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Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality
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OBSTETRICS
Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality Margaret E. Samuels-Kalow, MPhil; Edmund F. Funai, MD; Catalin Buhimschi, MD; Errol Norwitz, MD, PhD; Mary Perrin, DrPh; Ronit Calderon-Margalit, MD, MPH; Lisa Deutsch, PhD; Ora Paltiel, MDCM; Yechiel Friedlander, PhD; Orly Manor, PhD; Susan Harlap, MB, BS OBJECTIVE: Recent studies have shown increased maternal mortality
rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality. STUDY DESIGN: Data came from a 1975-1976 subset (n ⫽ 13,722
women) of a population-based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates. RESULTS: Overweight (BMI, 25-29.9 kg/m2) and obesity (BMI, ⱖ30
kg/m2) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.157.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.101.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight
(BMI, 18.5-24.9 kg/m2). HDP was significantly associated with increased mortality rates for women who survived ⬎15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14). CONCLUSION: Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI.
Key words: body mass index, hypertensive disorders of pregnancy, maternal mortality
Cite this article as: Samuels-Kalow ME, Funai EF, Buhimschi C, et al. Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality. Am J Obstet Gynecol 2007;197:490.e1-490.e6.
H
ypertensive disorders of pregnancy complicate between 6-8% of all pregnancies and are the second leading cause of maternal death.1 Although early reports argued that there
were no adverse maternal health consequences after delivery of a pregnancy that was complicated by hypertensive disease, more recent studies have shown elevated mortality and morbidity rates,
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT (Ms Samuels-Kalow and Drs Funai, Buhimschi, and Norwitz); the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY (Dr Perrin and Ms Harlap); and the Department of Hematology, Braun School of Public Health and Community Medicine, Hebrew University–Hadassah Medical School, Jerusalem, Israel (Drs Calderon-Margalit, Deutsch, Paltiel, Friedlander, and Manor). Presented at the 53rd Annual Scientific Meeting of the Society for Gynecologic Investigation, Toronto, ON, Canada, Mar. 22-25, 2006. Supported by a summer research grant from National Institutes of Health–National Heart, Lung and Blood Institute through the Office of Student Research, Yale University School of Medicine (M.E.S-K.); by the National Center for Research Resources, RR15536-05 (E.F.F.); and by National Alliance for Research on Schizophrenia and Depression and the National Cancer Institute (2R01CA-080197; S.H.). Reprints: Edmund Funai, MD, Department of Obstetrics & Gynecology, Yale University School of Medicine, PO Box 208063, 333 Cedar St, New Haven, CT 06520-8063. [email protected] 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.04.043
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particularly from cardiovascular causes.2-4 For example, in this cohort, long-term mortality rates have been shown to be significantly elevated after delivery of a pregnancy that is complicated by preeclampsia (relative risk, 2.1; 95% confidence interval [CI], 1.8-2.5), with deaths from cardiovascular disease as the strongest contributor.2 Similar findings have been reported in other studies,3 and additional associations have been reported between preeclampsia and subsequent maternal cardiovascular disease.4-8 Hypertensive disorders of pregnancy have been associated with a variety of metabolic abnormalities that are also known risk factors for cardiovascular disease including higher waist circumference, waist/hip ratio, body mass index (BMI), serum insulin level, and lower glucose/insulin ratio.9 Without information on the prepregnancy metabolic status, however, it is difficult to tell whether the subsequent development of
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www.AJOG.org cardiovascular disease in women who previously have had a hypertensive pregnancy is a result of pathologic events that occurred during the pregnancy or a result of preexisting risk factors. To further explore this issue, we chose to focus on a single risk factor that can be measured easily before pregnancy, namely BMI. Elevated prepregnancy BMI has been linked to a variety of pregnancy complications10,11 that include preeclampsia.12-17 A systematic review calculated that an increase in BMI of between 5-7 kg/m2 was associated with a doubled risk of preeclampsia.18 Elevated BMI has also been linked to increased morbidity and death from cardiovascular disease.19,20 However, the relationship between BMI, hypertensive disorders of pregnancy, and death has not been well-characterized. We examined the association between prepregnancy BMI, hypertensive disorders of pregnancy, and subsequent maternal death.
M ATERIALS AND M ETHODS Cohort The Jerusalem Perinatal Study is a population-based cohort of consecutive births to Israeli residents of urban Jerusalem and the surrounding rural county from 1964-1976. This dataset has been described in detail previously.2,21 This analysis used data on a subset of Jewish women who delivered between 1975-1976 who were interviewed about their prepregnancy weight and height. Hypertensive disorders of pregnancy were defined as gestational hypertension or preeclampsia. Gestational hypertension was defined as a systolic blood pressure of ⱖ140 mm Hg or a diastolic blood pressure of ⱖ90 mm Hg. On the basis of well-recognized clinical criteria, preeclampsia was defined as gestational hypertension with ⱖ1⫹ proteinuria and edema. Preexisting chronic hypertension was coded under a separate rubric. Long-term follow-up evaluation of the women was conducted by linking the personal identification numbers of the subjects to national registries. In the original follow-up evaluation, 92% of the women were traced successfully.2 The numbers were validated with the use
of the Population Registry of Israel, with the approval of the institutional review boards in New York and Jerusalem and the authorities at Israel’s Ministry of Health and Ministry of the Interior. The study was exempted from the requirement for written informed consent.2 The current analysis examines a subgroup of these women and was approved by the Human Investigation Committee at Yale University.
Data analysis The final analysis was restricted to women who had survived to 1978 and for whom data on prepregnancy BMI had been recorded (n ⫽ 13,722). Multiple logistic regression was used to examine the association between hypertensive disorders of pregnancy (HDP) and BMI and to compute the odds ratio and 95% CI. A BMI of ⬍18.5 kg/m2 was considered to be underweight, 18.5-24.9 kg/m2 was considered to be normal weight, 2529.9 kg/m2 was considered to be overweight, and ⱖ30 kg/m2 was considered to be obese.22 HDP were defined as a history of preeclampsia or gestational hypertension in the index pregnancy and/or past pregnancies. The results were unchanged by restriction of the analysis to women who had preeclampsia or gestational hypertension only in the index pregnancy. Survival was examined with multivariate Cox proportional hazards models and the computation of the hazard ratio (HR) and the 95% CI. Survivors were censored on January 1, 2005. Because of a change in the hazard function over time, we constructed 2 models: 1 model for women who survived ⬍15 years and 1 model for women who survived ⱖ15 years. Schoenfeld residuals were used to ensure the validity of the proportional hazards assumption. Age was modeled as a continuous variable, based on the mother’s age at the index pregnancy. Adjustment for parity did not change the results significantly. Survival analysis was used to examine the risk of death by BMI category, the risk of death after HDP, and how the risk of death after HDP changed after adjust-
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ment for prepregnancy BMI. In addition, we modeled the HR for death after HDP for women in each BMI category separately.
R ESULTS Characteristics of the cohort Demographic characteristics of the population are summarized in Table 1. Of the 13,722 women in the cohort, 30.5% were having their first birth; 45.3% were having their second to third birth; 19.6% were having their fourth to fifth birth, and 4.6% were having their seventh birth or more. The following statistics were calculated for the cohort: 1.2% of the mothers had no formal education; 61.1% had 1-12 years of education; 37.7% had ⱖ13 years of education; 99.5% were married at the time of the interview; 46.2% were immigrants: of these, 12% were from Western Asia, 15.9% were from North Africa, and 18.3% were from Western Europe.
BMI and HDP Figure 1 shows the association between prepregnancy BMI and HDP. As expected, there was an increasing prevalence of HDP with increasing BMI. Compared with the reference category of normal weight, overweight women showed nearly a 3-fold excess; those women who were obese showed more than a 5-fold excess of HDP. The crude prevalence rates of HDP were 3.3% and 5.3% for underweight and normal weight, compared with 14.8% and 26.9% for women who were overweight and obese, respectively. After adjustment for age, the odds ratios were 0.67 (95% CI, 0.48-0.92) for underweight, 1 for normal weight (reference category), 2.82 (95% CI, 2.40-3.31) for overweight, and 5.51 (95% CI, 4.15-7.31) for obese women.
BMI and mortality risk Figure 2 shows the HRs for subsequent maternal death by categories of prepregnancy BMI. Compared with women who were of normal weight before pregnancy, those women who were overweight showed a 42% increase in subsequent death and those women who were obese
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TABLE 1
Characteristics of the cohort Ever had HDP (n ⴝ 926)
Never had HDP (n ⴝ 12,796)
Total cohort (n ⴝ 13,722)
Characteristic
.......................................................................................................................................................................................................................................................................................................................................................................
Age (y)*
29.3 ⫾ 5.9
27.3 ⫾ 5.2
27.4 ⫾ 5.2
.......................................................................................................................................................................................................................................................................................................................................................................
BMI category (n)
....................................................................................................................................................................................................................................................................................................................................................................... 2
Underweight (⬍18.5 kg/m )
41 (4.4%)
1185 (9.3%)
Normal weight (18.5-24.9 kg/m )
555 (59.9%)
9946 (77.7%)
10,501 (76.5%)
1712 (12.5%)
Overweight (25-29.9 kg/m )
254 (27.4%)
1458 (11.4%)
283 (2.1%)
76 (8.2%)
207 (1.6%)
1226 (8.9%)
....................................................................................................................................................................................................................................................................................................................................................................... 2 ....................................................................................................................................................................................................................................................................................................................................................................... 2 ....................................................................................................................................................................................................................................................................................................................................................................... 2
Obese (⬎30 kg/m )
.......................................................................................................................................................................................................................................................................................................................................................................
Survival (n)
..............................................................................................................................................................................................................................................................................................................................................................
⬍15 y
7 (0.8%)
ⱖ15 y
919 (99.2%)
12,691 (99.2%)
13,610 (99.2%)
873 (94.3%)
12,426 (97.1%)
13,299 (96.9%)
105 (0.8%)
112 (0.8%)
.............................................................................................................................................................................................................................................................................................................................................................. .......................................................................................................................................................................................................................................................................................................................................................................
Alive in 2005 (n)
.......................................................................................................................................................................................................................................................................................................................................................................
Dead before 2005 (n)
53 (5.7%)
370 (2.9%)
423 (3.1%)
................................................................................................................................................................................................................................................................................................................................................................................
* Data given as mean ⫾ SD.
showed a 143% increase. The age-adjusted HRs in the 4 groups were 1.05 (95% CI, 0.73-1.53), 1 (reference group), 1.42 (95% CI, 1.10-1.83), and 2.43 (95% CI, 1.61-3.68).
Maternal mortality after HDP Because of underlying differences in the hazard function and to be consistent with previous analyses, we created 2 models for survival after HDP: 1 model for the first 15 years of follow-up evaluation and 1 model for the follow-up evaluation after 15 years. In the first 15 years after delivery, there were no significant
differences in survival between those women who had HDP and those women who had normotensive pregnancies (age adjusted HR, 1.05 (95% CI, 0.49-2.27); and age and BMI adjusted HR, 1.14 (95% CI, 0.42-2.49). After 15 years of follow-up evaluations, there was a significant decrease in survival for women who had HDP, compared with women who did not have HDP. The age-adjusted HR for death after HDP was 1.94 (95% CI, 1.42-2.67). This result remained significant, although slightly attenuated, after the addition of prepregnancy BMI to the model (HR, 1.65; 95% CI, 1.19-2.79).
overweight women, HDP conferred almost a 2-fold increase in the risk of death, compared with overweight women who did not have HDP. For obese women, the increased risk was even larger (HR, 2.90; 95% CI, 1.28-6.58).
C OMMENT This study demonstrates that elevated BMI is associated with an increased risk of HDP, and that HDP are associated with increased maternal deaths for those women who survive ⬎15 years. The HR for death after HDP remained significant, although attenuated, after the addi-
FIGURE 1
Prevalence of HDP by prepregnancy BMI
The odds ratios (OR) and 95% CIs are adjusted for age. Samuels-Kalow ME, et al. Preeclampsia, BMI, and Later Mortality. AJOG 2007.
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Relationship between prepregnancy BMI and maternal mortality after HDP Table 2 shows the excess risk of death after HDP for women in each BMI category who survived ⱖ15 years, compared with women in that category who did not have HDP. Because of small sample sizes and few deaths, this model was stable only for the women who survived ⬎15 years. This model allows us to examine in detail the role of BMI in attenuating the association between HDP and death. HDP were not associated with a significant increase in deaths for those women who were underweight or normal weight before their pregnancy. However, for
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FIGURE 2
HR for mortality rates by prepregnancy BMI
HRs and 95% CIs are adjusted for age. Samuels-Kalow ME, et al. Preeclampsia, BMI, and Later Mortality. AJOG 2007.
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TABLE 2
Mortality rate after HDP for women who survived >15 years, by BMI category Variable
Underweight
Normal
Overweight
Obese
No HDP
1.00 (reference)
1.00 (reference)
1.00 (reference)
1.00 (reference)
HDP*
1.31
1.26
1.86
2.90
95% CI
0.18-9.76
0.74-2.14
1.07-3.20
1.28-6.58
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
* Age-adjusted.
tion of BMI to the model, which suggests that BMI contributes to, but does not fully explain, the excess mortality rate. Elevated prepregnancy BMI was associated with increased maternal mortality rate after HDP. The increasing evidence for the association between HDP and maternal cardiovascular disease later in life has inspired a number of theories that seek to explain this association. The injury caused by an elevated BMI could be additive or synergistic with that of HDP resulting in an increased later-life risk of death from the maternal insults that were sustained, or elevated BMI could be associated with an increased severity of HDP during pregnancy. Alternatively, the elevated BMI could be associated with vascular or metabolic derangements that function both as risk factors for HDP and as risk factors for death later in life, but through 2 different pathologic pathways. This would be similar to the way in which elevated BMI is associated with increased risk of heart disease and of weight-related joint injuries. Although both are associated with BMI, it would be difficult to argue that they are on the same causal pathway. Perhaps the most intriguing theory has been advanced by Sattar and Greer,23 who suggested that the metabolic changes of pregnancy could serve as a “stress test” of the maternal metabolic pathways and vascular function. The basic principle is that preexisting subclinical risk factors (such as subtle metabolic derangements or endothelial dysfunction) appear as clinical disease during the metabolic and vascular stress of pregnancy. After the cessation of the pregnancy stress, the clinical manifestations of the disease disappear, only to reappear later in life with the increased stress of aging and other pathologic events. Pre-
vious reviews have addressed the concept,24-26 but few studies have measured the prepregnancy risk factors that are required to test the hypothesis adequately. Moreover, studies that have attempted to address this issue27 have used study designs that do not adequately allow the investigators to determine whether the factors under study represent first manifestation of pathologic changes occurring in the pregnancy or true preexisting risk factors that are being unmasked and brought to clinical attention by the stress of pregnancy. We investigated the association between a risk factor that had been measured prepregnancy, namely BMI, and both HDP and postpregnancy maternal mortality rates. Although we hope to examine a wider variety of risk factors in future papers, maternal obesity is of particular interest because it has been linked to a variety of physiologic changes that could underlie the association between HDP and subsequent maternal death. In particular, the components of the metabolic syndrome (abdominal obesity, dyslipidemia, elevated blood pressure, and insulin resistance), which are believed to represent an underlying proinflammatory and prothrombotic state28 appear to be strong candidates for a role in the pathologic relationship between obesity, HDP, and later-life mortality. It has been suggested that central obesity is the main etiologic factor in the development of the metabolic syndrome,29 and many of the pathologic changes that are associated with the metabolic syndrome have been reported in obese pregnant women, including elevated fasting insulin, impaired endothelial function, elevated blood pressure, and increased proinflammatory markers.30 Components of the metabolic syndrome have also been found at higher rates in women with
pregnancy-induced hypertension, compared with women with normotensive pregnancies.31 Many related factors (such as diabetes mellitus,32 obesity,31 elevated cholesterol and insulin levels,33 or glucose intolerance34) are known to increase the risk of gestational hypertension, preeclampsia, and cardiovascular disease.35 These pathologic alterations are not limited only to the time of pregnancy. Insulin resistance and hyperinsulinemia has been reported to persist for up several months after delivery in women who had a pregnancy that was complicated by preeclampsia.36,37 The impairment in microvascular function also has been found in subsequent pregnancies for women who had a preeclamptic pregnancy38 and even in nonpregnant women 15-25 years after the delivery of a preeclamptic pregnancy.39 Postpartum endothelial dysfunction has been reported in women who had pregnancies that were complicated by preeclampsia,40,41 which has been suggested as a possible explanation for their increased risk of cardiovascular disease later in life.41 This evidence, combined with the observation that the vascular lesion of preeclampsia has features that are similar to those seen in atherosclerotic plaque,42 is strongly suggestive of a common pathologic pathway that links preeclampsia and later-life cardiovascular disease. Unfortunately, most of the studies that have examined risk factors for HDP and later-life disease measured these factors during pregnancy, thereby making it impossible to determine whether they are risk factors for pregnancy complications or simply evidence of a more widespread underlying systemic disorder. To avoid this problem, this study used a risk factor that predated the pregnancy,
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namely prepregnancy BMI. In addition, the examination of prepregnancy BMI avoids the confounder of relative weight changes during pregnancy, which have been found to be associated with preeclampsia, but not gestational nonproteinuric hypertension.34 In this cohort, increased prepregnancy BMI was associated with an increased risk of later-life death after HDP. This suggests that prepregnancy risk factors can affect the relationship between pregnancy complications and later-life disease. Although these observations do not exclude a role for pathologic events in pregnancy and subsequent cardiovascular disease, they argue strongly in favor of the importance of prepregnancy risk factors as a major determinant of both the development of HDP and long-term maternal mortality rates. In addition, these findings suggest that women with HDP should be followed after their pregnancy and that appropriate interventions should be instituted to increase their long-term survival. Further investigation, ideally with larger sample sizes and the measurement of a greater spectrum of prepregnancy risk factors, should help to further elucidate the pathologic mechanisms underlying the relationship between BMI, HDP, and later-life maternal mortality. f REFERENCES 1. Report of the National High Blood Pressure Education Program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1-22. 2. Funai EF, Friedlander Y, Paltiel O, et al. Longterm mortality after preeclampsia. Epidemiology 2005;16:206-15. 3. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:1213-7. 4. Arnadottir GA, Geirsson RT, Arngrimsson R, Jonsdottir LS, Olafsson O. Cardiovascular death in women who had hypertension in pregnancy: a case-control study. BJOG 2005;112:286-92. 5. Haukkamaa L, Salminen M, Laivuori H, Leinonen H, Hiilesmaa V, Kaaja R. Risk for subsequent coronary artery disease after preeclampsia. Am J Cardiol 2004;93:805-8. 6. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001;357:2002-6.
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www.AJOG.org 7. Kestenbaum B, Seliger SL, Easterling TR, et al. Cardiovascular and thromboembolic events following hypertensive pregnancy. Am J Kidney Dis 2003;42:982-9. 8. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366:1797-803. 9. Pouta A, Hartikainen AL, Sovio U, et al. Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension 2004;43: 825-31. 10. Kristensen J, Vestergaard M, Wisborg K, Kesmodel U, Secher NJ. Pre-pregnancy weight and the risk of stillbirth and neonatal death. BJOG 2005;112:403-8. 11. Leeners B, Rath W, Kuse S, Irawan C, Imthurn B, Neumaier-Wagner P. BMI: new aspects of a classical risk factor for hypertensive disorders in pregnancy. Clin Sci (Lond) 2006;111:81-6. 12. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330:565. 13. Sibai BM, Ewell M, Levine RJ, et al. Risk factors associated with preeclampsia in healthy nulliparous women: the Calcium for Preeclampsia Prevention (CPEP) Study group. Am J Obstet Gynecol 1997;177:1003-10. 14. Barden AE, Beilin LJ, Ritchie J, Walters BN, Michael C. Does a predisposition to the metabolic syndrome sensitize women to develop pre-eclampsia? J Hypertens 1999;17:1307-15. 15. Sebire NJ, Jolly M, Harris JP, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001;25:1175-82. 16. Murakami M, Ohmichi M, Takahashi T, et al. Prepregnancy body mass index as an important predictor of perinatal outcomes in Japanese. Arch Gynecol Obstet 2005;271:311-5. 17. Baeten JM, Bukusi EA, Lambe M. Pregnancy complications and outcomes among overweight and obese nulliparous women. Am J Public Health 2001;91:436-40. 18. O’Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology 2003;14:368-74. 19. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA 2005;293:1868-74. 20. Katzmarzyk PT, Janssen I, Ardern CI. Physical inactivity, excess adiposity and premature mortality. Obesity Rev 2003;4:257-90. 21. Harlap SDA, Deutsch L, Calderon-Margalit R, et al. The Jerusalem Perinatal Study cohort, 1964-2005: methods and a review of the main results. Paediatr Perinat Epidemiol 2007;21: 256-73. 22. National Heart, Lung and Blood Institute, National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. (NIH publi-
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cation no. 98-4083) 1998. Available at: http:// [email protected]/guidelines/obesity/ob_ gdlns.htm. Accessed June 15, 2007 . 23. Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ 2002;325:157-60. 24. Williams D. Pregnancy: a stress test for life. Curr Opin Obstet Gynecol 2003;15:465-71. 25. Sattar N. Do pregnancy complications and CVD share common antecedents? Atheroscler Suppl 2004;5:3-7. 26. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592-4. 27. Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab 2002;87: 1563-8. 28. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-8. 29. Tenenbaum A, Motro M, Schwammenthal E, Fisman EZ. Macrovascular complications of metabolic syndrome: an early intervention is imperative. Int J Cardiol 2004;97:167-72. 30. Ramsay JE, Ferrell WR, Crawford L, Wallace AM, Greer IA, Sattar N. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocrinol Metab 2002;87:4231-7. 31. Solomon CG, Seely EW. Brief review: hypertension in pregnancy: a manifestation of the insulin resistance syndrome? Hypertension 2001;37:232-9. 32. Funai EF, Paltiel OB, Malaspina D, Friedlander Y, Deutsch L, Harlap S. Risk factors for pre-eclampsia in nulliparous and parous women: the Jerusalem perinatal study. Paediatr Perinat Epidemiol 2005;19:59-68. 33. Solomon CG, Carroll JS, Okamura K, Graves SW, Seely EW. Higher cholesterol and insulin levels in pregnancy are associated with increased risk for pregnancy-induced hypertension. Am J Hypertens 1999;12:276-82. 34. Solomon CG, Graves SW, Greene MF, Seely EW. Glucose intolerance as a predictor of hypertension in pregnancy. Hypertension 1994;23:717-21. 35. Mensah GA, Mokdad AH, Ford E, et al. Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implications. Cardiol Clin 2004;22: 485-504. 36. Fuh MM, Yin CS, Pei D, et al. Resistance to insulin-mediated glucose uptake and hyperinsulinemia in women who had preeclampsia during pregnancy. Am J Hypertens 1995;8: 768-71. 37. Kaaja R, Laivuori H, Laakso M, Tikkanen MJ, Ylikorkala O. Evidence of a state of increased insulin resistance in preeclampsia. Metabolism 1999;48:892-6.
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www.AJOG.org 38. Spaanderman ME, Willekes C, Hoeks AP, Ekhart TH, Peeters LL. The effect of pregnancy on the compliance of large arteries and veins in healthy parous control subjects and women with a history of preeclampsia. Am J Obstet Gynecol 2000;183:1278-86. 39. Ramsay JE, Stewart F, Greer IA, Sattar N. Microvascular dysfunction: a link between pre-
eclampsia and maternal coronary heart disease. BJOG 2003;110:1029-31. 40. Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285:1607-12. 41. Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK. Impairment
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of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol Heart Circ Physiol 2004;286:H1389-93. 42. Rodie VA, Freeman DJ, Sattar N, Greer IA. Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy? Atherosclerosis 2004;175:189-202.
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OBSTETRICS
Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality Margaret E. Samuels-Kalow, MPhil; Edmund F. Funai, MD; Catalin Buhimschi, MD; Errol Norwitz, MD, PhD; Mary Perrin, DrPh; Ronit Calderon-Margalit, MD, MPH; Lisa Deutsch, PhD; Ora Paltiel, MDCM; Yechiel Friedlander, PhD; Orly Manor, PhD; Susan Harlap, MB, BS OBJECTIVE: Recent studies have shown increased maternal mortality
rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality. STUDY DESIGN: Data came from a 1975-1976 subset (n ⫽ 13,722
women) of a population-based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates. RESULTS: Overweight (BMI, 25-29.9 kg/m2) and obesity (BMI, ⱖ30
kg/m2) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.157.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.101.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight
(BMI, 18.5-24.9 kg/m2). HDP was significantly associated with increased mortality rates for women who survived ⬎15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14). CONCLUSION: Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI.
Key words: body mass index, hypertensive disorders of pregnancy, maternal mortality
Cite this article as: Samuels-Kalow ME, Funai EF, Buhimschi C, et al. Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality. Am J Obstet Gynecol 2007;197:490.e1-490.e6.
H
ypertensive disorders of pregnancy complicate between 6-8% of all pregnancies and are the second leading cause of maternal death.1 Although early reports argued that there
were no adverse maternal health consequences after delivery of a pregnancy that was complicated by hypertensive disease, more recent studies have shown elevated mortality and morbidity rates,
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT (Ms Samuels-Kalow and Drs Funai, Buhimschi, and Norwitz); the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY (Dr Perrin and Ms Harlap); and the Department of Hematology, Braun School of Public Health and Community Medicine, Hebrew University–Hadassah Medical School, Jerusalem, Israel (Drs Calderon-Margalit, Deutsch, Paltiel, Friedlander, and Manor). Presented at the 53rd Annual Scientific Meeting of the Society for Gynecologic Investigation, Toronto, ON, Canada, Mar. 22-25, 2006. Supported by a summer research grant from National Institutes of Health–National Heart, Lung and Blood Institute through the Office of Student Research, Yale University School of Medicine (M.E.S-K.); by the National Center for Research Resources, RR15536-05 (E.F.F.); and by National Alliance for Research on Schizophrenia and Depression and the National Cancer Institute (2R01CA-080197; S.H.). Reprints: Edmund Funai, MD, Department of Obstetrics & Gynecology, Yale University School of Medicine, PO Box 208063, 333 Cedar St, New Haven, CT 06520-8063. [email protected] 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.04.043
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particularly from cardiovascular causes.2-4 For example, in this cohort, long-term mortality rates have been shown to be significantly elevated after delivery of a pregnancy that is complicated by preeclampsia (relative risk, 2.1; 95% confidence interval [CI], 1.8-2.5), with deaths from cardiovascular disease as the strongest contributor.2 Similar findings have been reported in other studies,3 and additional associations have been reported between preeclampsia and subsequent maternal cardiovascular disease.4-8 Hypertensive disorders of pregnancy have been associated with a variety of metabolic abnormalities that are also known risk factors for cardiovascular disease including higher waist circumference, waist/hip ratio, body mass index (BMI), serum insulin level, and lower glucose/insulin ratio.9 Without information on the prepregnancy metabolic status, however, it is difficult to tell whether the subsequent development of
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www.AJOG.org cardiovascular disease in women who previously have had a hypertensive pregnancy is a result of pathologic events that occurred during the pregnancy or a result of preexisting risk factors. To further explore this issue, we chose to focus on a single risk factor that can be measured easily before pregnancy, namely BMI. Elevated prepregnancy BMI has been linked to a variety of pregnancy complications10,11 that include preeclampsia.12-17 A systematic review calculated that an increase in BMI of between 5-7 kg/m2 was associated with a doubled risk of preeclampsia.18 Elevated BMI has also been linked to increased morbidity and death from cardiovascular disease.19,20 However, the relationship between BMI, hypertensive disorders of pregnancy, and death has not been well-characterized. We examined the association between prepregnancy BMI, hypertensive disorders of pregnancy, and subsequent maternal death.
M ATERIALS AND M ETHODS Cohort The Jerusalem Perinatal Study is a population-based cohort of consecutive births to Israeli residents of urban Jerusalem and the surrounding rural county from 1964-1976. This dataset has been described in detail previously.2,21 This analysis used data on a subset of Jewish women who delivered between 1975-1976 who were interviewed about their prepregnancy weight and height. Hypertensive disorders of pregnancy were defined as gestational hypertension or preeclampsia. Gestational hypertension was defined as a systolic blood pressure of ⱖ140 mm Hg or a diastolic blood pressure of ⱖ90 mm Hg. On the basis of well-recognized clinical criteria, preeclampsia was defined as gestational hypertension with ⱖ1⫹ proteinuria and edema. Preexisting chronic hypertension was coded under a separate rubric. Long-term follow-up evaluation of the women was conducted by linking the personal identification numbers of the subjects to national registries. In the original follow-up evaluation, 92% of the women were traced successfully.2 The numbers were validated with the use
of the Population Registry of Israel, with the approval of the institutional review boards in New York and Jerusalem and the authorities at Israel’s Ministry of Health and Ministry of the Interior. The study was exempted from the requirement for written informed consent.2 The current analysis examines a subgroup of these women and was approved by the Human Investigation Committee at Yale University.
Data analysis The final analysis was restricted to women who had survived to 1978 and for whom data on prepregnancy BMI had been recorded (n ⫽ 13,722). Multiple logistic regression was used to examine the association between hypertensive disorders of pregnancy (HDP) and BMI and to compute the odds ratio and 95% CI. A BMI of ⬍18.5 kg/m2 was considered to be underweight, 18.5-24.9 kg/m2 was considered to be normal weight, 2529.9 kg/m2 was considered to be overweight, and ⱖ30 kg/m2 was considered to be obese.22 HDP were defined as a history of preeclampsia or gestational hypertension in the index pregnancy and/or past pregnancies. The results were unchanged by restriction of the analysis to women who had preeclampsia or gestational hypertension only in the index pregnancy. Survival was examined with multivariate Cox proportional hazards models and the computation of the hazard ratio (HR) and the 95% CI. Survivors were censored on January 1, 2005. Because of a change in the hazard function over time, we constructed 2 models: 1 model for women who survived ⬍15 years and 1 model for women who survived ⱖ15 years. Schoenfeld residuals were used to ensure the validity of the proportional hazards assumption. Age was modeled as a continuous variable, based on the mother’s age at the index pregnancy. Adjustment for parity did not change the results significantly. Survival analysis was used to examine the risk of death by BMI category, the risk of death after HDP, and how the risk of death after HDP changed after adjust-
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ment for prepregnancy BMI. In addition, we modeled the HR for death after HDP for women in each BMI category separately.
R ESULTS Characteristics of the cohort Demographic characteristics of the population are summarized in Table 1. Of the 13,722 women in the cohort, 30.5% were having their first birth; 45.3% were having their second to third birth; 19.6% were having their fourth to fifth birth, and 4.6% were having their seventh birth or more. The following statistics were calculated for the cohort: 1.2% of the mothers had no formal education; 61.1% had 1-12 years of education; 37.7% had ⱖ13 years of education; 99.5% were married at the time of the interview; 46.2% were immigrants: of these, 12% were from Western Asia, 15.9% were from North Africa, and 18.3% were from Western Europe.
BMI and HDP Figure 1 shows the association between prepregnancy BMI and HDP. As expected, there was an increasing prevalence of HDP with increasing BMI. Compared with the reference category of normal weight, overweight women showed nearly a 3-fold excess; those women who were obese showed more than a 5-fold excess of HDP. The crude prevalence rates of HDP were 3.3% and 5.3% for underweight and normal weight, compared with 14.8% and 26.9% for women who were overweight and obese, respectively. After adjustment for age, the odds ratios were 0.67 (95% CI, 0.48-0.92) for underweight, 1 for normal weight (reference category), 2.82 (95% CI, 2.40-3.31) for overweight, and 5.51 (95% CI, 4.15-7.31) for obese women.
BMI and mortality risk Figure 2 shows the HRs for subsequent maternal death by categories of prepregnancy BMI. Compared with women who were of normal weight before pregnancy, those women who were overweight showed a 42% increase in subsequent death and those women who were obese
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TABLE 1
Characteristics of the cohort Ever had HDP (n ⴝ 926)
Never had HDP (n ⴝ 12,796)
Total cohort (n ⴝ 13,722)
Characteristic
.......................................................................................................................................................................................................................................................................................................................................................................
Age (y)*
29.3 ⫾ 5.9
27.3 ⫾ 5.2
27.4 ⫾ 5.2
.......................................................................................................................................................................................................................................................................................................................................................................
BMI category (n)
....................................................................................................................................................................................................................................................................................................................................................................... 2
Underweight (⬍18.5 kg/m )
41 (4.4%)
1185 (9.3%)
Normal weight (18.5-24.9 kg/m )
555 (59.9%)
9946 (77.7%)
10,501 (76.5%)
1712 (12.5%)
Overweight (25-29.9 kg/m )
254 (27.4%)
1458 (11.4%)
283 (2.1%)
76 (8.2%)
207 (1.6%)
1226 (8.9%)
....................................................................................................................................................................................................................................................................................................................................................................... 2 ....................................................................................................................................................................................................................................................................................................................................................................... 2 ....................................................................................................................................................................................................................................................................................................................................................................... 2
Obese (⬎30 kg/m )
.......................................................................................................................................................................................................................................................................................................................................................................
Survival (n)
..............................................................................................................................................................................................................................................................................................................................................................
⬍15 y
7 (0.8%)
ⱖ15 y
919 (99.2%)
12,691 (99.2%)
13,610 (99.2%)
873 (94.3%)
12,426 (97.1%)
13,299 (96.9%)
105 (0.8%)
112 (0.8%)
.............................................................................................................................................................................................................................................................................................................................................................. .......................................................................................................................................................................................................................................................................................................................................................................
Alive in 2005 (n)
.......................................................................................................................................................................................................................................................................................................................................................................
Dead before 2005 (n)
53 (5.7%)
370 (2.9%)
423 (3.1%)
................................................................................................................................................................................................................................................................................................................................................................................
* Data given as mean ⫾ SD.
showed a 143% increase. The age-adjusted HRs in the 4 groups were 1.05 (95% CI, 0.73-1.53), 1 (reference group), 1.42 (95% CI, 1.10-1.83), and 2.43 (95% CI, 1.61-3.68).
Maternal mortality after HDP Because of underlying differences in the hazard function and to be consistent with previous analyses, we created 2 models for survival after HDP: 1 model for the first 15 years of follow-up evaluation and 1 model for the follow-up evaluation after 15 years. In the first 15 years after delivery, there were no significant
differences in survival between those women who had HDP and those women who had normotensive pregnancies (age adjusted HR, 1.05 (95% CI, 0.49-2.27); and age and BMI adjusted HR, 1.14 (95% CI, 0.42-2.49). After 15 years of follow-up evaluations, there was a significant decrease in survival for women who had HDP, compared with women who did not have HDP. The age-adjusted HR for death after HDP was 1.94 (95% CI, 1.42-2.67). This result remained significant, although slightly attenuated, after the addition of prepregnancy BMI to the model (HR, 1.65; 95% CI, 1.19-2.79).
overweight women, HDP conferred almost a 2-fold increase in the risk of death, compared with overweight women who did not have HDP. For obese women, the increased risk was even larger (HR, 2.90; 95% CI, 1.28-6.58).
C OMMENT This study demonstrates that elevated BMI is associated with an increased risk of HDP, and that HDP are associated with increased maternal deaths for those women who survive ⬎15 years. The HR for death after HDP remained significant, although attenuated, after the addi-
FIGURE 1
Prevalence of HDP by prepregnancy BMI
The odds ratios (OR) and 95% CIs are adjusted for age. Samuels-Kalow ME, et al. Preeclampsia, BMI, and Later Mortality. AJOG 2007.
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Relationship between prepregnancy BMI and maternal mortality after HDP Table 2 shows the excess risk of death after HDP for women in each BMI category who survived ⱖ15 years, compared with women in that category who did not have HDP. Because of small sample sizes and few deaths, this model was stable only for the women who survived ⬎15 years. This model allows us to examine in detail the role of BMI in attenuating the association between HDP and death. HDP were not associated with a significant increase in deaths for those women who were underweight or normal weight before their pregnancy. However, for
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FIGURE 2
HR for mortality rates by prepregnancy BMI
HRs and 95% CIs are adjusted for age. Samuels-Kalow ME, et al. Preeclampsia, BMI, and Later Mortality. AJOG 2007.
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TABLE 2
Mortality rate after HDP for women who survived >15 years, by BMI category Variable
Underweight
Normal
Overweight
Obese
No HDP
1.00 (reference)
1.00 (reference)
1.00 (reference)
1.00 (reference)
HDP*
1.31
1.26
1.86
2.90
95% CI
0.18-9.76
0.74-2.14
1.07-3.20
1.28-6.58
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
* Age-adjusted.
tion of BMI to the model, which suggests that BMI contributes to, but does not fully explain, the excess mortality rate. Elevated prepregnancy BMI was associated with increased maternal mortality rate after HDP. The increasing evidence for the association between HDP and maternal cardiovascular disease later in life has inspired a number of theories that seek to explain this association. The injury caused by an elevated BMI could be additive or synergistic with that of HDP resulting in an increased later-life risk of death from the maternal insults that were sustained, or elevated BMI could be associated with an increased severity of HDP during pregnancy. Alternatively, the elevated BMI could be associated with vascular or metabolic derangements that function both as risk factors for HDP and as risk factors for death later in life, but through 2 different pathologic pathways. This would be similar to the way in which elevated BMI is associated with increased risk of heart disease and of weight-related joint injuries. Although both are associated with BMI, it would be difficult to argue that they are on the same causal pathway. Perhaps the most intriguing theory has been advanced by Sattar and Greer,23 who suggested that the metabolic changes of pregnancy could serve as a “stress test” of the maternal metabolic pathways and vascular function. The basic principle is that preexisting subclinical risk factors (such as subtle metabolic derangements or endothelial dysfunction) appear as clinical disease during the metabolic and vascular stress of pregnancy. After the cessation of the pregnancy stress, the clinical manifestations of the disease disappear, only to reappear later in life with the increased stress of aging and other pathologic events. Pre-
vious reviews have addressed the concept,24-26 but few studies have measured the prepregnancy risk factors that are required to test the hypothesis adequately. Moreover, studies that have attempted to address this issue27 have used study designs that do not adequately allow the investigators to determine whether the factors under study represent first manifestation of pathologic changes occurring in the pregnancy or true preexisting risk factors that are being unmasked and brought to clinical attention by the stress of pregnancy. We investigated the association between a risk factor that had been measured prepregnancy, namely BMI, and both HDP and postpregnancy maternal mortality rates. Although we hope to examine a wider variety of risk factors in future papers, maternal obesity is of particular interest because it has been linked to a variety of physiologic changes that could underlie the association between HDP and subsequent maternal death. In particular, the components of the metabolic syndrome (abdominal obesity, dyslipidemia, elevated blood pressure, and insulin resistance), which are believed to represent an underlying proinflammatory and prothrombotic state28 appear to be strong candidates for a role in the pathologic relationship between obesity, HDP, and later-life mortality. It has been suggested that central obesity is the main etiologic factor in the development of the metabolic syndrome,29 and many of the pathologic changes that are associated with the metabolic syndrome have been reported in obese pregnant women, including elevated fasting insulin, impaired endothelial function, elevated blood pressure, and increased proinflammatory markers.30 Components of the metabolic syndrome have also been found at higher rates in women with
pregnancy-induced hypertension, compared with women with normotensive pregnancies.31 Many related factors (such as diabetes mellitus,32 obesity,31 elevated cholesterol and insulin levels,33 or glucose intolerance34) are known to increase the risk of gestational hypertension, preeclampsia, and cardiovascular disease.35 These pathologic alterations are not limited only to the time of pregnancy. Insulin resistance and hyperinsulinemia has been reported to persist for up several months after delivery in women who had a pregnancy that was complicated by preeclampsia.36,37 The impairment in microvascular function also has been found in subsequent pregnancies for women who had a preeclamptic pregnancy38 and even in nonpregnant women 15-25 years after the delivery of a preeclamptic pregnancy.39 Postpartum endothelial dysfunction has been reported in women who had pregnancies that were complicated by preeclampsia,40,41 which has been suggested as a possible explanation for their increased risk of cardiovascular disease later in life.41 This evidence, combined with the observation that the vascular lesion of preeclampsia has features that are similar to those seen in atherosclerotic plaque,42 is strongly suggestive of a common pathologic pathway that links preeclampsia and later-life cardiovascular disease. Unfortunately, most of the studies that have examined risk factors for HDP and later-life disease measured these factors during pregnancy, thereby making it impossible to determine whether they are risk factors for pregnancy complications or simply evidence of a more widespread underlying systemic disorder. To avoid this problem, this study used a risk factor that predated the pregnancy,
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namely prepregnancy BMI. In addition, the examination of prepregnancy BMI avoids the confounder of relative weight changes during pregnancy, which have been found to be associated with preeclampsia, but not gestational nonproteinuric hypertension.34 In this cohort, increased prepregnancy BMI was associated with an increased risk of later-life death after HDP. This suggests that prepregnancy risk factors can affect the relationship between pregnancy complications and later-life disease. Although these observations do not exclude a role for pathologic events in pregnancy and subsequent cardiovascular disease, they argue strongly in favor of the importance of prepregnancy risk factors as a major determinant of both the development of HDP and long-term maternal mortality rates. In addition, these findings suggest that women with HDP should be followed after their pregnancy and that appropriate interventions should be instituted to increase their long-term survival. Further investigation, ideally with larger sample sizes and the measurement of a greater spectrum of prepregnancy risk factors, should help to further elucidate the pathologic mechanisms underlying the relationship between BMI, HDP, and later-life maternal mortality. f REFERENCES 1. Report of the National High Blood Pressure Education Program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1-22. 2. Funai EF, Friedlander Y, Paltiel O, et al. Longterm mortality after preeclampsia. Epidemiology 2005;16:206-15. 3. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:1213-7. 4. Arnadottir GA, Geirsson RT, Arngrimsson R, Jonsdottir LS, Olafsson O. Cardiovascular death in women who had hypertension in pregnancy: a case-control study. BJOG 2005;112:286-92. 5. Haukkamaa L, Salminen M, Laivuori H, Leinonen H, Hiilesmaa V, Kaaja R. Risk for subsequent coronary artery disease after preeclampsia. Am J Cardiol 2004;93:805-8. 6. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001;357:2002-6.
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