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1.  Assessing fetal growth impairments based on family data as a tool for identifying high-risk babies. An example with neonatal mortality 
Low birth weight is associated with an increased risk of neonatal and infant mortality and morbidity, as well as with other adverse conditions later in life. Since the birth weight-specific mortality of a second child depends on the birth weight of an older sibling, a failure to achieve the biologically intended size appears to increase the risk of adverse outcome even in babies who are not classified as small for gestation. In this study, we aimed at quantifying the risk of neonatal death as a function of a baby's failure to fulfil its biologic growth potential across the whole distribution of birth weight.
We predicted the birth weight of 411,957 second babies born in Denmark (1979–2002), given the birth weight of the first, and examined how the ratio of achieved birth weight to predicted birth weight performed in predicting neonatal mortality.
For any achieved birth weight category, the risk of neonatal death increased with decreasing birth weight ratio. However, the risk of neonatal death increased with decreasing birth weight, even among babies who achieved their predicted birth weight.
While a low achieved birth weight was a stronger predictor of mortality, a failure to achieve the predicted birth weight was associated with increased mortality at virtually all birth weights. Use of family data may allow identification of children at risk of adverse health outcomes, especially among babies with apparently "normal" growth.
PMCID: PMC2233632  PMID: 18045458
2.  Case gender and severity in cerebral palsy varies with intrauterine growth 
Archives of Disease in Childhood  2005;90(5):474-479.
Background: There is an unexplained excess of cerebral palsy among male babies. There is also variation in the proportion of more severe cases by birth weight. It has recently been shown that the rate of cerebral palsy increases as intrauterine size deviates up or down from an optimum about one standard deviation heavier than population mean weight-for-gestation.
Aims: To determine whether the gender ratio or the severity of cases also varies with intrauterine size.
Methods: A total of 3454 cases of cerebral palsy among single births between 1976 and 1990 with sufficient data to assign case severity (based on intellectual impairment and walking ability) and to compare weight-for-gestation at birth to sex specific fetal growth standards, were aggregated from nine separate registers in five European countries.
Results: The greater the degree to which growth deviates either up or down from optimal weight-for-gestation at birth, the higher is the rate of cerebral palsy, the larger is the proportion of male cases, and the more severe is the functional disability. Compared to those with optimum growth the risk of more severe cerebral palsy in male babies is 16 times higher for those with a birth weight below the 3rd centile and four times higher when birth weight is above the 97th centile. In contrast, for mild cerebral palsy in female babies the excess risks at these growth extremes are about half these magnitudes.
Conclusions: Among singleton children with cerebral palsy, abnormal intrauterine size, either small or large, is associated with more severe disability and male sex.
PMCID: PMC1720399  PMID: 15851428
3.  An Outcome-based Approach for the Creation of Fetal Growth Standards: Do Singletons and Twins Need Separate Standards? 
American Journal of Epidemiology  2009;169(5):616-624.
Contemporary fetal growth standards are created by using theoretical properties (percentiles) of birth weight (for gestational age) distributions. The authors used a clinically relevant, outcome-based methodology to determine if separate fetal growth standards are required for singletons and twins. All singleton and twin livebirths between 36 and 42 weeks’ gestation in the United States (1995–2002) were included, after exclusions for missing information and other factors (n = 17,811,922). A birth weight range was identified, at each gestational age, over which serious neonatal morbidity and neonatal mortality rates were lowest. Among singleton males at 40 weeks, serious neonatal morbidity/mortality rates were lowest between 3,012 g (95% confidence interval (CI): 3,008, 3,018) and 3,978 g (95% CI: 3,976, 3,980). The low end of this optimal birth weight range for females was 37 g (95% CI: 21, 53) less. The low optimal birth weight was 152 g (95% CI: 121, 183) less for twins compared with singletons. No differences were observed in low optimal birth weight by period (1999–2002 vs. 1995–1998), but small differences were observed for maternal education, race, parity, age, and smoking status. Patterns of birth weight-specific serious neonatal morbidity/neonatal mortality support the need for plurality-specific fetal growth standards.
PMCID: PMC2640160  PMID: 19126584
birth weight; fetal development; gestational age; infant mortality; morbidity
4.  The impact of nonlinear exposure-risk relationships on seasonal time-series data: modelling Danish neonatal birth anthropometric data 
Birth weight and length have seasonal fluctuations. Previous analyses of birth weight by latitude effects identified seemingly contradictory results, showing both 6 and 12 monthly periodicities in weight. The aims of this paper are twofold: (a) to explore seasonal patterns in a large, Danish Medical Birth Register, and (b) to explore models based on seasonal exposures and a non-linear exposure-risk relationship.
Birth weight and birth lengths on over 1.5 million Danish singleton, live births were examined for seasonality. We modelled seasonal patterns based on linear, U- and J-shaped exposure-risk relationships. We then added an extra layer of complexity by modelling weighted population-based exposure patterns.
The Danish data showed clear seasonal fluctuations for both birth weight and birth length. A bimodal model best fits the data, however the amplitude of the 6 and 12 month peaks changed over time. In the modelling exercises, U- and J-shaped exposure-risk relationships generate time series with both 6 and 12 month periodicities. Changing the weightings of the population exposure risks result in unexpected properties. A J-shaped exposure-risk relationship with a diminishing population exposure over time fitted the observed seasonal pattern in the Danish birth weight data.
In keeping with many other studies, Danish birth anthropometric data show complex and shifting seasonal patterns. We speculate that annual periodicities with non-linear exposure-risk models may underlie these findings. Understanding the nature of seasonal fluctuations can help generate candidate exposures.
PMCID: PMC2151954  PMID: 17937794
5.  Defining Smallness for Gestational Age in the Early Years of the Danish Medical Birth Registry 
PLoS ONE  2011;6(1):e16668.
Being born small for gestational age (SGA) is associated with decreased insulin sensitivity and increased blood pressure in childhood, but the association with clinical disease in early adulthood is less certain. The Danish Medical Birth Registry has registered all births in Denmark since 1973, but due to variable data quality, data is most often used only from 1981 onwards, and birth registers in other countries may have similar problems for the early years. We wanted to examine whether the data can be used for identification of children born SGA and used in future research.
Methodology/Principal Findings
All persons born between 1974 and 1996 were identified in the Danish Medical Birth Registry (n = 1.704.890). Immigrants and children without data on gestational age and birth weight were excluded, and a total of 1.348.106 children were included in the analysis. The difference between the different variables used in the history of the registry were examined, and the quality of data in the birth registry from 1974-1981 was examined and compared to subsequent years.
Data on birth weight and gestational age in the early years of the registry is inconsistent, and the identification of children born SGA is inaccurate, with 49% false-positives. The biggest source of error is due to the rough and inaccurate intervals used for gestational age. By using –3 standard deviations as a cut-off for the identification of children born SGA, the number of false-positives was reduced to 9%, while the amount of false-negatives were increased.
Choosing –3 standard deviations for identifying children born SGA is a viable, though not optimal solution for identifying children born SGA. Overall the data in the registry is of sufficient quality to be used in further medical research.
PMCID: PMC3031617  PMID: 21304958
6.  Preterm birth and risk of epilepsy in Swedish adults 
Neurology  2011;77(14):1376-1382.
To determine whether preterm birth is associated with epilepsy in a national cohort of adults aged 25–37 years.
We conducted a national cohort study of 630,090 infants born in Sweden from 1973 through 1979, including 27,953 born preterm (<37 weeks), followed from 2005 to 2009 for 1) hospitalization for epilepsy and 2) outpatient and inpatient prescription of antiepileptic drugs. Epilepsy diagnoses and medication data were obtained from all hospitals and pharmacies throughout Sweden.
We found a strong association between preterm birth and epilepsy that increased by earlier gestational age. After adjusting for fetal growth and potential confounders, odds ratios for hospitalization for epilepsy were 4.98 (95%confidence interval [CI] 2.87–8.62) for those born at 23–31 weeks, 1.98 (95% CI 1.26–3.13) for those born at 32–34 weeks, and 1.76 (95% CI 1.30–2.38) for those born at 35–36 weeks, relative to those born full-term (37–42 weeks). A similar but slightly weaker trend was observed for the association between preterm birth and antiepileptic drug prescription. These associations persisted after excluding individuals with cerebral palsy, inflammatory diseases of the CNS, cerebrovascular disease, and brain tumors.
These findings suggest that preterm birth, including late preterm birth, is strongly associated with epilepsy in Swedish adults aged 25–37 years. This association was independent of fetal growth and was not mediated by cerebral palsy or other comorbidities.
PMCID: PMC3182754  PMID: 21968843
7.  Birth weight differences between preterm stillbirths and live births: analysis of population-based studies from the U.S. and Sweden 
Many stillbirths show evidence of fetal growth restriction, and most occur at preterm gestational age. The objective of this study is to compare birth weights at preterm gestational ages between live births and stillbirths, and between those occurring before or during labour.
Based on singleton births from the United States (U.S.) 2003–2005 (n=902,491) and Sweden 1992–2001 (n=946,343), we compared birth weights between singleton live births and stillbirths at 24–36 completed weeks of gestation from the U.S. and at 28–42 completed weeks from Sweden.
In both the U.S. and Sweden, stillbirth weight-for-gestational-age z-scores were at least one standard deviation lower than live birth z-scores at all preterm gestational ages (GA). In Sweden, no birth weight difference was observed between antepartum and intrapartum stillbirths at preterm GAs, whereas birth weights among intrapartum stillbirths were similar to those among live births at 37–42 weeks.
Birth weights observed at preterm gestation are abnormal, but preterm stillbirths appear to be more growth-restricted than preterm live birth. Similar birth weights among ante- and intrapartum preterm stillbirths suggest serious fetal compromise before the onset of labor.
PMCID: PMC3514233  PMID: 23110432
Stillbirth; Preterm birth; Fetal growth; Intrauterine growth restriction
8.  Outdoor air pollution, low birth weight, and prematurity. 
Environmental Health Perspectives  2000;108(2):173-176.
This study tested the hypothesis, suggested by several recent reports, that air pollution may increase the risk of adverse birth outcomes. This study analyzed all singleton live births registered by the Czech national birth register in 1991 in 67 districts where at least one pollutant was monitored in 1990-1991 (n = 108,173). Maternal exposures to sulfur dioxide (SO(2)), total suspended particles (TSP), and nitrous oxides (NO(x)) in each trimester of pregnancy were estimated as the arithmetic means of all daily measurements taken by all monitors in the district of birth of each infant. Odds ratios of low birth weight (< 2,500 g), prematurity (< 37 weeks of gestation), and intrauterine growth retardation (IUGR; < 10th percentile of birth weight for gestational age and sex) were estimated by robust logistic regression. The median (and 25th and 75th percentile) trimester exposures were 32 (18, 56) microg/m(3) for SO(2); 72 (55, 87) microg/m(3) for TSP; and 38 (23, 59) microg/m(3) for NO(x). Low birth weight (prevalence 5.2%) and prematurity (prevalence 4.8%) were associated with SO(2) and somewhat less strongly with TSP. IUGR was not associated with any pollutant. The effects on low birth weight and prematurity were marginally stronger for exposures in the first trimester, and were not attenuated at all by adjustment for socioeconomic factors or the month of birth. Adjusted odds ratios of low birth weight were 1.20 [95% confidence interval (CI), 1.11-1.30] and 1.15 (CI, 1.07-1.24) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester; adjusted odds ratios of prematurity were 1.27 (CI, 1.16-1.39) and 1.18 (CI, 1.05-1.31) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester. Low gestational age accounted for the association between SO(2) and low birth weight. These findings provide further support for the hypothesis that air pollution can affect the outcome of pregnancy.
PMCID: PMC1637893  PMID: 10656859
9.  Postnatal growth in infants born before 30 weeks' gestation. 
Archives of Disease in Childhood  1986;61(6):549-553.
The postnatal weight pattern up to 14 weeks after birth was determined in 184 singleton survivors born at 23 to 29 weeks' gestation in whom routine parenteral nutrition was used before milk feeding was established. A mean postnatal weight loss of 14% of birth weight occurred at a mean of 6 days. The more immature infants had significantly higher postnatal weight loss and longer time to regain birth weight despite a higher volume intake in the first week. From the fourth postnatal week all gestational subgroups had a mean weight gain at above intrauterine growth rate. As a result of the initial period of weight loss, however, the mean body weight remained below the 10th percentile of the intrauterine growth curve. The early growth rate in infants small for gestational age was higher than those who were appropriate weight for gestation, although the mean body weight of the former group remained significantly lower at 2 years.
PMCID: PMC1777845  PMID: 3729523
10.  Apgar score and hospitalization for epilepsy in childhood: a registry-based cohort study 
BMC Public Health  2006;6:23.
A depressed Apgar score at 5 minutes is a marker for perinatal insults, including neurologic damage. We examined the association between 5-minute Apgar score and the risk of epilepsy hospitalization in childhood.
Using records linked from population registries, we conducted a cohort study among singleton children born alive in the period 1978–2001 in North Jutland County, Denmark. The first hospital discharge diagnosis of epilepsy during the follow-up time was the main outcome. We followed each child for up to 12 years, calculated absolute risks and risk differences, and used a Poisson regression model to estimate risk ratios for epilepsy hospitalization. We adjusted risk ratio estimates for birth weight, gestational age, mode of delivery, birth presentation, mother's age at delivery, and birth defects.
One percent of the 131,853 eligible newborns had a 5-minute Apgar score <7. These children were more likely to be hospitalized with epilepsy during the follow-up than were children with an Apgar score of 7 or greater. The crude risk difference for epilepsy hospitalization was 2.5 cases per 100 (95% confidence interval [CI] 1.3 to 3.8). The risk difference estimates were greater in the presence of other perinatal risk factors. The adjusted risk ratio was 2.4 (95% CI 1.5 to 3.8). Half of the 12-year risk for epilepsy hospitalization in those with a depressed Apgar score occurred during the first year of life. The risk ratio during the first year of life was 4.9 (95% CI 2.0 to 12.3).
An Apgar score <7 at five minutes predicts an increase in the subsequent risk of epilepsy hospitalization. This association is amplified by other perinatal risk factors.
PMCID: PMC1409783  PMID: 16451724
11.  Birth weight, gestational age, fetal growth and childhood asthma hospitalization 
Childhood asthma may have a fetal origin through fetal growth and development of the immunocompetence or respiratory organs.
We examined to which extent short gestational age, low birth weight and fetal growth restriction were associated with an increased risk of asthma hospitalization in childhood.
We undertook a cohort study based on several national registers in Denmark, Sweden and Finland. We included all live singleton born children in Denmark during 1979-2005 (N = 1,538,093), in Sweden during 1973-2004 (N = 3,067,670), and a 90% random sample of singleton children born in Finland during 1987-2004 (N = 1,050,744). The children were followed from three years of age to first hospitalization for asthma, emigration, death, their 18th birthday, or the end of study (the end of 2008 in Denmark, and the end of 2007 in Sweden or Finland), whichever came first. We computed the pseudo-values for each observation and used them in a generalized estimating equation to estimate relative risks (RR) for asthma hospitalization.
A total of 131,783 children were hospitalized for asthma during follow-up. The risk for asthma hospitalization consistently increased with lower birth weight and shorter gestational age. A 1000-g decrease in birth weight corresponded to a RR of 1.17 (95% confidence interval (CI) 1.15-1.18). A one-week decrease in gestational age corresponded to a RR of 1.05 (95% CI 1.04-1.06). Small for gestational age was associated with an increased risk of asthma hospitalization in term but not in preterm born children.
Fetal growth and gestational age may play a direct or indirect causal role in the development of childhood asthma.
PMCID: PMC3973844  PMID: 24602245
Asthma; Birth weight; Gestational age; Hospitalization; Small for gestational age
12.  Gestational Age and Fetal Growth in Relation to Maternal Ovarian Cancer Risk in a Swedish Cohort 
Pregnancy influences subsequent maternal ovarian cancer risk. To date, there is limited evidence whether two characteristics of pregnancy, gestational age and birth weight, could modify risk.
Materials and Methods
We studied 1.1 million Swedish women who delivered singleton births between 1973 and 2001. Information on infant gestational age and birth weight was abstracted from the nationwide Swedish Birth Register. Women were followed prospectively through linkage with other population-based registers for occurrence of ovarian cancer, death, or emigration through 2001. Hazard ratios [relative risk (RR), 95% confidence interval (95% CI)] from Cox models were used to estimate associations between gestational age, birth weight, and epithelial ovarian cancer risk.
During 12.6 million person-years, 1,017 epithelial ovarian cancers occurred. Mean age at diagnosis was 43 years. Compared with women with term deliveries (≥40 weeks), women with moderately (35–36 weeks) or very (<35 weeks) preterm deliveries had increased risks of epithelial ovarian cancer (RR 1.4, 95% CI 1.0–2.0 and RR 2.3, 95% CI 1.3–3.8, respectively). In contrast, women giving birth to small-for-gestational-age babies had a reduced risk (RR 0.7, 95% CI 0.4–1.0). Stratifying on birth weight and gestational age, there was a strong protective effect of low birth weight on maternal risk of epithelial ovarian cancer among term deliveries, whereas birth weight seemed to have little effect among preterm births (Pinteraction = 0.022).
Our results lend further support that the hormonal milieu of a pregnancy may modify long-term risk of developing ovarian cancer.
PMCID: PMC2646123  PMID: 17855701
13.  Birth weight as a predictor of breast cancer: a case–control study in Norway 
British Journal of Cancer  2002;86(1):89-91.
The hypothesis that birth weight is positively associated with adult risk of breast cancer implies that factors related to intrauterine growth may be important for the development of this malignancy. Using stored birth records from the two main hospitals in Trondheim and Bergen, Norway, we collected information on birth weight, birth length and placenta weight among 373 women who developed breast cancer. From the same archives, we selected as controls 1150 women of identical age as the cases without a history of breast cancer. Information on age at first birth and parity were collected from the Central Person Registry in Norway. Based on conditional logistic regression analysis, breast cancer risk was positively associated with birth weight and with birth length (P for trend=0.02). Birth weights in the highest quartile (3730 g or more) were associated with 40% higher risk (odds ratio, 1.4, 95% confidence interval, 1.1–1.9) of breast cancer compared to birth weights in the lowest quartile (less than 3090 g). For birth length, the odds ratio for women who were 51.5 cm or more (highest quartile) was 1.3 (95% confidence interval, 1.0–1.8) compared to being less than 50 cm (lowest quartile) at birth. Adjustment for age at first birth and parity did not change these estimates. Placenta weight was not associated with breast cancer risk. This study provides strong evidence that intrauterine factors may influence future risk of breast cancer. A common feature of such factors would be their ability to stimulate foetal growth and, simultaneously, to influence intrauterine development of the mammary gland.
British Journal of Cancer (2002) 86, 89–91. DOI: 10.1038/sj/bjc/6600011
© 2002 The Cancer Research Campaign
PMCID: PMC2746526  PMID: 11857017
breast cancer; birth weight; birth length; placenta weight
14.  Atopic dermatitis and birth factors: historical follow up by record linkage. 
BMJ : British Medical Journal  1997;314(7086):1003-1008.
OBJECTIVE: To study if factors at birth are associated with later development of atopic dermatitis. DESIGN: Historical follow up by record linkage from Danish medical birth register. Children were followed up for 5.5 to 8.5 years. Second historical follow up study comprising questionnaire to mothers of singleborn children 6.5 to 9.5 years after birth. SETTING: Private dermatology clinics and dermatology and paediatric departments in the municipality of Aarhus, Denmark. SUBJECTS: 7862 singletons born in hospital between 1 January 1984 and 31 December 1986 to mothers living in the municipality of Aarhus. Questionnaires sent to 985 mothers. MAIN OUTCOME MEASURES: Gestational age, birth weight, parity, and age of mother at the time of birth. Atopy in children diagnosed by specialists in dermatology and physicians. Family size; diagnosis of atopic dermatitis, allergic rhinitis, and asthma; family predisposition; and mothers' smoking habits during pregnancy determined from questionnaires. RESULTS: Of 7862 children, 403 were diagnosed as having atopic dermatitis by a specialist; the cumulative incidence at age 7 was 5.6%. High gestational age and low parity were associated with an increased risk of atopic dermatitis. Among 985 children atopic dermatitis had been diagnosed by any physician in 184; the cumulative incidence at age 7 was 18.7%. High birth weight, high gestational age, and family history of atopy were associated with increased risk of atopic dermatitis. CONCLUSION: In both studies the incidence of atopic dermatitis was associated with high gestational age and in one with high birth weight also. The causes for these associations are at present unknown but may indicate that even during gestation factors associated with atopic dermatitis influence maturation.
PMCID: PMC2126413  PMID: 9112844
15.  Customized birth weight for gestational age standards: Perinatal mortality patterns are consistent with separate standards for males and females but not for blacks and whites 
Some currently available birth weight for gestational age standards are customized but others are not. We carried out a study to provide empirical justification for customizing such standards by sex and for whites and blacks in the United States.
We studied all male and female singleton live births and stillbirths (22 or more weeks of gestation; 500 g birth weight or over) in the United States in 1997 and 1998. White and black singleton live births and stillbirths were also examined. Qualitative congruence between gestational age-specific growth restriction and perinatal mortality rates was used as the criterion for identifying the preferred standard.
The fetuses at risk approach showed that males had higher perinatal mortality rates at all gestational ages compared with females. Gestational age-specific growth restriction rates based on a sex-specific standard were qualitatively consistent with gestational age-specific perinatal mortality rates among males and females. However, growth restriction patterns among males and females based on a unisex standard could not be reconciled with perinatal mortality patterns. Use of a single standard for whites and blacks resulted in gestational age-specific growth restriction rates that were qualitatively congruent with patterns of perinatal mortality, while use of separate race-specific standards led to growth restriction patterns that were incompatible with patterns of perinatal mortality.
Qualitative congruence between growth restriction and perinatal mortality patterns provides an outcome-based justification for sex-specific birth weight for gestational age standards but not for the available race-specific standards for blacks and whites in the United States.
PMCID: PMC551609  PMID: 15720720
16.  Low Birth Weight, Small for Gestational Age and Preterm Births before and after the Economic Collapse in Iceland: A Population Based Cohort Study 
PLoS ONE  2013;8(12):e80499.
Infants born small for gestational age (SGA) or preterm have increased rates of perinatal morbidity and mortality. Stressful events have been suggested as potential contributors to preterm birth (PB) and low birth weight (LBW). We studied the effect of the 2008 economic collapse in Iceland on the risks of adverse birth outcomes.
Study design
The study population constituted all Icelandic women giving birth to live-born singletons from January 1st 2006 to December 31st 2009. LBW infants were defined as those weighing <2500 grams at birth, PB infants as those born before 37 weeks of gestation and SGA as those with a birth weight for gestational age more than 2 standard deviations (SD's) below the mean according to the Swedish fetal growth curve. We used logistic regression analysis to estimate odds ratios [OR] and corresponding 95 percent confidence intervals [95% CI] of adverse birth outcomes by exposure to calendar time of the economic collapse, i.e. after October 6th 2008.
Compared to the preceding period, we observed an increased adjusted odds in LBW-deliveries following the collapse (aOR = 1.24, 95% CI [1.02, 1.52]), particularly among infants born to mothers younger than 25 years (aOR = 1.85, 95% CI [1.25, 2.72]) and not working mothers (aOR = 1.61, 95% CI [1.10, 2.35]). Similarly, we found a tendency towards higher incidence of SGA-births (aOR = 1.14, 95% CI [0.86, 1.51]) particularly among children born to mothers younger than 25 years (aOR = 1.87, 95% CI [1.09, 3.23]) and not working mothers (aOR = 1.86, 95% CI [1.09, 3.17]). No change in risk of PB was observed. The increase of LBW was most distinct 6–9 months after the collapse.
The results suggest an increase in risk of LBW shortly after the collapse of the Icelandic national economy. The increase in LBW seems to be driven by reduced fetal growth rate rather than shorter gestation.
PMCID: PMC3851132  PMID: 24324602
17.  An analysis of birth weight by gestational age in Canada. 
Birth-weight-gestational-age standards help to identify infants in need of special care and to determine causes and means for preventing retardation of intrauterine growth. Previously published standards either were based on small samples, data several decades old or characteristics of subpopulations in the United States or they were not specific for type of birth and sex. We compared the data for live births in 1972 with those in 1986 to develop current Canadian standards for type of birth (singleton or twin) and sex. We found that the 10th, 50th and 90th percentile figures for weight were slightly higher in 1986 than in 1972 for term deliveries (at 37 weeks' gestation or later), but the figures were virtually unchanged for preterm deliveries. The availability of reliable population-based standards should enhance the clinician's ability to identify true cases of retardation or acceleration of intrauterine growth.
PMCID: PMC1268586  PMID: 2597238
18.  Comparison of Fetal and Neonatal Growth Curves in Detecting Growth Restriction 
Obstetrics and gynecology  2008;112(6):1227-1234.
To evaluate the outcome of intrauterine growth restriction (IUGR) infants with abnormal pulsatility index of the umbilical artery according to the neonatal birth weight/gestational age standards and the intrauterine growth charts.
We analyzed 53 pregnancies with severe IUGR classified as Group 2 (22 IUGR: abnormal pulsatility index and normal fetal heart rate) and Group 3 (31 IUGR: abnormal pulsatility index and fetal heart rate). Neonatal birth weight/gestational age distribution, body size measurements, maternal characteristics and obstetric outcome, and neonatal major and minor morbidity and mortality were compared with those obtained in 79 singleton pregnancies with normal fetal growth and pulsatility index, matched for gestational age [appropriate for gestational age (AGA) group]. Differences were analyzed with the χ2 test and the Student’s t test. Differences between means corrected for gestational age in the different groups were assessed by analysis of covariance test. A P value <0.05 was considered significant.
At delivery, utilizing the neonatal standards, 25/53 (47%) IUGR showed a birthweight above the 10th percentile (IUGRAGA) whereas in 28, birthweight was below the 10th percentile (IUGRSGA). All body size measurements were significantly higher in AGA than in IUGRAGA and IUGRSGA. Forty-nine out of 79 (62%) AGA and 49/53 (92%) IUGR were admitted in the neonatal intensive care unit (p<0.001). One out of 79 (1%) AGA and 6/53 (11%) IUGR newborns died within 28 days (p<0.02). Major and minor morbidity was not different.
This study shows that neonatal outcome is similar in IUGR of the same clinical severity, whether or not they could be defined AGA or SGA according to the neonatal standards. Neonatal curves are misleading in detecting low birthweight infants and should be utilized only when obstetrical data are unavailable.
PMCID: PMC2752730  PMID: 19037030
19.  Chronic Hypertension Related to Risk for Preterm and Term Small-for-Gestational-Age Births 
Obstetrics and gynecology  2008;112(2 Pt 1):290-296.
Evidence relating chronic hypertension to risk of small for gestational age (SGA) births is conflicting. To identify factors associated with SGA that may involve a placental pathogenesis, we related chronic hypertension and other maternal factors that may be markers of endothelial dysfunction to preterm compared with term SGA births.
Chronic hypertension, diabetes, body mass index, age, and subfertility were related to risk of term and preterm SGA births in the Danish National Birth Cohort (n=81,008). SGA births were those with a birth weight adjusted for gestational age greater than 2 standard deviations below the mean based on fetal growth curves.
Risk of preterm SGA increased 5.5-fold (95% CI 3.2-9.4) and risk of term SGA increased 1.5-fold (1.0-2.2) among women with definite chronic hypertension. Risk of preterm SGA but not term SGA was increased among women less than 20 (odds ratio [OR] 2.8, 95% CI: 1.1-6.8) or greater than 36 (OR 2.0 , 95% CI:1.3-3.1) years of age and among those with at least 2 early spontaneous abortions (OR 2.0, CI:1.3-3.3). Smoking, parity, time to pregnancy greater than 12 months, and underweight status were similarly related to term and preterm SGA. Overweight status, obesity, and presence of diabetes were unrelated to either SGA subtype.
Chronic hypertension, young or older maternal age, and recurrent early spontaneous abortions increased risk for preterm SGA. These factors may involve abnormal placentation and likely represent a pathogenesis distinct from that leading to term SGA.
PMCID: PMC2596352  PMID: 18669725
20.  Body Weight, Length and Head Circumference at Birth in a Cohort of Turkish Newborns 
Objective: Intrauterine growth references are primarily useful indicators in the assessment of the general health status of newborn infants. Although Lubchenco’s references are still used in many neonatal care units, we believe that there is a need for up-to-date intrauterine growth references specific for different populations. To develop gestational age-and gender-specific national references for birth weight, birth length and head circumference.
Methods: Data were collected from neonatal records of perinatology services of eleven hospitals from January to December 2009. The anthropometry of a total of 4750 singleton live births born between 28 and 41 weeks of gestation were recorded. Means and standard deviations were calculated, and percentiles for each gender and gestational week were produced using the LMS program. The results were compared with US infants and also with local data.
Results: Gestational age- and gender-specific 3rd, 5th, 10th, 15th, 25th, 50th, 75th, 85th, 90th, 95th and 97th percentile values were produced. Comparison of the 10th, 50th and 90th percentile values showed that the boys were heavier and longer than the girls. Head circumference values were also higher in the boys. Proportions of small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants in the sample were 10.1%, 79.1% and 10.8%, respectively.
Conclusion: These gender- and gestational age-specific references will be of use in clinical practice and also for research purposes until more comprehensive, reliable and accessible national data pertaining to the intrauterine growth of Turkish infants are produced.
Conflict of interest:None declared.
PMCID: PMC3459161  PMID: 22664362
Intrauterine growth percentiles; SGA; LGA
21.  Mode of Delivery and Neonatal Outcomes in Preterm, Small-for-Gestational-Age Newborns 
Obstetrics and gynecology  2012;120(3):560-564.
To compare neonatal outcomes by method of delivery in preterm (34 weeks of gestation or prior), small-for-gestational-age (SGA) newborns in a large diverse cohort.
Birth data for 1995–2003 from New York City were linked to hospital discharge data. Data were limited to singleton, liveborn, vertex neonates delivered between 25 and 34 weeks of gestation. Births complicated by known congenital anomalies and birth weight less than 500 g were excluded. Small for gestational age was used as a surrogate for intrauterine growth restriction. Associations between method of delivery and neonatal morbidities were estimated using logistic regression.
Two thousand eight hundred eighty-five SGA neonates meeting study criteria were identified; 42.1% were delivered vaginally, and 57.9% were delivered by cesarean. There was no significant difference in intraventricular hemorrhage, subdural hemorrhage, seizure, or sepsis between the cesarean delivery and vaginal delivery groups. Cesarean delivery compared with vaginal delivery was associated with increased odds of respiratory distress syndrome. The increased odds persisted after controlling for maternal age, parity, ethnicity, education, primary payer, prepregnancy weight, gestational age at delivery, diabetes, and hypertension.
Cesarean delivery was not associated with improved neonatal outcomes in preterm SGA newborns and was associated with an increased risk of respiratory distress syndrome.
PMCID: PMC3739844  PMID: 22914464
22.  Pregnancy complications among women born preterm 
Adults who were born with low birth weights are at increased risk of cardiovascular and metabolic conditions, including pregnancy complications. Low birth weight can result from intrauterine growth restriction, preterm birth or both. We examined the relation between preterm birth and pregnancy complications later in life.
We conducted a population-based cohort study in the province of Quebec involving 7405 women born preterm (554 < 32 weeks, 6851 at 32–36 weeks) and a matched cohort of 16 714 born at term between 1976 and 1995 who had a live birth or stillbirth between 1987 and 2008. The primary outcome measures were pregnancy complications (gestational diabetes, gestational hypertension, and preeclampsia or eclampsia).
Overall, 19.9% of women born at less than 32 weeks, 13.2% born at 32–36 weeks and 11.7% born at term had at least 1 pregnancy complication at least once during the study period (p < 0.001). Women born small for gestational age (both term and preterm) had increased odds of having at least 1 pregnancy complication compared with women born at term and at appropriate weight for gestational age. After adjustment for various factors, including birth weight for gestational age, the odds of pregnancy complications associated with preterm birth was elevated by 1.95-fold (95% confidence interval [CI] 1.54–2.47) among women born before 32 weeks’ gestation and 1.14-fold (95% CI 1.03–1.25) among those born at 32–36 weeks’ gestation relative to women born at term.
Being born preterm, in addition to, and independent of, being small for gestational age, was associated with a significantly increased risk of later having pregnancy complications.
PMCID: PMC3494353  PMID: 23008489
23.  Birth weight in a large series of triplets 
BMC Pediatrics  2011;11:24.
Triplets are often born premature and with a low birth weight. Because the incidence of triplet births is rare, there are relatively few studies describing triplet birth weight characteristics. Earlier studies are often characterized by small sample sizes and lack information on important background variables such as zygosity. The objective of this study is to examine factors associated with birth weight in a large, population-based sample of triplets registered with the Netherlands Twin Register (NTR).
In a sample of 1230 triplets from 410 families, the effects of assisted reproductive techniques, zygosity, birth order, gestational age, sex, maternal smoking and alcohol consumption during pregnancy on birth weight were assessed. The resemblance among triplets for birth weight was estimated as a function of zygosity. Birth weight discordance within families was studied by the pair-wise difference between triplets, expressed as a percentage of the birth weight of the heaviest child. We compare data from triplets registered with the NTR with data from population records, which include live births, stillbirths and children that have deceased within days after birth.
There was no effect of assisted reproductive techniques on triplet birth weight. At gestational age 24 to 40 weeks triplets gained on average 130 grams per week; boys weighed 110 grams more than girls and triplets of smoking mothers weighted 104 grams less than children of non-smoking mothers. Monozygotic triplets had lower birth weights than di- and trizygotic triplets and birth weight discordance was smaller in monozygotic triplets than in di- and trizygotic triplets. The correlation in birth weight among monozygotic and dizygotic triplets was 0.42 and 0.32, respectively. In nearly two-thirds of the families, the heaviest and the lightest triplet had a birth weight discordance over 15%. The NTR sample is representative for the Dutch triplet population that is still alive 28 days after birth.
Birth weight is an important determinant of childhood development. Triplet status, gestational age, sex, zygosity and maternal smoking affect birth weight. The combined effects amount to a difference of 364 grams between monozygotic girl triplets of smoking mothers compared to dizygotic boy triplets of non-smoking mothers of the same gestational age. Birth weight in triplets is also influenced by genetic factors, as indicated by a larger correlation in monozygotic than in di- and trizygotic triplets.
PMCID: PMC3087677  PMID: 21453554
24.  Intrauterine growth pattern and risk of childhood onset insulin dependent (type I) diabetes: population based case-control study. 
BMJ : British Medical Journal  1996;313(7066):1174-1177.
OBJECTIVE: To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus. DESIGN: Population based case-control study. SETTING: Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry. SUBJECTS: Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband. MAIN OUTCOME MEASURES: Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD). RESULTS: There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42). CONCLUSIONS: Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.
PMCID: PMC2352527  PMID: 8916747
25.  Reexamining the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality 
Low birth weight (<2,500 g) is a strong predictor of infant mortality. Yet low birth weight, in isolation, is uninformative since it is comprised of two intertwined components: preterm delivery and reduced fetal growth. Through nonparametric logistic regression models, we examine the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality.
We derived data on over 10 million singleton live births delivered at ≥ 24 weeks from the 1998–2000 U.S. natality data files. Nonparametric multivariable logistic regression based on generalized additive models was used to examine neonatal mortality (deaths within the first 28 days) in relation to fetal growth (gestational age-specific standardized birth weight), gestational age, and number of cigarettes smoked per day. All analyses were further adjusted for the confounding effects due to maternal age and gravidity.
The relationship between standardized birth weight and neonatal mortality is nonlinear; mortality is high at low z-score birth weights, drops precipitously with increasing z-score birth weight, and begins to flatten for heavier infants. Gestational age is also strongly associated with mortality, with patterns similar to those of z-score birth weight. Although the direct effect of smoking on neonatal mortality is weak, its effects (on mortality) appear to be largely mediated through reduced fetal growth and, to a lesser extent, through shortened gestation. In fact, the association between smoking and reduced fetal growth gets stronger as pregnancies approach term.
Our study provides important insights regarding the combined effects of fetal growth, gestational age, and smoking on neonatal mortality. The findings suggest that the effect of maternal smoking on neonatal mortality is largely mediated through reduced fetal growth.
PMCID: PMC535930  PMID: 15574192

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