Objective To investigate infant mortality and causes of infant death in relation to gestational age (GA) and birth weight for GA in non-malformed term and post-term infants.
Design Observational, retrospective nationwide cohort study.
Setting Sweden 1983–2006.
Participants 2 152 738 singleton non-malformed infants born at 37 gestational weeks or later.
Main outcome measures Infant, neonatal and postneonatal mortality and causes of infant death.
Results Infant mortality rate was 0.12% (n=2687). Compared with infants born at 40 weeks, risk of infant mortality was increased among early term infants (37 weeks, adjusted OR 1.70, 95% CI 1.43 to 2.02). Compared with infants with normal birth weight for GA, very small for gestational age (SGA; <3rd percentile) infants faced a doubled risk of infant mortality (adjusted OR 2.13, 95% CI 1.80 to 2.53), and corresponding risk was also increased among moderately SGA infants (3rd to <10th percentile; adjusted OR 1.46, 95% CI 1.26 to 1.68). Sudden infant death syndrome (SIDS) was the most common cause of death, accounting for 39% of all infant mortality. Compared with birth at 40 weeks, birth at 37 weeks was associated with increased risks of death by infections, cardiovascular disorders, SIDS and malignant neoplasms. Very and moderately SGA were associated with increased risks of death by neonatal respiratory disorders, infections, cardiovascular disorders, SIDS and neuromuscular disorders. High birth weight for GA was associated with increased risks of death by asphyxia and malignant neoplasms.
Conclusion Early term birth and very to moderately low birth weight for GA are independent risk factors for infant mortality among non-malformed term infants.
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Term infants (born at 37 gestational weeks or more) contribute with 30% to all neonatal mortality. Infants born at 37 and 38 weeks have higher rates of infant mortality than infants born at 40 weeks. Little is known about the interplay between GA and birth weight for GA and its effect on infant mortality.
This study adds detailed analyses of the relationships between GA and birth weight for GA and risks of neonatal and postneonatal mortality and causes of infant death. We conclude that induced deliveries before 39 weeks gestation should be avoided when possible and that extra caution should be taken in term pregnancies with suspected severe or moderate intrauterine growth restriction.
Strengths and limitations of this study
The main strengths of this study are related to sample size and to the large number of predefined risk factors and confounders. Limitations were that some malformations may not have been detected, causing a theoretical selection bias, and that time trends may have influenced the outcome.
In studies of gestational age (GA) and risks of infant mortality and morbidity, infants born at term (ie, at 37–41 weeks) are commonly used as a reference group. However, recent studies highlight that compared with infants born at 40 weeks, infants born at 37 and 38 weeks have higher rates of infant, neonatal and postneonatal mortality, as well as neonatal morbidity.1 ,2 Term infants contribute approximately 30% of all infant mortality.3 Low birth weight may be a result of short GA and/or restricted fetal growth and infants born small for gestational age (SGA) are at increased risk of infant mortality. In a study of more than 300 000 infants, both late preterm (34–36 weeks) and term born SGA infants were at increased risk of infant mortality compared with infants with a normal birth weight for GA. Almost half of infant mortality among these infants was caused by congenital conditions, but SGA infants were also at increased risk of infant mortality after excluding infant deaths caused by congenital anomalies.4
To our knowledge, there are no previous studies on how GA interacts with birth weight for GA on risks of neonatal and postneonatal mortality or causes of infant death in term and post-term infants. Moreover, earlier studies have not separated neonatal and postneonatal mortality or compared risks of mortality or causes of infant deaths in term and post-term infants. In addition, information about possible confounders was also limited in previous studies.
In the present nationwide Swedish investigation, we have included information on maternal and infant characteristics on more than 2 million singleton live births. The aims of this study are to clarify the associations between GA and birth weight for GA and risks of infant, neonatal and postneonatal mortality as well as causes of infant death in term and post-term born non-malformed infants.
The Swedish National Board of Health and Welfare and Statistics Sweden provided data from four population-based registers. Record linkage of individuals across these registries was made possible through the unique National Registration Number assigned to each Swedish resident at birth or immigration.5 The Swedish Birth Register started in 1973 and contains prospectively collected data on the mother, pregnancy, delivery and infant on 98%–99% of all births in Sweden.6 ,7 The Education Register includes information on highest level of formal education level and is updated yearly. The Cause of Death Register collects data on date and cause of death on all Swedish residents. The Register of Population and Population Changes holds information on dates of birth, death, immigration and emigration of all Swedish residents. The study protocol was approved by the regional ethical vetting board at Karolinska Institutet.
The study population was defined as all live singleton infants with information on birth weight and GA, born at 37 completed gestational weeks or later and registered in the Birth Registry in 1983–2006 (n=2 242 591). In the Birth and Cause of Death Registers, diagnoses and causes of death are coded according to the International Classification of Diseases (ICD). The eighth revision (ICD-8) was used from 1983 to 1986, ICD-9 was used from 1987 to 1996 and ICD-10 was used from 1997 to 2006. We excluded infants with a malformation diagnosis (ICD-8: 740–759, ICD-9: 740–759 or ICD-10: Q00–Q99) in the Birth Registry and/or the Cause of Death Registry (n=89 853). The final study population included 2 152 738 infants.
Our two main exposures were GA and birth weight for GA. Estimation of GA was made by ultrasound around the 17th week of gestation. If no early second trimester ultrasound scan was available, last menstrual period was used to calculate GA. Birth weight for GA was categorised into percentiles of expected birth weight for GA according to the Swedish reference curve for normal fetal growth (3rd, 10th, 25th, 75th, 90th and 97th percentiles).8 At the first antenatal visit (usually at 8–12 gestational weeks), women were interviewed on their smoking habits (non-smoker, 1–9 cigarettes daily and 10 or more cigarettes daily) and health status, and the data were forwarded to the Birth Registry. At delivery, information on the mother's age and parity, diagnoses (pre-eclampsia, premature rupture of membranes, hypertension and diabetes), mode of delivery (cesarean, vaginal instrumental and vaginal non-instrumental delivery), infant's year of birth, birth weight, sex, GA and diagnoses at discharge was collected and forwarded to the Birth Register. Information on mother's education level was obtained from the Education Registry in 2005 and was categorised into 9 years or less, 10–11 years, 12 years, 13–14 years and 15 years or more. Largely, this categorisation corresponds with Swedish compulsory education (7–16 years of age), vocational secondary education, pre-academic secondary education, college and university-level studies. Information on the mother's country of birth (Sweden, other Nordic countries (Denmark, Finland, Iceland and Norway) and outside the Nordic countries) was provided by the Register of Population and Population Changes.
Outcome was defined by information on time or cause of death, provided by the Cause of Death Registry. Infant mortality was defined as death of a live born infant during the first year of life (0–364 completed days of age). Infant mortality was categorised into neonatal mortality, defined as death at 0–27 completed days of age, and postneonatal mortality, defined as death at 28–364 completed days of age. Cause of death was categorised into nine groups according to the following ICD codes: asphyxia (ICD-8: 77640–77650, 76840, 76890; ICD-9: 768; ICD-10: P20–P21), neonatal respiratory disorders (ICD-8: 77600–77629, 77660; ICD-9: 769–770, 786; ICD-10: P22, P24), infections (ICD-8: 000–139, 320–324, 460–486, 590; ICD-9: 000–139, 320–324, 464–466, 480–499, 590, 770–771; ICD-10: A01–A99, B01–B99, G00–G09, J02–J22, P23, P35–P39), cardiovascular disorders (ICD-8/ICD-9: 391–459; ICD-10: I00–I99, P29, P91), sudden infant death syndrome (SIDS; ICD-8: 79500; ICD-9: 798; ICD-10: R95), neuromuscular disorders (ICD-8/ICD-9: 330–359; ICD-10: G10–G99), malignant neoplasms (ICD-8/ICD-9: 140–209; ICD-10: C00–C99), external causes of death (ICD-8/ICD-9: 800–999; ICD-10: V00–V99, W00–W99, Y00–Y99, X00–X99) and other (remaining) causes of death.
Stratum-specific death rates were calculated as ((number of deaths in the stratum)/(number of infants at risk in the stratum)). Outcome was stratified by GA at birth and birth weight for GA. Crude and adjusted ORs were calculated by logistic regression. In the first model, we adjusted for year of birth, and GA was adjusted for birth weight for GA and vice versa. In the second adjusted model, we also adjusted for mother's country of birth, education level, age, parity, smoking status in early pregnancy, pre-eclampsia, premature rupture of membranes, diagnosis of pregestational and/or gestational hypertension or diabetes, mode of delivery, year of delivery and infant's sex. Infants who were born at 40 gestational weeks and/or with normal birth weight for GA (within the 25th to 75th percentiles) served as reference group. In analyses of postneonatal mortality, we included infants alive at 28 days of age. Birth weight for GA was a priori considered a possible effect modifier on the association of GA and infant, neonatal and postneonatal mortality. Effect modification was tested by likelihood ratio interaction test and stratification.
Of the total 2 152 738 infants born at 37 completed weeks or later, 2687 (0.12%) infants died during the first year of life. There were 882 (0.04%) neonatal deaths and 1805 (0.08%) postneonatal deaths. The infant mortality rate/1000 live births was 2.37 among infants born at 37 weeks, 1.52 at 38 weeks, 1.18 at 39 weeks, 1.08 at 40 weeks, 1.13 at 41 weeks and 1.30 at 42 weeks or more. The distribution of risk factors among survivors and non-survivors at 1 year of age is presented in eTable 1.
Compared with infants born at 40 weeks, infants born at 37 gestational weeks had a more than doubled risk of infant mortality in crude analyses. After adjustment for maternal, pregnancy and infant factors, being born at 37 weeks was associated with a 70% increased risk of infant mortality. Compared with infants with normal birth weight for GA, infants who were assessed as very small for GA (very SGA; <3rd percentile) had a doubled infant mortality risk and moderately small for GA infants (moderately SGA; between the 3rd and the 10th percentiles) had a 50% increased risk in the fully adjusted model (table 1).
Compared with infants born at 40 weeks, infants born at 37 weeks were at a 2.6-fold increased risk of neonatal mortality in the crude analysis and a 70% increased risk in the fully adjusted analysis. Post-term infants had a 70% increased risk of neonatal mortality in the crude analysis and a 40% increased risk in the fully adjusted analysis. Compared with normal birth weight infants, very SGA infants had a 2.5-fold increased risk and moderately SGA infants a more than 50% increased risk of neonatal mortality in the fully adjusted model (table 2).
Compared with infants born at 40 weeks, infants born at 37 weeks had a doubled risk of postneonatal mortality in the crude analysis and a 70% increased risk in the fully adjusted analysis. Infants born at 38 weeks also had an increased risk of postneonatal mortality. Compared with infants with normal birth weight for GA, very SGA infants had an almost doubled risk and moderately SGA infants a 40% increased risk of postneonatal mortality in the fully adjusted model (table 3). We did not detect any interactions between GA and birth weight for GA on the risk of infant, neonatal or postneonatal mortality. Observations with missing data on any risk factor were excluded from the fully adjusted models. We did not detect any significant difference of results when comparing analysis before and after exclusion of missing data.
Cause of death
The main causes of infant death were asphyxia (9.9%), neonatal respiratory disorders (3.6%), infections (11.3%), cardiovascular disorders (3.4%), SIDS (39.5%), neuromuscular disorders (5.3%), malignant neoplasms (2.0%), external causes (3.5%) and other causes (22.3%). In the ‘other causes’ category, three subcategories (neonatal morbidity except respiratory diseases and infections, birth trauma and metabolic diseases) accounted for two-thirds of the mortality.
Table 4 shows GA and birth weight for GA and risks of infant mortality by cause. Compared with infants born at 40 weeks, infants born at early term age were at increased risks of death by infections (a more than threefold risk at 37 weeks and a more than twofold risk at 38 weeks), cardiovascular disorders (an almost threefold risk at 37 weeks), SIDS (an almost twofold risk at 37 weeks and an almost 50% risk increase at 38 weeks), malignant neoplasms (a more than threefold risk at 37 weeks) and other causes of death (an almost threefold risk at 37 weeks). Infants born at 41 weeks or post-term (≥42 weeks) infants were at increased risk of death by asphyxia (a 50% risk increase at 41 weeks and a 2.5-fold risk increase at ≥42 weeks), neonatal respiratory disorders (a doubled risk at ≥42 weeks) and infections (a 50% risk increase at ≥42 weeks). Compared with infants with normal birth weight for GA (25th to 75th percentiles), very SGA infants (<3rd percentile) had more than fourfold increased risks of death by neonatal respiratory disorders and cardiovascular disorders, more than tripled risks of deaths by neuromuscular disorders and other causes of death, and more than doubled risks of deaths by infections and SIDS. For moderately SGA infants (3rd to 10th percentiles), risks of death by neonatal respiratory disorders and other causes of death were more than doubled and risk of SIDS was increased by 40%. Infants who were very large for GA (very LGA; above the 97th percentile) had more than a tripled increase in risk of death by asphyxia and malignant neoplasms. Infants with a modestly increased birth weight for GA (75th to 90th percentiles) had a doubled risk of death by neoplasms.
In this nationwide population-based study, we found that the increased all-cause infant mortality risk among early term (37 weeks) non-malformed infants was due to increased risks of death by infections, cardiovascular diseases, SIDS and malignant neoplasms. Being born very SGA (<3rd percentile) was associated with a more than doubled risk, and being born moderately SGA (3rd to 10th percentiles) was associated with an almost 50% increased risk of infant mortality. Low birth weight for GA was associated with increased risks of death by all causes except malignant diseases. Post-term birth (42+ weeks) was a risk factor for neonatal but not for postneonatal mortality and was associated with increased risks of death by infections, neonatal respiratory disorders and asphyxia. High birth weight for GA was associated with increased risks of death by asphyxia and malignant diseases. This is the first study to show the interplay between GA and birth weight for GA with respect to risks of neonatal and postneonatal mortality and causes of infant death in term, non-malformed infants. Access to a large database permitted the inclusion of a wide range of possible confounders and enabled the separation of infant mortality into neonatal and postneonatal mortality. Additionally, an analysis of the contribution of GA and birth weight for GA to cause of death in term and post-term infants was performed.
Strengths and limitations
The main strengths of our study were related to sample size and precision but also to the large number of predefined risk factors and confounders. GA was determined by ultrasound in most pregnancies, data were prospectively recorded and the number of pregnancies with missing information was low. The validity of self-reported smoking has been reported to be high among pregnant women in the Swedish Birth Registry.9 However, one limitation was that some malformations may not have been detected and diagnosed at the physical examination after birth. As all malformation-related death causes were excluded from the study, the majority of these undetected malformations would probably not be related to infant mortality. However, the remaining malformations in the study group could be a theoretical source of selection bias. In addition, sample size was not large enough to adjust analyses of causes of death for all confounders. Time trends may also have influenced the outcome, as obstetric and neonatal care as well as diagnostic practices and rates of infant mortality have changed during the study period. We have tried to control for this time effect by adjusting all analyses for year of birth.
GA and infant mortality
Infant mortality is inversely related to GA at birth, and this association persists even at late preterm and term gestations.2 ,10 ,11 This fact may not be publicly recognised and the heterogeneity of risk within the group of term infants deserves more attention. Data on risks of infant, neonatal and postneonatal mortality in different gestational weeks and identification of especially vulnerable individuals are necessary when planning elective deliveries and for assembling the right competence and surveillance around the newborn infant after delivery.10 There has been a tendency to electively deliver infants on relative indications at early term GAs in Western countries, instead of postponing delivery until the pregnancy has reached full term. As demonstrated in this and other studies,1 ,2 early term delivery may have detrimental effects on infant morbidity and mortality rates on a population-based level and must be avoided when not medically indicated. When compared with full-term birth, early term birth has also been associated with negative long-term effects, such as increased use of asthma medication, higher prevalence of attention deficit disorders, lower cognition and an over-representation of psychiatric disorders.12–14 To put the effect size into perspective, our results also show that, compared with being born post-term (a recognised risk group at delivery), being born early term is associated with a 60% higher risk of infant mortality.
Birth weight and infant mortality
A higher infant mortality among SGA infants is well documented at all GAs. 4 ,15 ,16 Our results show that very and even moderately SGA infants must be regarded as extra vulnerable to adverse events during the course of their first year of life. In Sweden, SGA is defined as a birth weight of <−2 SD of expected birth weight for GA, a limit approximately corresponding to the 2, 5th percentile. But in international literature, SGA is usually defined as less than the 10th percentile of expected birth weight for GA. In this study, we show that risks of infant, neonatal and postneonatal mortality are increased already at the 10th percentile, which calls for a review of the current Swedish SGA definition. This is the first study on the impact of GA and birth weight for GA on risks of infant, neonatal and postneonatal mortality among term infants that is able to adjust for important socioeconomic, maternal, delivery and infant confounders. After adjusting for these factors, the risk estimates decreased, but associations were still significant. Although adjusted risk estimates may be important from an etiologic perspective, unadjusted risks may be more relevant from a clinical perspective.
Cause of death
Several of the examined causes of death in this study may be preventable in term infants by improved prenatal, delivery and neonatal care routines. First, early term birth per se was associated with increased risks of death by infections and SIDS. We conclude that non-medically indicated deliveries should be avoided at 37–38 gestational weeks when possible. Second, SGA was associated with increased risks of death caused by infections and SIDS, which again puts the focus on intrauterine growth patterns and the importance of appropriate growth surveillance during pregnancy. Third, post-term delivery was associated with increased risks of death by asphyxia, infections and neonatal respiratory disorders. In recent years, induction of delivery has become more common from gestational week 42+0 in Sweden, mainly to avoid intrauterine death. This study suggests that these interventions may be lifesaving also after a live birth. Fourth, a high birth weight for GA was associated with an increased risk of death by asphyxia and malignant neoplasms. Among high-risk mothers, that is, mothers with high body mass index and/or diabetes,17 ,18 preferable interventions may be normalised prepregnancy body mass index, minimalised weight gain during pregnancy and improved metabolic control. In lack of effective nutritional and metabolic strategies, asphyxia could possibly be avoided by special attention at delivery in this risk group.
To the field of studies on infant mortality among term infants, our study adds detailed analyses of the relationships between GA and birth weight for GA and risks of neonatal and postneonatal mortality and causes of infant death. Our main conclusions are that non-medically indicated deliveries before 39 weeks gestation should be avoided when possible and that extra caution should be taken in term pregnancies with suspected severe or moderate intrauterine growth restriction. We also conclude that at least some of the infant mortality among non-malformed term infants might be prevented by improvements in antenatal and neonatal care.
To cite: Altman M, Edstedt Bonamy A-K, Wikström A-K, et al. Cause-specific infant mortality in a population-based Swedish study of term and post-term births: the contribution of gestational age and birth weight. BMJ Open 2012;2:e001152. doi:10.1136/bmjopen-2012-001152
Contributors All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, and the study hypothesis arose before inspection of the data. MA has contributed to the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation of the manuscript. A-KEB has contributed to the design and conduct of the study, interpretation of the data and review of the manuscript. A-KW has contributed to the design and conduct of the study, interpretation of the data and review of the manuscript. SC has contributed to the design and conduct of the study; collection, management and interpretation of the data; and review of the manuscript. The final version of the manuscript has been approved by all authors.
Funding This work was supported by the European Union's Seventh Framework Programme (FP7/2007-2011).
Competing interests None.
Ethics approval Ethics approval was provided by the Ethics Committee at Karolinska Institutet, Stockholm.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The statistical code is available from the corresponding author (firstname.lastname@example.org). Participants consent was not obtained but the presented data are anonymised and risk of identification is low.
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