenagers that gave birth for the third time and 47 that gave birth for the second time, that is 18.07% (n=62) of teenagers that had more than one pregnancy until the age of adulthood.The organization "Save the Children" published a report in 2018 "The many faces of exclusion," where they explained that teenage pregnancy can have negative economic consequences on girls and their families and communities, and costs countries billions of dollars each year. Because of their lower educational status, many teen mothers have fewer skills and opportunities for employment, often perpetuating cycles of poverty. Nationally, this can also have an economic cost, with countries losing out on the income that young women would have earned over their lifetimes in case they had not early pregnancies .In Romania, the teenagers that gave birth were mainly unemployed: in 2017, there were 97.25% (n=177) unemployed teenagers and in 2018, there were 91.92% (n=148) unemployed and only a few attended schools.According to Romanian law in 2019 (law 287/2009), a marriage can take place if future spouses are 18 years of age, but for good reasons, the minor who has reached the age of 16 years may marry on the basis of a medical opinion, with the consent of his parents or, as the case may be, of the guardian and with the authorization of the guardianship court in which the minor has his domicile [In our study, during all analyzed periods, we found that 97.09 (n=333) teenagers were not married and 89.79% (n=308) did not seek professional health care services at all during their pregnancy, a fact that confirms the Indian study by Paul et al., which revealed that women who married at <18 years were significantly less likely to use maternal health care services than those married at ≥18 years even after accounting for the socio-economic and demographic characteristics of women .In the studied group aged 12-17, we noticed that almost a third (n=118) of the teenagers that gave birth presented diseases associated with pregnancy that were previously undiagnosed and untreated. Of them, 18.64% (n=22) had infectious diseases. In this context, special attention should be given to sexually transmitted diseases that can infect the young pregnant woman and then can be transmitted to the new-born, affecting, in this way, the life of the future child -21.The majority of the teenagers chose to give birth in the hospital with the aid of the midwife . There were only 4.66% (n=16) of teenagers that experienced homebirth. All of them were from rural areas and were not married. We identified them as being of Rroma ethnicity and Orthodox religion. We could not associate with our study any of the themes from the literature on unassisted childbirth and high-risk homebirth such as (1) resisting the biomedical model of birth by trusting intuition, (2) challenging the dominant discourse on risk by considering the hospital as a dangerous place, (3) feeling that true autonomous choice is only possible at home, (4) perceiving birth as an intimate or religious experience, and (5) taking responsibility as a reflection of true control over decision-making . The facAs in other countries from the world, where homebirth was not integrated into the maternity care system, in Romania, the midwife is needed to attend high-risk homebirth. Munro et al., in 2013, have shown that there are significant barriers in the collaboration between care provider groups, including skill sets, professional orientation, and funding models . The rurOur study showed that most of the teenagers that experienced childbirth had a poor education. We believe that the midwife is very important and may help and improve medical care, especially in rural communities. Teenagers may benefit from the midwives' experience and may be advised to understand the danger of birthing outside the system in Romania, where there is no legal background for homebirth. Particular importance should be given to the sexual and reproductive health of teenagers. Midwives can help and support these educational programs if they could act as individual entities and the law would support them.Improving the health of teenagers, increasing their security and well-being presents a complex approach that requires the efforts of several sectors and social institutions such as educational institutions, health and social care institutions, local government, youth organizations, the church, and the media, including parents and families. We consider that the development of national programs and strategies in the field of sexual and reproductive health with a strong accent on family planning is needed. Midwives may hold a key role in education and prevention. Family planning may act as an intervention, including services for the prevention of unwanted pregnancy, reduction of sexually transmitted infections, aiming at reducing the morbidity and mortality of infants and mothers, preventing/treating infertility, preventing abuse and sexual violence. Collaborations between specialists, including midwives in all these programs, or creating a multidisciplinary network could be of great help. To conclude, high teenage pregnancy rates are determined by the low level of information about sexuality and family planning, the insufficiency of sexual education programs, and the lack of structures and laws that involve midwives in the programs.


During the whole pregnancy, maternal exposure to PM2.5, PM10, SO2, and CO all significantly reduced the term birth weight and increased the risk of TLBW. However, NO2 and O3 exposure have significantly increased the term birth weight, and O3 even increased the risk of macrosomia significantly. Those effects were also observed in the first and second trimesters of pregnancy. But during the third trimester, high level of air quality index (AQI) and maternal exposure to PM2.5, PM10, SO2, NO2, and CO increased the term birth weight and the risk of macrosomia, while O3 exposure was contrary to this effect. The findings suggested that prenatal exposure to air pollution might cause adverse impacts on term birth weight, and the effects varied with trimesters and pollutants, which provides further pieces of evidence for the adverse effects of air pollution exposure in heavy polluted-area on term birth weight.Previous studies have suggested that maternal exposure to air pollution might affect term birth weight. However, the conclusions are controversial. Birth data of all term newborns born in Xi’an city of Shaanxi, China, from 2015 to 2018 and whose mother lived in Xi’an during pregnancy were selected form the Birth Registry Database. And the daily air quality data of Xi’an city was collected from Chinese Air Quality Online Monitoring and Analysis Platform. Generalized additive models (GAM) and 2-level binary logistic regression models were used to estimate the effects of air pollution exposure on term birth weight, the risk term low birth weight (TLBW), and macrosomia. Finally, 321521 term newborns were selected, including 4369(1.36%) TLBW infants and 24,960 (7.76%) macrosomia. The average pollution levels of PMThe online version of this article (10.1007/s11356-020-10705-3) contains supplementary material, which is available to authorized users. With the rapid development of global industrialization and urbanization, the problem of ambient air pollution has been getting increasingly prominent, which is the largest health environmental risk affecting all regions, socioeconomic groups, and age groups , but not in other air pollutants, and it also suggested that 3% of LBW cases can be directly attributed to residential PM2.5 exposure higher than 13.8 μg/m3 during pregnancy . The data on newborns were collected from the Birth Registry Database covering all midwifery clinics and hospitals in Xi’an city . Among them, only term newborns with a gestational age of ≥ 37 weeks and < 42 weeks were enrolled (n = 332405). And those records in which maternal gestational age was missing or less than 15 years or older than 50 years were excluded (n = 254). In addition, some records with missed information of birth weight (n = 445) and ambiguous or incorrect residence (n = 1548) were also excluded. In addition, since exposure data on air pollution prior to May 13, 2014, were not available, we excluded pregnant women who were pregnant before this date (n = 8637). Finally, 321,521 newborns’ records were included in our study. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2017LSK-106).In a total of 536993 newborns, we only selected newborns who lived in Xi’an city during pregnancy and recorded the exact residential address to the street as study objects (https://www.aqistudy.cn/). It covered 13 air pollution monitoring sites in Xi’an city of Shaanxi province and originated mainly from the real-time data recorded by the Ministry of Ecology and Environment of the People’s Republic of China (http://www.mee.gov.cn/). Differential optical absorption spectroscopy method was used to analyze the concentration of NO2, SO2, CO, and O3, and the tapered element oscillating microbalance method was used to analyze the concentration of PM2.5 and PM10 automatically. AQI is an important indicator that presents the overall air pollution level, which is calculated according to the new ambient air quality standards (GB3095-2012). The definition of the used AQI is presented in the Real-time data of ambient air pollution exposure from May 13, 2014, to December 30, 2018, were provided by Chinese Air Quality Online Monitoring and Analysis Platform , the first trimester (from pregnancy to the 13th week of gestation), the second trimester (from the 14th to 27th week of gestation), and the third trimester (from the 28th week of gestation to delivery).Maternal exposure estimates were calculated by pollutant concentrations measured at the nearest monitoring station to their residence. Prior to the assessment, the 24-h average of AQI, PMOur main outcomes were term birth weight, TLBW, and macrosomia. Term birth weights for each newborn were collected from birth records directly. Term low birth weight (TLBW) was defined as birth weight less than 2500 g and gestational age of 37 weeks or more. And macrosomia was defined as birth weight equal or more than 4000 g. Meanwhile, maternal age, gestational age, ethnicity, and the date of birth of each newborn were all recorded. Pregnancy date was calculated based on birth date and gestational age to classify the season of beginning pregnancy (including warm season (from April to September) and cold season (from October to March of the next year)). And average temperature exposures during pregnancy were calculated based on the date of birth, gestational age, and hourly temperature distribution in Xi’an city from 2015 to 2018.2.5, PM10, SO2, NO2 CO, and O3 from 2015 to 2018 in Xi’an city were estimated based on hourly average exposure levels by the weighted average method. Generalized additive model (GAM) fitting in the Gaussian distribution was performed to evaluate the nonlinear relationship of air pollution exposure and birth weight  is the expected birth weight for newborn t, Xt represents the exposure level of air pollution for pregnant women t. Based on this model, the effects of per 10 unit increase of AQI, per 10 μg/m3 increase of PM2.5, PM10, SO2, NO2, O3, and per 0.1 mg/m3 increase of CO on term birth weight, were evaluated.n = 292192) were selected as a reference, and then 2-level binary logistic regression model was performed to investigate the associations between air pollution exposure and the risk of TLBW and macrosomia. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the effects of per 0.1 mg/m3 increase of CO and per 10 unit increase of AQI, PM2.5, PM10, NO2, SO2, and O3 on the risk of TLBW and macrosomia.In addition, macrosomia or low birth weight infants were selected as the case group, while those infants with normal birth weight .Due to the non-significant relationship between average temperature and birth weight, we only included maternal age, gestational age, ethnic group, and pregnancy season as confounding factors in the final GAM and binary logistic regression model. All analyses were conducted using “mgcv (Mixed GAM Computation Vehicle)” and “glm” package and in R version 3.5.3. Significant results were considered at a A total of 321,521 newborns’ birth records were included in this study. The mean (10th–90th percentile) maternal age was 28.48 (23–34) years. And the Han ethnic group accounted for the majority (96.19%). The mean gestational age of newborns was 275.65 (265–287) days. And the mean birth weight was 3328.74 g. Among them, the incidence of TLBW and macrosomia were 1.36% (4369 cases) and 7.76% (24960 cases), respectively  limits. Among them, the concentration of PM10 exposure was the most severe. In addition, the exposure levels of SO2, CO, and O3 were lower than the National Ambient Air Quality Standard (GB 3095–2012) limits  values were − 2.739 , − 2.458 , − 3.982  and − 1.511 , respectively) and increased the risk of TLBW (OR (95%CI) values were 1.025 (1.005–1.045), 1.035 (1.020–1.049), 1.034 (1.004–1.065), and 1.013 (1.004–1.023), respectively). However, every 10 μg/m3 increase in NO2 ) and O3 ) significantly increased the birth weight of term newborns, and O3 even increased the risk of macrosomia significantly (1.028 (1.015–1.040)) ; PM2.5: − 1.700 ; PM10: − 4.258 ; − 4.258 ; CO: − 1.105 ) and positively associated with the incidence of TLBW (AQI: 1.016 (1.006–1.027); PM2.5: 1.017 (1.006–1.028); PM10: 1.017 (1.009–1.026); SO2: 1.033 (1.010–1.057); CO: 1.007 (1.001–1.014)). But maternal O3 exposure increased the risk of term birth weight  and macrosomia . No significant association was found between maternal NO2 exposure and birth weight during early pregnancy ; PM2.5: 2.344 ; PM10: 1.705 ; SO2: 3.270 ; NO2: 5.219 ; CO: 0.855 ). Conversely, O3 exposure reduced the term birth weight  and increases the risk of TLBW  significantly for newborns   during pregnancy, we comprehensively estimated the impact of air pollution exposure during four different periods of pregnancy on the term birth weight and the risk of TLBW and macrosomia and drawn comprehensive and significant conclusions.But several limitations should be considered in interpreting the results of this study. Due to the limited information collected by the birth registration system, some confounding factors were not considered in our study, such as diet, maternal BMI, sex of newborns, and the history of diseases during pregnancy. However, previous studies have found the effect value changed little whether or not the above risk factors were adjusted