Pregnancy Complications and Subsequent Maternal Cerebrovascular Events: A Retrospective Cohort Study of 119,668 Births
Jill P. Pell1 ,
Gordon C. S. Smith2 and
David Walsh3
1 Greater Glasgow National Health Service Board, Department of Public Health, Glasgow, United Kingdom.
2 University of Cambridge, Cambridge, United Kingdom.
3 Public Health Institute of Scotland, Glasgow, United Kingdom.
Received for publication May 8, 2003; accepted for publication October 2, 2003.
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ABSTRACT
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Low birth weight infants are at increased risk of cerebrovascular disease in adulthood. This has been attributed to physiologic programming following inadequate intrauterine nutrition. The authors sought to determine whether mothers who deliver low birth weight infants or who suffer related pregnancy complications are also at increased risk. They used routine data to identify all first singleton livebirths in Scotland (19811985) and found that 342 of the 119,668 mothers suffered cerebrovascular events over 1419 years follow-up. Compared with women who delivered babies of
3,500 g, women who delivered low birth weight (<2,500 g) infants were at increased risk of cerebrovascular disease (adjusted hazards ratio (HR) = 2.51, 95% confidence interval (CI): 1.71, 3.70) with a consistent trend across birth weight categories. The lowest birth weight quintile (adjusted HR = 1.29, 95% CI: 1.01, 1.65), preterm delivery (adjusted HR = 1.91, 95% CI: 1.35, 2.70), and previous spontaneous abortion (adjusted HR = 1.49, 95% CI: 1.09, 2.03) were all predictive of subsequent maternal cerebrovascular events. The effects were additive. Women who experienced all three complications had a sevenfold risk (adjusted HR = 7.03, 95% CI: 2.24, 22.06). The association with low birth weight in mothers, as well as offspring, is unlikely to be explained by intrauterine programming and suggests that cerebrovascular disease and low birth weight may share common genetic or lifestyle risk factors.
abortion, spontaneous; cerebrovascular accident; fetal growth retardation; gestational age; labor, premature; pre-eclampsia
Abbreviations:
Abbreviations: CI, confidence interval; HR, hazards ratio; ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases, Tenth Revision; SMR, Scottish Morbidity Record.
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INTRODUCTION
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Previous studies have demonstrated that low birth weight infants are at increased risk of cerebrovascular disease in later life (14). Barker (5) and others have suggested that poor maternal diet may lead to inadequate nutrition in utero that, in turn, results in physiologic programming of the infant. An alternative hypothesis is that genetic or lifestyle factors common to both mother and infant predispose to both low birth weight and cerebrovascular disease. If this is true, birth weight should be predictive of cerebrovascular events in the mother, as well as in the infant. The aim of this study was to determine whether mothers who deliver low birth weight infants or who suffer related pregnancy complications are also at increased risk of cerebrovascular events.
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MATERIALS AND METHODS
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Data sources
The Scottish Morbidity Record (SMR) system collects routine discharge data on all patients admitted to all Scottish National Health Service acute (SMR1) and maternity (SMR2) hospitals. The information collected from the maternity hospital records includes demographic information, past and current obstetric history, comorbid conditions, and delivery outcomes. Data on maternal smoking status have been collected only since 1992 and relate to whether or not the mother was smoking at the time of attendance at the first antenatal booking clinic (usually around 12 weeks gestation). The General Registrars Office for Scotland collects information on all deaths that occur in Scotland whether inside or outside a hospital. The Information and Statistics Division of the Common Services Agency links all records from the Scottish Morbidity Record system relating to the same patient to each other and to the death database of the General Registrars Office. Record linkage is performed via probability matching. It has been demonstrated to be more than 98 percent accurate (6) and is as effective at following up patients as direct patient contact used in clinical trials (7).
Selection criteria
The maternity hospital database was used to identify all singleton births resulting in a live baby between 1981 and 1985 inclusive. Stillbirths were excluded because birth weight may be misleading as a result of maceration. Livebirths prior to 24 weeks of gestation and infants with a birth weight under 500 g were also excluded. To overcome the effect of parity, we included only first livebirths.
Definitions
Maternal age was defined as the age of the mother at the time of birth. Postcodes of residence were used to derive the socioeconomic deprivation categories described by Carstairs and Morris (8). These are based on 1991 census data on car ownership, unemployment, overcrowding, and social class within postcode sectors. Category 1 denotes the most affluent areas and category 7 denotes the least affluent. Gestational age at delivery was defined as completed weeks of gestation according to the estimated date of delivery. Preterm delivery was defined as delivery between 24 and 36 weeks of gestation inclusive. Analysis of birth weight was performed using sex- and gestation-specific quintiles as previously described (9). The analyses were repeated using absolute birth weight to allow comparison with previous papers. Low birth weight was defined as less than 2,500 g.
Statistical analyses
The statistical significance of differences in case mix was assessed using Mann-Whitney U,
2, and
2 for trend tests for continuous, categorical, and ordinal data, respectively. Linkage to the Scottish Morbidity Record systems acute hospital database and to the database of the General Registrars Office provided follow-up information on readmission to hospitals and death up to the end of 1999. We used the composite endpoint of cerebrovascular event as our primary endpoint, which we defined as death or hospital admission due to a principal diagnosis of cerebrovascular disease (International Classification of Diseases, Ninth Revision (ICD-9), codes 430438 or International Classification of Diseases, Tenth Revision (ICD-10), codes I60I69 and G45). The cumulative probability of event-free survival was determined using the Kaplan-Meier product limit estimate, and survival curves were compared using the log-rank test. Multivariate analyses of event-free survival were performed with Cox proportional hazards models using age, measured in days, as the time variable. Statistical significance was defined as the 5 percent level other than in tests of interaction where 10 percent was applied. Statistical analyses were undertaken using SPSS version 11.0 software (SPSS, Inc., Chicago, Illinois). We repeated the analyses using a number of more specific endpoints: ischemic stroke (ICD-9 code 434, ICD-10 code I63), intracranial hemorrhage (ICD-9 codes 430432, ICD-10 codes I6062), and transient ischemic attack (ICD-9 code 435, ICD-10 code G44).
Because smoking status was not available for this cohort and therefore could not be included as a covariate in the analyses, the association between smoking status and pregnancy complications was examined separately for a similarly selected cohort of births between 1992 and 1998 inclusive.
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RESULTS
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Over the study period, there were 137,094 first live singleton deliveries. Data on gestation at delivery or birth weight were missing in 1,142 (0.8 percent) subjects. A further 61 were ineligible for inclusion because of delivery prior to 24 weeks of gestation or birth weight of 500 g or less. Of the remaining 135,891 deliveries, 119,668 (88.1 percent) had complete data on maternal age, height, socioeconomic deprivation category, and infants sex and were therefore included in the analyses.
The median birth weight was 3,300 (interquartile range, 2,9803,620) g. Women who delivered infants in the lowest sex- and gestation-specific birth weight quintile were significantly younger (Mann-Whitney U test, p < 0.001), shorter (Mann-Whitney U test, p < 0.001), and more socioeconomically deprived (
2 trend test, p < 0.001) (table 1). There were no significant associations between birth weight quintile and other pregnancy complications such as preterm delivery, preeclampsia, and previous spontaneous abortion (table 1).
The linkage provided between 14 and 19 years of follow-up data. Over this period, 342 women experienced cerebrovascular events. The median age at first cerebrovascular event was 40 years (interquartile range, 3743 years) in the subgroups of both the lowest birth weight quintile and the highest four quintiles. The maximum age at follow-up was 67 years. On univariate analysis, the lowest birth weight quintile and preterm delivery were significant predictors of subsequent cerebrovascular events, and previous spontaneous abortion was of borderline significance (table 2; figure 1). After adjustment for maternal age at delivery, height, socioeconomic deprivation, and preeclampsia, there were significant independent associations with all three (table 2). There were no statistically significant interactions among these three variables. Women who experienced all three pregnancy complications were seven times more likely to suffer subsequent cerebrovascular events than were those who experienced none (table 2). Previous therapeutic abortion was not associated with subsequent cerebrovascular events in either the univariate (hazards ratio (HR) = 1.05, 95 percent confidence interval (CI): 0.70, 1.56; p = 0.825) or multivariate (adjusted HR = 1.12, 95 percent CI: 0.75, 1.68; p = 0.570) analyses.
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TABLE 2. Univariate and multivariate Cox proportional hazards models of the association between pregnancy complications in 19811985 and subsequent maternal cerebrovascular events over 1419 years of follow-up, Scotland
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FIGURE 1. Kaplan-Meier plots of maternal cerebrovascular event-free survival over 1419 years of follow-up after delivery in 19811985 in Scotland, by preterm delivery, lowest birth weight quintile, and previous spontaneous abortion.
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A total of 7,626 (6.4 percent) women delivered low birth weight (<2,500 g) infants. Delivery of a low birth weight infant was associated with increased risk of cerebrovascular events in both the univariate (HR = 1.96, 95 percent CI: 1.41, 2.72; p < 0.001) and multivariate (adjusted HR = 1.83, 95 percent CI: 1.31, 2.55; p < 0.001) analyses. When absolute birth weight was grouped into four categories, there was a consistent trend of increasing risk of cerebrovascular events with decreasing birth weight (table 3). Adjustment for potential confounding factors had minimal effect.
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TABLE 3. Univariate and multivariate Cox proportional hazards models of the association between absolute birth weight in 19811985 and subsequent maternal cerebrovascular events over 1419 years of follow-up, Scotland
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In the multivariate analyses of more specific endpoints, preterm delivery was significantly associated with maternal risk of intracranial hemorrhage (adjusted HR = 1.85, 95 percent CI: 1.16, 2.94; p = 0.010). The lowest birth weight quintile was of borderline statistical significance (adjusted HR = 1.37, 95 percent CI: 1.00, 2.94; p = 0.059), and previous spontaneous abortion was nonsignificant. Possessing all three risk factors was associated with an adjusted hazards ratio of 8.6 (95 percent CI: 2.11, 34.9; p = 0.003). For the outcome of ischemic stroke, only preterm delivery reached statistical significance (adjusted HR = 3.20, 95 percent CI: 1.21, 8.36; p = 0.019). The only significant independent predictor of transient ischemic attacks was previous spontaneous abortion (adjusted HR = 2.07, 95 percent CI: 1.07, 4.02; p = 0.031).
Between 1992 and 1998, there were 147,918 first singleton livebirths, of which 42,753 (29 percent) were to women who smoked at booking. Smoking was significantly associated with the lowest birth weight quintile, preterm delivery, and previous spontaneous abortion (table 4). However, the associations between smoking and pregnancy complications were not sufficiently strong to explain the associations between pregnancy complications and cerebrovascular events. Taking the example of preterm birth, we found that the prevalence of smoking was 28 percent among women who delivered at term and 35 percent among those who delivered preterm. The relative risks of cerebrovascular disease from smoking of 2.0 and 4.0 produced predicted relative risks for preterm delivery due to the confounding effect of smoking of 1.05 and 1.11, respectively. Even if the relative risk of cerebrovascular disease associated with smoking were 10.0, the predicted relative risk for preterm delivery would be only 1.18, which is still far less than the association demonstrated (Appendix).
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TABLE 4. Associations between smoking and pregnancy complications examined in 19921998 for a Scottish birth cohort
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DISCUSSION
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Our study is the first to demonstrate an increased risk of subsequent cerebrovascular events in mothers who deliver low birth weight infants. There is a large body of evidence demonstrating an inverse association between an individuals birth weight and his or her own risk of cerebrovascular disease in later life (14). These observations led to an hypothesis that poor maternal diet during pregnancy may lead to inadequate nutrition in utero, which, in turn, results in physiologic programming of the infant. If maternal diet during pregnancy were causal of later disease in the offspring, interventions to improve diet during pregnancy should reduce the burden of disease in future generations. However, we have demonstrated that low birth weight is associated with risk of cerebrovascular disease in the mother as well as the infant. This finding is unlikely to be explained by fetal programming and suggests that birth weight and adult cerebrovascular disease may, instead, be caused by common genetic or lifestyle factors. In our study, we had follow-up only to 67 years of age. Premature cerebrovascular events are more likely to have a genetic component. Further studies are required to analyze the association with later events.
Low birth weight may result from preterm delivery or intrauterine growth restriction. In the present study, we assessed the independent effects of preterm delivery and birth weight corrected for gestational age in order to distinguish the relative contributions of these two determinants of birth weight. Growth restriction and preterm delivery were both significant independent predictors of maternal cerebrovascular disease. However, the association was stronger for preterm delivery. The only previous study to examine the association between pregnancy complications and maternal risk of cerebrovascular disease demonstrated an increased risk of fatal strokes among women who delivered preterm infants (10). However, the investigators included in their definition of preterm delivery stillbirths and second trimester miscarriages, as well as livebirths. Therefore, it was impossible to determine which of these factors were independent predictors of maternal stroke. Furthermore, it is impossible to compare the magnitude of risk in the mother with that in the infant if analyses of the former include pregnancies in which the fetus dies in utero and is therefore not at risk of adult disease. In addition, the investigators were unable to adjust for socioeconomic status and absolute birth weight and, therefore, to demonstrate that the association with preterm delivery was independent of potential confounding factors.
We included only first births because the risks of intrauterine growth restriction, preterm delivery, and preeclampsia all differ profoundly according to parity. It would be extremely difficult to interpret associations with pregnancy complications among a cohort of women of heterogeneous parity, since much of the difference in the exposures would be determined by parity. This could potentially obscure any association between genetic or lifestyle factors and subsequent maternal disease.
Our results do not support the hypothesis of a causal association between maternal diet during pregnancy and risk of adult disease in the offspring. Other evidence also throws doubt on this hypothesis. Maternal diet has little impact on fetal growth other than in situations of chronic starvation, and dietary supplementation of women at risk of delivering a low birth weight baby has a minimal effect on birth weight (11). Moreover, both preterm labor and intrauterine growth restriction are associated with impaired fetal growth in the first trimester before the fetus makes significant caloric demands on the mother (12, 13). These early pregnancy associations with low birth weight led us to determine whether a history of spontaneous abortion was also associated with an increased risk of cerebrovascular disease. Our study is the first to demonstrate an independent association between previous spontaneous abortion and maternal risk of cerebrovascular disease. Risk of stroke was almost 50 percent higher among women who had experienced any spontaneous miscarriages prior to their first livebirth. The association demonstrated was unlikely to simply reflect the effect of an increased number of pregnancies since no association was demonstrated with previous therapeutic abortion.
In our study, the associations with preterm delivery, intrauterine growth restriction, and previous spontaneous abortion were all independent of each other and of the potential confounding effects of maternal age, height, socioeconomic status, and preeclampsia. Our findings in relation to maternal cerebrovascular disease are similar to those from previous studies on maternal cardiovascular disease that also demonstrated an increased risk associated with low birth weight (1416), preterm delivery (14), intrauterine growth restriction (14), and previous spontaneous abortion (17). In our study, we did not have access to data on paternal risk of disease. In a small study, Lawlor et al. (18) demonstrated a nonsignificant negative association between offspring birth weight and paternal carotid artery intimal-medial thickness. Davey Smith et al. (15) demonstrated an inverse association between offspring birth weight and paternal death due to cardiovascular disease that included cerebrovascular events. An association with paternal risk of disease cannot be explained by offspring intrauterine environment and casts further doubt on the role of fetal programming.
The main limitation of our study was that we were unable to adjust for the potential confounding effect of maternal smoking. Nonetheless, it is unlikely that the associations we demonstrated were simply the result of the confounding effect of smoking. The relative importance of the three pregnancy complications was different for cerebrovascular disease than that for smoking. Preterm delivery had a weaker association with smoking than lowest birth weight quintile, yet it was the strongest predictor of maternal cerebrovascular events. We performed sensitivity analyses to predict the confounding effect of smoking. In women, smoking is associated with a relative risk of about 2.6 for stroke prior to 67 years of age (19). Even women who smoke heavily have a relative risk of less than 4.0 (20, 21). In our sensitivity analyses, relative risks in this range produced a predicted relative risk for preterm delivery due to the confounding effect of smoking of only 1.051.11. Even a relative risk of 10.0 due to smoking produced a predicted relative risk for preterm delivery due to confounding of only 1.18 that was still much lower than the observed value of 1.91 and outside the 95 percent confidence interval of 1.35, 2.70.
In our study, we used any cerebrovascular event as the primary endpoint. Focusing on more specific disease endpoints, such as ischemic stroke, intracranial hemorrhage, and transient ischemic events may produce more useful insights into the underlying etiology. However, our study was underpowered to study these. In addition, over the period studied, definitive investigations such as computerized tomography or magnetic resonance imaging scans were not available to all patients admitted to Scottish hospitals with cerebrovascular disease. Overall, 14 percent of the events in our study were given nonspecific disease codes (ICD-9 code 436.9 or ICD-10 code I64.X). Therefore, we have included the more specific endpoints as secondary outcomes and would advise caution in interpreting these results.
We conclude that fetal growth restriction, preterm delivery, and a history of spontaneous abortion are all associated with an increased risk of subsequent cerebrovascular disease in the mother. This may reflect common genetic determinants of pregnancy complications and cerebrovascular disease, such as thrombophilia. We hypothesize that occult cerebrovascular disease or hemostatic dysfunction may be manifested in pregnancy by complications predisposing to low birth weight and spontaneous abortion, and that symptomatic cerebrovascular disease may be a later manifestation of the same underlying defect.
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ACKNOWLEDGMENTS
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The authors are grateful to the Chief Scientist Office in the Scottish Executive Health Department for funding this study (reference code CZG/4/2/22).
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APPENDIX
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Consider a population of 10,000 women. From our data, 9,430 women will deliver at term. Of these, 28 percent will smoke (n = 2,640) and 72 percent will not (n = 6,790). From our data, 570 women will deliver preterm. Of these, 35 percent will smoke (n = 200) and 65 percent will not (n = 370). We assume that the relative risk of events associated with smoking is 10.0. Therefore, if the incidence of events in nonsmokers is 0.3 percent, it will be 3 percent in smokers. (The results are consistent for a given relative risk, irrespective of the absolute risk.)
Risk of events in women delivering at term = ((0.03 x 2,640) + (0.003 x 6,790))/9,430 = 0.0106.
Risk of events in women delivering preterm = ((0.03 x 200) + (0.003 x 370))/570 = 0.0125.
Apparent relative risk of preterm delivery due to the confounding effect of smoking = 0.0125/0.0106 = 1.18.
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NOTES
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Correspondence to Dr. Jill Pell, Consultant in Public Health Medicine, Greater Glasgow NHS Board, Dalian House, 350 St. Vincents Street, Glasgow G3 8YU, United Kingdom (e-mail: jill.pell{at}gghb.scot.nhs.uk). 
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