Reproduction after the loss of a child: a population-based matched cohort study.

STUDY QUESTION: Is the death of a child associated with higher subsequent fertility? SUMMARY ANSWER: Women who had lost a child had higher fertility both shortly after the loss and throughout the entire follow-up, independent of the child's age at the time of death. WHAT IS KNOWN ALREADY: Women who lose a child in the perinatal period often have another child shortly after. However, to our knowledge no previous study has investigated if the death of an older child affects reproductive behavior. STUDY DESIGN, SIZE, DURATION: The source population for this matched cohort study consisted of all women who gave birth in Denmark from 1978 to 2004 and in Sweden from 1973 to 2002 (N = 1 979 958). Women were followed through to the end of 2008 in Denmark and the end of 2006 in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had lost a child before the age of 45 years during the study period (exposed group; n = 36 511) were matched with up to five women who were from the same country and of similar age and family characteristics and had not lost a child at the time of matching (unexposed group; n = 182 522). MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 74% of exposed and 46% of unexposed women had another birth (live- or stillbirth) after a gestation of 28 weeks or more. Compared with unexposed women, exposed women had a shorter interpregnancy interval and, consequently, a higher rate of conception leading to a birth (HR = 5.5 [95% CI: 5.4-5.6]). Rates for exposed women were higher from the first month following the child's death, but the largest difference was between 2 and 3 months after the event. This pattern was independent of the age of the deceased child. Exposed women had more subsequent children than unexposed, leading to a comparable number of living children at the end of follow-up. LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of virtually all eligible women and nearly complete follow-up; the potential for selection bias is thus negligible. However, only pregnancies that led to a live birth or a stillbirth could be identified, thus fetal losses occurring before week 28 of gestation were missing. WIDER IMPLICATIONS OF THE FINDINGS: Our findings corroborate the previous evidence suggesting that women try to conceive again shortly after a perinatal death, and many succeed. In addition, this is the first study to investigate the reproductive trajectory after losing an older child. The current study indicates that most women who lose a child between the ages of 6 months and 5 years conceive shortly after the loss, and they have a comparable number of living children at the end of the follow-up compared to those who do not lose a child. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant ERC-2010-StG-260242 from the European Research Council, 176673 and 186200 from the Nordic Cancer Union, DFF-6110-00019 from the Danish Council for Independent Research, 904414 and 15199 from TrygFonden, Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors do not declare any conflicts of interests. TRIAL REGISTRATION NUMBER: N/A.

Maternal age at birth and daughters' subsequent childlessness.

STUDY QUESTION: Does maternal age at a daughter's birth predict her subsequent probability of lifelong childlessness? SUMMARY ANSWER: In this study population, women born to older mothers were more likely to be childless. WHAT IS KNOWN ALREADY: Although maternal age at childbearing is increasing in many countries, there is limited evidence on whether being born to older parents may influence offspring fertility. STUDY DESIGN SIZE AND DURATION: This analysis included 43 135 women from the US-based Sister Study, a cohort study of 50 884 sisters of women with breast cancer recruited between 2003 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants had no breast cancer at baseline. Women were included in the analytic sample if they were born between 1930 and 1964 and were at least 44 years old at enrolment. Median age when reproductive history was last ascertained was 63.8 years. We estimated relative risks (RR) and 95% CI of lifelong childlessness as a function of maternal age at birth, using multivariable log-binomial models, including total number of siblings, birth order, socioeconomic indicators of the family of origin, race and birth cohort. We examined the association in different subgroups and in a sibling-matched analysis including 802 sister pairs discordant for childlessness. MAIN RESULTS AND ROLE OF CHANCE: Compared with women born to 20-24-year-old mothers, those born to mothers aged 25-29, 30-34 and ≥35 years were more likely to be childless [RR (95% CI): 1.21 (1.14-1.29), 1.30 (1.22-1.39) and 1.40 (1.31-1.50), respectively]. The association was consistent in strata defined by birth cohort, number of siblings, birth order, and participant's educational level, as well as within sister pairs. Overall, we found weak evidence for an independent contribution of paternal age at birth to the daughter's probability of childlessness. LIMITATIONS REASONS FOR CAUTION: All participants had at least one sister, and all information was self-reported. We had no knowledge of whether childlessness was intentional and found only a modest association between maternal age at birth and self-reported indicators of infertility. Still, the association with childlessness was highly consistent. WIDER IMPLICATIONS OF THE FINDING: Given the widespread tendency to delay childbearing, evaluating the influence of maternal age at birth on offspring fertility is a public health priority. STUDY FUNDING/COMPETING INTERESTS: This research was supported in part by the Intramural Research Programme of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005). The authors report no conflict of interest.

Causal inference in studies of preterm babies: a simulation study.

OBJECTIVE: Using a simple simulation, we illustrate why associations estimated from studies restricted to preterm births cannot be interpreted causally. DESIGN, SETTING AND POPULATION: Data simulation involving a hypothetical cohort of fetuses who may be healthy or have one or more of four pathological factors (termed A through D, increasing in severity) with known effects on gestational length and risk of mortality. We focus on babies born at ≤32 weeks of gestation. METHODS: We visually represent the simulated population and compare the association between A (which may represent pre-eclampsia) and neonatal death. We then repeat the exercise with D (standing in for chorioamnionitis) as the exposure of interest. MAIN OUTCOME MEASURES: Odds ratios of neonatal death in the simulated data. RESULTS: In most weeks, and for both A and D, the calculated odds ratios are substantially biased and underestimate the true risk of neonatal death associated with each pathology. For example, factor A has a true causal odds ratio of 1.50, yet it appears protective among births ≤32 weeks (estimated crude odds ratio 0.39; gestational age-adjusted odds ratio 0.71). CONCLUSIONS: Among very preterm births, virtually all babies are born with pathologies that increase the risk of adverse outcomes. Hence, babies exposed to one factor (e.g. pre-eclampsia) are compared with babies who have a mix of other pathologies. Such selection bias affects studies carried out among very preterm births (e.g. where pre-eclampsia appears to reduce risk of adverse neonatal outcomes). TWEETABLE ABSTRACT: Selection bias affects studies of preterm births, complicating interpretation.

Maternal stress before and during pregnancy and subsequent infertility in daughters: a nationwide population-based cohort study.

STUDY QUESTION: Is maternal stress following the death of a close relative before or during pregnancy associated with the risk of infertility in daughters? SUMMARY ANSWER: Compared with unexposed women, women whose mothers had experienced bereavement stress during, or in the year before, pregnancy had a similar risk of infertility overall, but those exposed to maternal bereavement during the first trimester had a higher risk of infertility. WHAT IS KNOWN ALREADY: Animal studies have shown that prenatal maternal stress results in reduced offspring fertility. In humans, there is evidence that girls who have been prenatally exposed to stress have a more masculine behaviour and a slight delay in having their first child. STUDY DESIGN, SIZE AND DURATION: This population-based cohort study, included 660 099 females born in Denmark between 1 January 1973 and 31 December 1993 to mothers of Danish origin and with at least one living relative in the exposure window, and followed the women through 31 December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 13 334 women (2.0%) were considered prenatally exposed to stress because their mother had lost a spouse/partner, a child, a parent, or a sibling during pregnancy or in the year before conception. Infertility was defined as any record of infertility treatment or diagnosis of female infertility. We considered the date of onset as the date of the first appearance of any such record. The association between exposure and outcome was examined using hazard ratios (HR) with 95% confidence intervals (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Based on our definition, 40 052 (6.5%) women were infertile in the follow-up period (median age at the end of follow-up: 26.7 years, maximum age: 39 years). Overall, prenatal exposure to maternal stress was not associated with risk of infertility (adjusted HR = 1.04 [CI: 0.95-1.14]). However, women prenatally exposed during the first trimester had a higher estimated risk (adjusted HR = 1.40 [CI: 1.05-1.86]). These findings were consistent in subgroups defined by the relationship of the mother to the deceased and in several sensitivity analyses, including a sibling-matched analysis, and in analyses restricted to women who were married or cohabitating with a man, or to women born at term. LIMITATIONS, REASONS FOR CAUTION: We did not have a direct measure of stress, but bereavement due to death of a close relative is likely to be very stressful. We based the timing of exposure on the date of the death of the family member, although the stress may well have started earlier. Infertility was also defined indirectly, and many women in the cohort were too young at the end of the follow-up to have been diagnosed. However, misclassification of the outcome was most likely non-differential, and the similar results from all sensitivity analyses suggest that it is unlikely that the effect observed in first trimester exposure would be due to chance. WIDER IMPLICATIONS OF THE FINDINGS: Prenatal exposure to maternal stress in the first trimester may affect the later fecundity of daughters. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from the European Research Council (ERC-2010-StG-260242-PROGEURO) to the ProgEuro project (http://progeuro.au.dk). O.P.-R. is partly supported by a fellowship from Aarhus University and a travel grant from Oticon Fonden. The authors report no conflict of interests.

Small-for-gestational-age birth and maternal plasma antioxidant levels in mid-gestation: a nested case-control study.

OBJECTIVE: To assess whether maternal plasma antioxidant levels in mid-pregnancy are associated with small-for-gestational-age (SGA) birth. DESIGN: Case-control study nested within a population-based cohort study. SETTING: Four hospitals in Montreal, Canada. POPULATION: Pregnant women recruited before 24 weeks of gestation, whose pregnancies were not complicated by pre-eclampsia or preterm delivery. METHODS: Blood samples were obtained at 24-26 weeks and assayed for nutritionally derived antioxidant levels in SGA cases (n = 324) and randomly selected controls with birthweights between the 25th and 75th centiles (n = 672). We performed logistic regression analyses using the standardised z-score of each antioxidant as the main independent variable, after summing highly correlated antioxidants or combining via principle component analysis. We adjusted for risk factors for SGA that were associated with antioxidant levels. MAIN OUTCOME MEASURES: SGA, birthweight <10th centile for gestational age and sex. RESULTS: Retinol was positively associated with risk of SGA (adjusted odds ratio [OR] 1.41; 95% confidence interval [95% CI] 1.22-1.63, per SD increase). Carotenoids (log of the sum of ß-carotene, lutein/zeaxanthin, α- and ß-cryptoxanthin) were negatively associated with SGA (adjusted OR 0.64; 95% CI 0.54-0.78, per SD increase). We found no significant associations between SGA and lycopene or any of the forms of vitamin E assessed, including α-tocopherol, corrected α-tocopherol (per nmol/l of low-density lipoprotein articles), or γ-tocopherol. CONCLUSIONS: Elevated retinol may be associated with an increased risk of SGA, whereas elevated carotenoid levels may reduce the risk. A better understanding of the nature of these associations is required, however, before recommending specific nutritional interventions in an attempt to prevent SGA birth.

Fetal death and preterm birth associated with maternal influenza vaccination: systematic review.

BACKGROUND: Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently. OBJECTIVES: To review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. SEARCH STRATEGY: We searched bibliographic databases from inception to April 2014. SELECTION CRITERIA: Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data from studies meeting the inclusion criteria. MAIN RESULTS: We included one randomised clinical trial and 26 observational studies. Meta-analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56-0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at ≥20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non-significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta-regression did not explain the moderate between-study heterogeneity (I(2) = 57%). AUTHORS' CONCLUSIONS: Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness.

Mother's age at menarche and offspring size.

OBJECTIVE: An individual's growth trajectory is, at least in part, inherited. Mother's early age at menarche has been associated with taller offspring height and greater body mass index (BMI) at age 9 years, suggesting that mother's age at menarche may be an intergenerational marker of growth. We examined the association between mother's age at menarche and childhood size at birth, and at ages 1, 3, 4, 7 and 8 years in the Collaborative Perinatal Project. SUBJECTS: We examined 128,636 measurements obtained from 31,474 Black and White children. We transformed the original measurements into z-scores. Child size was examined in mixed models, adjusted for center, child sex, race, socioeconomic index, child's exact age at measurement (in months), mother's age at recruitment and, depending on which measure was the outcome in the specific model, mother's height, pre-pregnancy weight or BMI. RESULTS: Compared with children whose mother had menarche at age 15 years or later, children whose mothers had age at menarche before age 12 years were taller from 1 year of age and had higher BMI, particularly at ages 7 and 8 years (0.17 and 0.19 z-score units, respectively). CONCLUSIONS: Mothers' age at menarche is a modest predictor of their children's growth trajectory. The mechanism is likely to be heritable, although other explanations are possible.

Using infertile patients in epidemiologic studies on subfecundity and embryonal loss.

Subfecundity is a frequent and serious problem that may sometimes be preventable, but we need to know more about its determinants. Different epidemiologic designs are available. The best of these use prospectively collected data from the population, but they are time consuming, expensive and often hampered by low-participation rates. Most patients undergoing infertility treatment are closely monitored for clinical reasons, making it feasible to use secondary data to study the period from conception to implantation and pregnancy. In spite that infertility patients are highly selected, there are specific exposure-effect relations that can be studied in cohorts of infertility patients. These patients offer a potentially useful setting for studying exposures that operate late in fertilization, whereas the designs may be inadequate to identify exposures that cause reduced sperm counts, anovulation and total occlusion. The clinical sampling and the treatment set limitations for what can be studied. In certain situations, infertile patients can, however, provide useful epidemiologic evidence for learning about the causes of subfecundity.

Having children with different men and subsequent cancer risk. A nationwide study in Denmark.

The more men by whom a woman has children, the more diverse will be the foetal antigens of paternal origin introduced into her bloodstream, and we investigated whether this has an impact on subsequent cancer risks. By using population registries we identified 64704 women who had children with at least two different partners from 1973 to 1996 in Denmark. We compared their cancer incidence with that of women who during the same time period had at least two births with no indication of partner change, adjusting for age, parity, socioeconomic factors and residence. The overall cancer incidence was more than 50% higher in women with two or more partners. Women having children with multiple partners had a higher incidence of cancer of the cervix and corpus uteri, a lower incidence of melanoma but a similar incidence of breast and ovarian cancer. Uncontrolled differences in lifestyle factors may explain the higher cancer risk associated with having multiple partners. The strong protective effect for melanoma was unexpected and deserves further study.

Pre-eclampsia and febrile convulsions.

An association between pre-eclampsia and febrile convulsions has been reported, but the association may not be causal. We compared the risk of febrile convulsions in 14 974 children who had been exposed to pre-eclampsia in fetal life with that of 39 210 unexposed children. Children exposed to pre-eclampsia had a slightly increased risk of febrile convulsions, but the association was apparently caused by a shorter gestation in pre-eclamptic women.

Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark.

To investigate whether parents of children with congenital malformations more often developed cancer after birth of the child, a population-based case-control study in Denmark was undertaken. By linking the Cancer Registry with the Central Population Registry, we identified 8783 cancer patients having their first child born between 1977 and 1995 before the cancer was diagnosed. Parents of 41 206 firstborn children of a 10% random sample of newborns from the Birth Registry between 1980 and 1995 were identified as controls. We obtained malformation diagnoses of children of cases and controls by linking to the Hospital Discharge Registry. We estimated the association between malformation and cancer by using logistic regression, adjusting for maternal age at birth and sex of child. We found no increased risk of cancer in parents having children with malformations in general, but a higher cancer risk in parents of children born with cleft lip/palate, odds ratio (OR) for all cancer=1.8 (95% confidence interval 1.0-3.2), OR for lymphomas=4.2 (1.3-13.5) and OR for leukaemia=8.1 (2.0-33.7). This association was not restricted to cancer cases diagnosed shortly after birth of the child. Our results suggest a common genetic association between these diseases, but further studies are needed.

Febrile convulsions and sudden infant death syndrome.

It has been suggested that sudden infant death syndrome (SIDS) and febrile convulsions are related aetiologically. We compared the risk of SIDS in 9877 siblings of children who had had febrile convulsions with that of 20 177 siblings of children who had never had febrile convulsions. We found no support for the shared susceptibility hypothesis.

The outcome of intra-articular debris, following anterior cruciate ligament reconstruction.

Following arthroscopic anterior cruciate ligament reconstruction, radio-opacities were noted on the post-operative radiographs in 40 of 50 consecutive cases. There was no correlation between the presence of these opacities and post-operative knee pain, joint effusion, arthrofibrosis or knee recovery. In 12 cases undergoing a subsequent radiograph between 3 and 18 months post-operatively, opacities were noted in only one case.

Higher risk of pre-eclampsia after change of partner. An effect of longer interpregnancy intervals?

Epidemiologic studies have shown that pre-eclampsia is mainly a disease of first pregnancy, possibly associated with primipaternity. The interpregnancy interval, which is strongly associated with change of partner, has received little attention. In this study, based on Danish hospital records, we evaluated whether the interpregnancy interval may confound or modify the paternal effect on pre-eclampsia. We studied the outcome of the second birth in a cohort of Danish women with pre-eclampsia in the previous birth (8,401 women) and in all women with pre-eclampsia in second (but not first) birth together with a sample of women with two births (26,596 women). A long interpregnancy interval was associated with a higher risk of pre-eclampsia in women with no previous pre-eclampsia when the father was the same. We estimated the risk of pre-eclampsia in second birth according to paternal change in different models. Although partner change was associated with an increased risk of pre-eclampsia in women with no history of pre-eclampsia, this effect disappeared after adjustment for the interpregnancy interval. We saw, however, different results when we stratified on the length of the interval. Our results indicate that the interval between births should be taken into consideration when studying the effect of changing partner on pre-eclampsia.

Sex ratio and twinning in women with hyperemesis or pre-eclampsia.

We examined twinning and fetal gender in births of women with a hospital diagnosis of pre-eclampsia or hyperemesis. We also investigated sex ratio in infants whose mothers had had hyperemesis or pre-eclampsia in a different pregnancy. From all the hospitalized cases in Denmark between 1980 and 1996 we extracted 6,227 births with hyperemesis and 24,764 with pre-eclampsia. Twins were more frequent in pregnancies with either condition. The male to female sex ratio was 1.04 (95%CI = 1.02-1.05) in the reference population, 0.87 (95% CI = 0.82-0.91) in births with hyperemesis, and 1.10 (95% CI = 1.07-1.12) in births with pre-eclampsia. Women with pre-eclampsia had slightly more males also in non-affected pregnancies.

Choice and chance: determinants of short interpregnancy intervals in Denmark.

BACKGROUND: It is still unclear whether short interpregnancy intervals are a marker for women at risk of poor pregnancy outcome or a direct risk factor for poor perinatal outcomes. The study objective was to identify risk factors associated with short interpregnancy intervals in Denmark. METHODS: From a cohort of pregnant women in a geographically defined area in Denmark (n=11,288) and using register linkage, we identified 5756 multiparous mothers who completed a detailed interview on social behavior during pregnancy. We restricted our analysis to 2904 mothers who had an interpregnancy interval of less than 37 months. Multiple logistic regression was used to estimate the Odds Ratio (OR) of having a short interval as a function of a number of determinants. RESULTS: About 4.8% of the mothers had an interpregnancy interval less than 9 months. Short interpregnancy intervals were more likely to occur in an unplanned pregnancy (OR=2.9, 95% CI: 2.2-3.9), to follow irregular menstruation (OR=1.7, 95% CI: 1.1, 2.5) and to occur in older (OR=1.7, 95% CI: 1.1, 2.5) and high parity mothers (OR=1.9, 95% CI: 1.1, 3.1). Poor housing, smoking and low social status were also associated with short interpregnancy interval CONCLUSION: Short interpregnancy intervals may be a marker for women at risk and these risk factors differ among populations. They also appear to be a result of choice (e.g. in older women). Biological factors also play a significant role in determining short interpregnancy intervals.

The anatomy of the patellar tendon.

The morphology of the attachment of the patellar tendon, its bundle orientation, the differential fascicles length and the position of the apex of the patella were assessed in 22 cadaveric human knees. The patellar apex was 39+/-6% of the width of the tendon from its medial edge. The bulk of tendon was attached to the distal two-thirds of the anterior aspect of the patella. In six cases tendon fibres originated from the posterior surface of the apex of the patella, forming a ridge on the back of tendon. This may represent an anatomical variant accounting for the increased tendon thickness noted on MRI, both incidentally and during assessment for patellar tendonitis. Fascicles were parallel in the sagittal plane but converged in the frontal plane toward their tibial attachment. When bone-patellar tendon-bone (B-PT-B) grafts were harvested, as for anterior cruciate ligament reconstruction, the grafts narrowed distally. When harvesting B-PT-B, the oblique orientation of the fibres in the coronal plane must be borne in mind.

Maternal prenatal lifestyle factors and infectious disease in early childhood: a follow-up study of hospitalization within a Danish birth cohort.

OBJECTIVES: To examine whether maternal prenatal lifestyle factors were associated with the risk of hospitalization with infectious disease during early childhood and whether a possible association was modified by fetal growth reduction. METHODS: The study was based on a birth cohort of 10 400 newborns whose mothers attended the midwife centers in Odense and Aalborg, Denmark, from April 1984 to April 1987 at approximately the 36th week of gestation. Information on hospitalization with infectious disease was extracted from the National Hospital Discharge Registry, and newborns were followed up to the end of 1996. RESULTS: Among 6022 children who were hospitalized at least once, 31.4% (n = 1892) were hospitalized with infectious diseases. The cumulative incidence rate of hospitalization with infections in children from the age of 6 months to 12 years was 18.9%. The incidence rate ratio in children born to mothers smoking during pregnancy was 1.24 (95% confidence interval: 1.13-1.36) compared with those of nonsmoking mothers. Mothers whose body mass index was <18 kg/m(2) were more likely to give birth to infants who were hospitalized with infectious disease (incidence rate ratio: 1.29; 95% confidence interval: 1.05-1.59). The increased risk was present in children only up to the age of 5 years. CONCLUSIONS: The study shows that maternal smoking during pregnancy and a low prepregnancy body mass index are associated with a higher risk of hospitalization with infectious disease during early childhood. These associations are independent of fetal growth indicators.

Indicators of fetal growth and infectious disease in childhood--a birth cohort with hospitalization as outcome.

We evaluated the association between indicators of fetal growth and hospitalization with infectious disease during childhood in a cohort of 10,400 newborns. The cohort was based on children born to mothers who at about 36 weeks of gestation attended the midwife centres in Odense and Aalborg, Denmark for a routine examination. Women were recruited to the study from April 1984 to April 1987. After linkage with the National Hospital Registry, the first hospitalization with infectious disease from 6 months up to 12 years of age was identified. The cumulative incidence of hospitalization with infectious disease during follow-up was 18.9%. Preterm birth was associated with an increased risk of being hospitalized with infections during childhood (incidence rate ratio: 1.67, 95% CI: 1.33-2.10); low birth weight had a similar association, but only in preterm birth. Reduced birth length related to the head was correlated with an increased risk of hospitalization with infections. The effect of gestational age was mainly seen in the period close to the time of birth, but the children who were short at birth appeared to remain at increased risk throughout the age interval under analysis. In conclusion, the study suggests that preterm birth was the main factor underlying the association between low birth weight and the increased risk of hospitalization with infectious disease during childhood. However, it could not explain the increased risk in children who were short at birth.