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Background Unexplained stillbirth and the sudden infant death syndrome (SIDS) share some features. A raised maternal serum level of alpha-fetoprotein during the second trimester of pregnancy is a marker of placental dysfunction and a strong predictor of the risk of unexplained stillbirth. It is unknown whether alpha-fetoprotein levels also predict the risk of SIDS.
Methods We linked a prenatal-screening database for women in western Scotland with databases of maternity, perinatal death, and birth and death certifications to assess the association between second-trimester levels of maternal serum alpha-fetoprotein and the subsequent risk of SIDS.
Results Among 214,532 women with singleton births, there were 114 cases of SIDS (incidence, 2.7 per 10,000 births among women with alpha-fetoprotein levels in the lowest quintile and 7.5 per 10,000 births among those with levels in the highest quintile). When the lowest quintile was used as a referent, the unadjusted odds ratios for SIDS for the second through fifth quintiles were 1.7 (95 percent confidence interval, 0.8 to 3.5), 1.8 (95 percent confidence interval, 0.9 to 3.7), 2.5 (95 percent confidence interval, 1.3 to 4.8), and 2.8 (95 percent confidence interval, 1.4 to 5.4), respectively (P for trend = 0.001). The risk of SIDS varied inversely with the birth-weight percentile and the gestational age at delivery; after adjustment for these factors, the odds ratios for SIDS were 1.7 (95 percent confidence interval, 0.8 to 3.5), 1.7 (95 percent confidence interval, 0.8 to 3.5), 2.2 (95 percent confidence interval, 1.1 to 4.4), and 2.2 (95 percent confidence interval, 1.1 to 4.3), respectively (P for trend = 0.01).
Conclusions There is a direct association between second-trimester maternal serum alpha-fetoprotein levels and the risk of SIDS, which may be mediated in part through impaired fetal growth and preterm birth.
The mechanisms linking complications of pregnancy and the risk of SIDS remain obscure. Previous studies have suggested similarities between unexplained stillbirth and SIDS with respect to clinical and pathological findings, suggesting that the two conditions may be related.4,5 A raised maternal serum level of alpha-fetoprotein during the second trimester of pregnancy is one of the best biochemical predictors of the risk of unexplained stillbirth.6 If SIDS and unexplained stillbirth have common pathophysiological determinants, there might be a direct association between maternal serum alpha-fetoprotein levels and the risk of SIDS. We designed this study to test the hypothesis that the risk of SIDS would increase with increasing maternal serum levels of alpha-fetoprotein in a large Scottish database linking biochemical, pregnancy, birth, and death records for 214,532 live-born singleton infants.
Methods
Sources of Data
The Scottish Morbidity Record is a registry in which information on clinical and demographic characteristics and outcomes is collected for all women discharged from Scottish maternity hospitals. The registry is subjected to regular quality-assurance checks and has been more than 99 percent complete since the late 1970s.7 The Scottish Stillbirth and Infant Death Enquiry is a national registry that routinely classifies all perinatal deaths in Scotland.2 All women attending prenatal care in western Scotland are offered biochemical screening, with their serum levels of alpha-fetoprotein and human chorionic gonadotropin used to assess their risk of having a fetus affected by Down's syndrome or a structural abnormality.8 The laboratory information management system for the prenatal screening program of the West of Scotland Regional Genetics Service of the Institute of Medical Genetics, in Glasgow, contains a database of maternal information and biochemical-screening results. Electronic storage of these data in their current form was started in September 1991. Although serum alpha-fetoprotein was measured during screening before this date, the data were not archived in a format that allowed weight-adjusted multiples of the median to be calculated. The General Register Office, Scotland, maintains electronic birth and death records.
We used a probability-based, matching approach9 with maternal identifiers to link the Scottish Morbidity Record, the Scottish Stillbirth and Infant Death Enquiry database, the Institute of Medical Genetics prenatal screening database, and the General Register Office database of birth certificates. The birth certificates contained offspring identifiers that were then used to link biochemical data, pregnancy data, and data on perinatal deaths to the death-certificate registry to identify deaths among the offspring. We excluded multiple births, stillbirths, and births before or after 24 to 43 weeks of gestation. Approval of the study was obtained from the Privacy Advisory Committee of the Information and Statistics Division, National Health Service, Scotland.
Definitions
For purposes of this study, SIDS was defined as the death of an infant during the first year of life with this diagnosis listed as the principal cause of death on the death certificate (code 798.0 in the International Classification of Diseases, 9th Revision [ICD-9] or code R95 in the International Classification of Diseases, 10th Revision [ICD-10]). During the period studied, a diagnosis of SIDS could be written on a death certificate in Scotland only after thorough investigation of the circumstances of the death. The minimal requirements are described by the Crown Office10 (the government body that oversees the Procurator Fiscal, whose duties include the investigation of sudden deaths), and an autopsy is mandatory. In practice, the investigation of these deaths was frequently much more involved.11 A previous, detailed study in which Scottish death certificates between 1992 and 1995 showed 201 deaths attributed to SIDS found that standard diagnostic criteria were fulfilled in all cases.12 SIDS is a diagnosis of exclusion and is not made in the presence of a major congenital abnormality. The death certificate could contain up to three ICD-9 or ICD-10 diagnostic codes. We ruled out coexisting congenital abnormalities by searching the second and third diagnostic codes (for ICD-9 codes 740.0 to 759.9 or ICD-10 codes beginning with "Q"); none of the cases in which death had been attributed to SIDS on the certificate also had these codes.
The mother's age and parity, the postal code of her residence, and all outcome data were obtained solely from the Scottish Morbidity Record. The mother's weight was obtained solely from the biochemical database. Her height and smoking status were obtained from the Scottish Morbidity Record or, in cases in which they were missing from the Scottish Morbidity Record, from the biochemical database. The smoking status (current, former, or never) was determined on the basis of information gathered at the time of the first prenatal visit or at the time of prenatal screening if this information was obtained from the biochemical database. The mother's age was defined as the age of the mother at the time of delivery. Her body-mass index was calculated as the weight in kilograms recorded at the time of sampling for the alpha-fetoprotein assay divided by the square of the height in meters. Socioeconomic status was estimated on the basis of the postal code of the mother's residence, according to Carstairs socioeconomic-deprivation categories13 (based on 1991 Census data on car ownership, employment status, number of occupants per household room, and social class within postal-code sectors of residence that contain, on average, about 1600 residents).
The gestational age at birth was defined as the number of weeks of gestation completed, on the basis of the estimated date of delivery in each woman's clinical record; standard national criteria exist for estimation of the date of delivery with the use of menstrual and ultrasonographic data.14 Since the early 1990s, the estimated gestational age has been confirmed by ultrasonography during the first half of pregnancy in more than 95 percent of pregnancies in the United Kingdom.15 The birth weight was categorized into sex-specific and gestational-age–specific percentiles, as previously described in detail.16 Maternal serum levels of alpha-fetoprotein and human chorionic gonadotropin were quantified as multiples of the median (the ratio of the individual value to the median value) for the given week of gestation, after correction for the mother's weight.17
Statistical Analysis
Univariate comparisons were performed with the Mann–Whitney U test, the chi-square test, and the chi-square test for trend, as appropriate. The P values for all hypothesis tests were two-sided. Crude and adjusted odds ratios for SIDS were obtained by means of logistic-regression analysis.18 Biochemical data were categorized into deciles or quintiles. The mother's age, height, body-mass index, and parity were treated continuously in logistic-regression models, as were the birth-weight percentile and the gestational age (in weeks) at delivery. Nonlinearity of continuous variables in the logistic regression was tested and modeled with the use of fractional polynomials. The regression techniques involved the use of robust standard errors, as well as unique maternal identifiers, to account for dependence between births to the same mother.
The statistical significance of interaction terms was assessed by means of the Wald test, and results were considered significant when the P value was less than 0.01. Observations for which values were missing for variables that were more than 99.8 percent complete in the linked database were dropped from the multivariate analysis. For variables that were 99.8 percent or less complete in the linked database, missing values were estimated by multiple multivariate imputation.19 The goodness of fit of the models was assessed with a Hosmer–Lemeshow test based on deciles of probability. All statistical analyses were performed with use of Stata software, version 8.2.
Results
A total of 1,321,646 live singleton births at 24 to 43 weeks of gestation were recorded in the Scottish Morbidity Record between 1980 and 2001, and 1673 of the infants died from SIDS (12.7 per 10,000). Figure 1 shows the incidence of SIDS according to year of birth and indicates a sharp decline around 1990 and 1991, coincident with the public appreciation of the effects of a prone sleeping position and environmental tobacco smoke on the risk of SIDS. There were 216,563 linked records for singleton births for which the maternal serum alpha-fetoprotein level had been recorded. Of these, we excluded 867 (0.40 percent) with extreme levels of alpha-fetoprotein (defined as values at or below the 0.2nd percentile or at or above the 99.8th percentile), 1060 stillbirths (0.49 percent), and 131 births at a gestational age of less than 24 weeks or more than 43 weeks (0.06 percent); 2031 records listed one or more of these reasons for exclusion. Thus, the study cohort comprised 214,532 live births between November 15, 1991, and December 31, 2001.
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The assays for alpha-fetoprotein were performed between 15 and 21 weeks of gestation. The range of the maternal serum level of alpha-fetoprotein, expressed as multiples of the median, was 0.35 to 3.75; the 5th percentile was 0.59 and the 95th percentile 1.82. The quintiles of the maternal serum level of alpha-fetoprotein, expressed as multiples of the median for gestational age, were less than or equal to 0.77; greater than 0.77 but less than or equal to 0.93; greater than 0.93 but less than or equal to 1.10; greater than 1.10 but less than or equal to 1.35; and greater than 1.35. The demographic and obstetrical characteristics of the study cohort are shown in Table 1. Women whose infants ultimately died of SIDS were younger, shorter, had a lower body-mass index, were of higher parity, were more likely to live in a very socioeconomically deprived area, were more likely to smoke, had higher second-trimester levels of alpha-fetoprotein, were more likely to have delivered a male infant, had offspring with lower birth-weight percentiles, and had delivered earlier than women whose infants did not die of SIDS (Table 1).
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There was no significant association between the risk of SIDS and maternal serum levels of human chorionic gonadotropin, either expressed as a continuous variable (odds ratio for an increase of 1 in the multiple of the median for gestational age, 0.92; 95 percent confidence interval, 0.67 to 1.24; P=0.57) or categorized into quintiles (P for trend = 0.19).
Discussion
The present study shows that the risk of an infant's death from SIDS increased with increasing serum levels of alpha-fetoprotein in the mother during the second trimester of pregnancy. The risk of SIDS among the infants of women with alpha-fetoprotein levels in the highest quintile was 2.8 times that among infants whose mothers' levels was in the lowest quintile, although the absolute risk of SIDS remained low, even in the highest quintile (7.5 per 10,000 live births). We observed no significant association between serum levels of human chorionic gonadotropin and the risk of SIDS.
Both preterm birth and intrauterine growth restriction are associated with an elevated maternal serum level of alpha-fetoprotein.6 The association between the maternal serum alpha-fetoprotein level and the risk of SIDS appeared to be mediated in part by these factors. However, even after adjusting for gestational age at birth and birth-weight percentile, we found that the infants of mothers with alpha-fetoprotein levels in the upper two quintiles had a risk of SIDS that was more than twice the risk among infants of mothers with values in the lowest quintile.
Alpha-fetoprotein is the main protein contributing to oncotic pressure in the fetal circulation and is comparable to albumin in adults.20 Elevated maternal serum levels of alpha-fetoprotein in the absence of fetal abnormality are thought to indicate increased placental permeability and therefore a defect in placental function.6 Associations between elevated maternal serum levels of alpha-fetoprotein and both poor fetal growth and preterm birth21 are believed to reflect the role of defective early placental function in these outcomes. Adjusting for gestational age and birth weight may thus result in an underestimation of the association between maternal serum alpha-fetoprotein levels and the risk of SIDS, since an adverse early intrauterine environment may mediate the subsequent risk of SIDS in part by its consequences on fetal growth and the timing of birth. In this study, a significant association remained after adjustment for these factors, however, suggesting that the intrauterine environment may influence the probability that a given postnatal environment will lead to SIDS. Experimental studies have shown that fetal hypoxemia induces a chemoreceptor-mediated redistribution of cardiac output, increasing flow to the cardiac and cerebral circulations.22 Chronic, mild fetal hypoxemia leads to premature maturation of fetal cardiovascular control, manifested as a lower heart rate and a higher blood pressure early during gestation.23 We speculate that a suboptimal intrauterine environment may lead to altered cardiorespiratory control, which could in turn predispose an infant toward SIDS, although this hypothesis requires further study.
The strengths of the present study include its large size, the availability of detailed information on the characteristics of the mothers, and the fact that all exposure data were collected independently of the ascertainment of events. Whereas previous studies have shown that the risk of SIDS varies according to both preterm birth and intrauterine growth restriction,1 many studies have dichotomized gestational age at birth as term or preterm and have dichotomized birth weight as above or below a given percentile for gestational age. We found continuous relationships between gestational age at birth and the risk of SIDS as well as between birth-weight percentile and the risk of SIDS; this approach reduces the likelihood of residual confounding due to categorization of continuous variables. Nevertheless, some misclassification is possible. We relied on women's postal codes to classify their socioeconomic status, and for women who reported smoking, we did not have data on the number of cigarettes they smoked. However, after adjustment for gestational age and birth-weight percentile, further adjustment for characteristics of the mothers based on the available data had no material effect.
The sharp decline in the incidence of SIDS after the inception of public health programs aimed at improving infants' sleeping conditions has led to a search for factors that might explain the remaining cases. The observed association between elevated maternal serum alpha-fetoprotein levels during the second trimester and the incidence of SIDS suggests that an adverse intrauterine environment during the first half of pregnancy may be another important determinant of the risk of SIDS.
Supported by a grant from the Foundation for the Study of Infant Deaths.
We are indebted to Patrick Royston (Medical Research Council Clinical Trials Unit, London) for assistance with the multiple imputation procedures.
Source Information
From the Department of Obstetrics and Gynaecology, Cambridge University, Cambridge (G.C.S.S.); the Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge (A.M.W., I.R.W.); the Department of Public Health, Greater Glasgow Health Board, Glasgow (J.P.P.); the Institute of Medical Genetics, Yorkhill National Health Service Trust, Glasgow (J.A.C.); and the Information and Statistics Division, Common Services Agency, Edinburgh (R.D.) — all in the United Kingdom.
Address reprint requests to Professor Smith at the Department of Obstetrics and Gynaecology, Cambridge University, Rosie Maternity Hospital, Robinson Way, Cambridge CB2 2QQ, United Kingdom, or at gcss2{at}cam.ac.uk.
References
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