If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Department of Epidemiology and Health Services Evaluation, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
The purpose of this study was to investigate whether a history of preterm delivery (PTD) poses a risk for subsequent maternal long-term cardiovascular morbidity.
Study Design
A population-based study compared the incidence of cardiovascular morbidity in a cohort of women who delivered preterm (<37 weeks' gestation) and those who gave birth at term at the same period. Deliveries occurred during the years 1988-1999 with follow up until 2010. Kaplan-Meier survival curves were used to estimate cumulative incidence of cardiovascular hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios for cardiovascular hospitalizations.
Results
During the study period 47,908 women met the inclusion criteria; 12.5% of the patients (n = 5992) delivered preterm. During a follow-up period of >10 years, patients with PTD had higher rates of simple and complex cardiovascular events and higher rates of total cardiovascular-related hospitalizations. A linear association was found between the number of previous PTD and future risk for cardiovascular hospitalizations (5.5% for ≥2 PTDs; 5.0% for 1 PTD vs 3.5% in the comparison group; P < .001). The association remained significant for spontaneous vs induced PTD and for early (<34 weeks) and late (34 weeks to 36 weeks 6 days' gestation) PTD. In a Cox proportional hazards model that adjusted for pregnancy confounders such as labor induction, diabetes mellitus, preeclampsia, and obesity, PTD was associated independently with cardiovascular hospitalizations (adjusted hazard ratio, 1.4; 95% confidence interval, 1.2–1.6).
Conclusion
PTD is an independent risk factor for long-term cardiovascular morbidity in a follow-up period of more than a decade.
The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth.
In 2007, the rate of PTD in the United States was 12.7%; this is an increase of 20% from the 1990s and 36% from the 1980s. This increase is due to an increase in the number of indicated PTD rather than spontaneous PTD.
studied a registry of 626,727 births and compared mothers with and without a history of preeclampsia. They found women with a history of preeclampsia to be at higher risk for cardiovascular-related death. Recently, Shalom et al
studied patients with a history of preeclampsia or gestational hypertension and found biochemical evidence predisposing them to later cardiovascular complications.
A similar trend was noted for gestational diabetes mellitus. Vrachnis et al
reviewed studies regarding gestational diabetes mellitus and future risk for CVD and concluded that these patients should be considered a population at risk for future CVD. This evidence led to recent recommendations published by the American Heart Association, which included preeclampsia and gestational diabetes mellitus in the guidelines for the preliminary risk evaluation for CVD in women.
Data regarding other pregnancy complications such as PTD and future risk for CVD are not well established. The underlining cause and mechanism of PTD delivery is not yet completely understood. The main mechanisms that have been suggested are inflammation, infection, and vascular diseases.
Maternal risk of ischemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750,350 single tone pregnancies.
Nevertheless, it is not yet understood clearly whether there is a direct association between PTD and future risk for CVD or whether this increased risk is due to other comorbidities such as hypertensive disorders or growth restriction.
Maternal risk of ischemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750,350 single tone pregnancies.
The objective of the present population- based study was to investigate whether PTD is an independent risk factor for subsequent long-term cardiovascular morbidity during a follow-up period of more than a decade. We also wanted to investigate the association between spontaneous vs induced PTD, early vs late PTD, and the number of PTDs to long-term cardiovascular hospitalizations.
Materials and Methods
Setting
The study was conducted at the Soroka University Medical Center, the sole hospital of the Negev, the southern region of Israel, that serves the entire population in this region. Thus, the study is based on a nonselective population data. The institutional review board (in accordance with the Helsinki declaration) approved the study.
Study population
The study population was composed of all patients who delivered in the years 1988-1998; the follow-up period was until 2010. Patients with multiple pregnancies and with known CVD before or during the index pregnancy were excluded from the study.
Study design
We conducted a population-based retrospective cohort study. The primary exposure was having had at least 1 PTD. Patients who for the entire period of follow up did not experience PTD comprised the comparison group; the last delivery was used as the index birth. A retrospective follow up of hospitalizations because of cardiovascular morbidity 10-20 years after the index birth was preformed. Cardiovascular morbidity was defined as hospitalizations for any cardiovascular reasons at the first cardiovascular hospitalization at Soroka University Medical Center. Cardiovascular morbidity was divided into 4 categories according to severity and type that included simple and complex cardiovascular events (eg, angina pectoris and congestive heart failure, respectively), and invasive and noninvasive cardiac procedures (eg, insertion of a stent and a treadmill stress test, respectively). The exact International Classification of Diseases, 9th edition (ICD-9) codes for each subtype of cardiovascular morbidity are presented in the Appendix (Supplementary Table).
Data were collected from 2 databases that were cross-linked and merged: the computerized perinatal database and the computerized hospitalization database of the Soroka University Medical Center. The perinatal database consists of information recorded directly after delivery by an obstetrician. Skilled medical secretaries routinely review the information before entering it into the database. Coding was performed after assessment of medical prenatal care records together with the routine hospital documents. The hospitalization database includes demographic information and ICD-9 codes for all medical diagnoses made during hospitalizations.
Statistical analysis
Statistical analysis was performed with the SPSS software (version 17; SPSS Inc, Chicago, IL). Statistical significance was calculated with the χ2 test for differences in qualitative variables and the Student t test for differences in continuous variables. Stratified analysis was performed (the pooled odds ratio was calculated with the Mantel-Haenszel test) to investigate the association between spontaneous vs induced PTD, early vs late, PTD with and without preterm premature rupture of membranes, PTD with and without preeclampsia, and long-term CVD. The association between the number of PTDs and the risk for subsequent cardiovascular hospitalizations and morbidity was evaluated with the χ2 test for trends (the linear-by-linear association test).
Kaplan-Meier survival curve was used to compare cumulative incidence of cardiovascular hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for long-term cardiovascular hospitalizations. A probability value of < .05 was considered statistically significant.
Results
During the study period, there were 47,908 women who met the inclusion criteria; 5992 women (12.5%) had at least 1 PTD, the first of which was considered the index delivery.
Table 1 presents a summary of the characteristics of the index delivery of patients with and without a diagnosis of PTD. Patients in the PTD group were significantly younger at the index birth, had a lower birth order than the comparison group, and were more likely to be Bedouin than women in the comparison group. The mean number of days from the index pregnancy to the cardiovascular hospitalization was significantly shorter in the PTD compared with the comparison group.
Table 1Characteristics of patients with and without a history of preterm delivery
Table 2 presents a comparison of cardiovascular morbidity and hospitalizations during the follow-up period. Patients with PTD had higher rates of simple and complex cardiovascular events and total cardiovascular-related hospitalizations.
Table 2Incidence of first hospitalizations for cardiovascular causes
Variable
Preterm delivery (n = 5992)
No preterm delivery (n = 41,916)
OR
95% CI
P value
Cardiac noninvasive diagnostic procedures
1.4%
1.1%
1.2
0.9–1.5
.062
Cardiac invasive diagnostic procedures
0.5%
0.4%
1.1
0.7–1.7
.610
Simple cardiovascular events
3.7%
2.5%
1.5
1.3–1.7
.001
Complex cardiovascular events
0.4%
0.1%
3.6
2.1–6.1
.001
Total cardiovascular hospitalizations
5.1%
3.5%
1.5
1.3–1.7
.001
CI, confidence interval; OR, odds ratio.
Kessous. PTD and future risk for cardiovascular disease. Am J Obstet Gynecol 2013.
Table 3 presents a comparison between the incidence of cardiovascular morbidity in women with early PTD (<34 weeks' gestation) and late preterm PTD (34-37 weeks' gestation). The risk for CVD remained significant in the early and the late PTD groups, and both groups were noted as having a risk factor for simple and complex events, and for cardiovascular hospitalizations in general. Nevertheless, the odds ratio was higher for the early PTD group.
Table 3ORs of cardiovascular morbidity and hospitalization during the follow-up period in patients with and without a history of PTD with a subdivision of early (<34 weeks' gestation) and late (34-37 weeks' gestation) PTD, compared with term deliveries
Table 4 presents a comparison between the incidence of cardiovascular morbidity in women with spontaneous PTD and women with a history of PTD after induction of labor. The risk for simple and complex cardiovascular events and total cardiovascular-related hospitalizations remained significant in both spontaneous and induced PTD.
Table 4OR of cardiovascular morbidity and hospitalization during the follow-up period in patients with spontaneous PTD and PTD after induction of labor
Table 5 presents a comparison between the number of PTD and the risk for subsequent cardiovascular hospitalizations and morbidity. A significant linear association was found between the number of PTD and the risk for simple CVD and cardiovascular hospitalizations.
Table 5A comparison of the incidence of cardiovascular-related hospitalizations and morbidity between patients with a history of ≥2 PTDs with patients with just 1 and no PTD (with the use of the χ2 test for trends)
Variable
PTD, %
P value
None (n = 41,916)
1 (n = 5217)
≥2 (n = 775)
Cardiac noninvasive diagnostic procedures
1.1
1.4
1.2
.150
Cardiac invasive diagnostic procedures
0.4
0.4
0.6
.582
Simple cardiovascular events
2.5
3.6
4.1
.001
Complex cardiovascular events
0.1
0.4
0.3
.001
Total cardiovascular hospitalizations
3.5
5.0
5.5
.001
PTD, preterm delivery.
Kessous. PTD and future risk for cardiovascular disease. Am J Obstet Gynecol 2013.
Table 6 presents the pooled odds ratio for cardiovascular-related hospitalizations in patients with a history of PTD; the Mantel-Haenszel test controlled for specific confounders. Stratified analysis showed a significant association between PTD and total cardiovascular hospitalizations after being controlled for premature rupture of membranes, preeclampsia, intrauterine growth restriction, and induction of labor.
Table 6OR for cardiovascular-related hospitalizations in patients with a history of PTD with the use of the Mantel-Haenszel test to control for specific confounders
The Figure presents a Kaplan-Meier hazard function curve for the cumulative incidence of cardiovascular hospitalizations after the index birth in both study groups (PTD or term). Patients with a history of PTD had a significantly higher risk for cardiovascular events during the whole follow-up period.
FigureKaplan-Meier hazard function curve for cardiovascular-associated hospitalization of patients with and without a history of PTD
Cox proportional hazards models were used to estimate the adjusted HRs and 95% CI for long-term cardiovascular hospitalizations (Table 7). After we controlled for recognized confounders that are related to the metabolic syndrome (eg, diabetes mellitus, preeclampsia, and obesity) and that are known to be associated with higher risk for CVD, PTD remained associated independently with cardiovascular hospitalizations (adjusted HR, 1.33; 95% CI, 1.17–1.5). Even after we controlled for additional variables (eg, maternal age, labor induction, ethnicity, and anemia), PTD remained independently associated with an increased risk for subsequent cardiovascular hospitalizations (adjusted HR, 1.4; 95% CI, 1.2–1.6).
Table 7Cox multivariable regression models for the risk of cardiovascular hospitalization
Variable
Adjusted hazard ratio
95% CI
P value
Model 1
Preterm delivery (<37 weeks' gestation)
1.3
1.2–1.5
.001
Diabetes mellitus (gestational and pregestational)
2.6
2.3–2.9
.001
Obesity (pregestational body mass index >30 kg/m2)
2.5
1.9–3.2
.001
Preeclampsia
2.4
2.1–2.8
.001
Model 2
Preterm delivery (<37 weeks' gestation)
1.4
1.2–1.6
.001
Diabetes mellitus (gestational and pregestational)
2.0
1.8–2.3
.001
Obesity (pregestational body mass index >30 kg/m2)
2.3
1.7–3.0
.001
Preeclampsia
2.2
1.9–2.6
.001
Maternal age
1.1
1.05–1.15
.001
Ethnicity (Bedouin vs Jewish)
2.0
1.7–2.5
.001
Anemia (hemoglobin <10 g/dL)
1.2
1.1–1.4
.002
Induction of labor
1.2
1.04–1.4
.004
CI, confidence interval.
Kessous. PTD and future risk for cardiovascular disease. Am J Obstet Gynecol 2013.
The major finding of the current study is that PTD is an independent risk factor for subsequent long-term cardiovascular morbidity and cardiovascular-related hospitalizations.
The results of our study add to the data from other studies regarding the relationship between PTD and future risk for cardiovascular morbidity.
Maternal risk of ischemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750,350 single tone pregnancies.
studied data regarding 129,920 first deliveries and found that patients with a history of PTD had significantly high rates of ischemic heart disease (adjusted HR, 1.8; 95% CI, 1.3–2.5). In our study, further categorization of the cardiovascular complications was performed according to ICD-9 codes. It emphasizes the importance of a previous history of PTD as a risk factor for not only the endpoint of cardiovascular hospitalizations but also for simple and complex morbidity. Hastie et al
Maternal risk of ischemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750,350 single tone pregnancies.
found a strong association between induced PTD and subsequent cardiovascular morbidity. The authors suggested that induced deliveries usually were due to suspicion of intrauterine growth restriction or preeclampsia, which might better explain the association with vascular events later in life. Therefore, the analysis in our study included an adjustment for preeclampsia, intrauterine growth restriction, premature rupture of membranes, and labor induction. PTD remained an independent risk factor for CVD, even after we controlled for these significant confounders.
The risk for CVD was more substantial when a patient had a history of early PTD (<34 weeks' gestation). Two previous studies addressed this issue with different conclusions: Bonamy et al
analyzed data from 923,686 patients in their first singleton birth. After controlling for confounders, they demonstrated an increasing risk for CVD with decreasing gestational age at birth. Catov et al
did not find an association between the lower gestational age and cardiovascular complications.
Interestingly, in our study, a significant linear association was documented between the number of previous PTDs and the future risk for simple CVD and cardiovascular hospitalizations. A similar “dose-response” association has been documented by only 1 previous study.
Although some previous studies that investigated the association between PTD and cardiovascular morbidity were based on self-reports of the patients regarding PTD, birthweight, smoking, and hypertensive disorders,
our study data were obtained from the computerized files and not based on self-reports, which might lead to a recall bias.
The proportion of Bedouin parturients was significantly higher in the PTD group than in the comparison group. The Bedouins are a traditional society that tends to under-utilize the existing prenatal care services and in general have different accessibility to health services. The higher prevalence of PTD among Bedouin parturients (as compared with Jewish parturients) was noted in other studies
; therefore, it was considered to be a potential confounder.
The main strength of the study lies in the fact that our hospital is the only hospital serving the entire population of southern Israel. The hospital provides both maternity services and tertiary cardiovascular medical services; thus, as long as patients live in the area, they would use this hospital. However, the ascertainment of cardiovascular events that occurred outside of the hospital could not be accomplished. It is therefore possible that some cardiovascular events were missed, but there is no reason to suspect differential rates of outcome ascertainment in the 2 study groups.
In conclusion, in our population, PTD was noted as an independent risk factor for subsequent long-term simple and complex cardiovascular complications that require hospitalization. This risk is more substantial in patients with early PTD and patients with >1 previous PTD.
The cardiovascular risk assessment for women is suboptimal; pregnancy could be considered a stress test to improve risk assessment for future risk of CVD. On the basis of our findings, patients after a PTD may benefit from cardiovascular risk screening, early detection, and perhaps secondary prevention of CVD.
Appendix
Supplementary TableCardiovascular morbidity divided to 4 groups from the International Classification of Diseases 9 (ICD-9)
Group
Investigated diagnoses
ICD-9
1: simple cardiovascular events
Chronic ischemic heart disease, unspecified
4149
Cardiovascular disease, unspecified
4292
Acute, but ill-defined, cerebrovascular disease
436
Other and ill-defined cerebrovascular disease
437
Cerebral atherosclerosis
4371
Other specified peripheral vascular diseases
4438
Other peripheral vascular disease
44389
Mixed hyperlipidemia
2722
Other and unspecified hyperlipidemia
2724
Angina pectoris
413
Other and unspecified angina pectoris
4139
Hypertensive heart disease
402
Other acute and subacute forms of ischemic heart disease
411
Other acute and subacute forms of ischemic heart disease
4118
Acute ischemic heart disease without myocardial infarction
41181
Other forms of chronic ischemic heart disease
414
Other specified forms of chronic ischemic heart disease
4148
Heart disease, unspecified
4299
Atherosclerosis
440
Atherosclerosis of arteries of the extremities
4402
Unspecified essential hypertension
4019
Peripheral vascular disease, unspecified
4439
2: cardiac noninvasive diagnostic procedures
Diagnostic ultrasound scanning of peripheral vascular system
Z8877
Cardiovascular stress test with treadmill
Z8941
Cardiovascular stress test with bicycle ergometer
Z8943
Other cardiovascular stress test
Z8944
Other nonoperative cardiac and vascular diagnostic procedures
Z895
Screening for other and unspecified cardiovascular conditions
V812
Other cardiovascular procedures
Z005
Other nonoperative cardiac and vascular diagnostic procedures
Z895
Screening for ischemic heart disease
V810
3: complex cardiovascular events
Acute myocardial infarction (different types)
410
Congestive heart failure
4280
Left heart failure
4281
Heart failure, unspecified
4289
Congestive heart failure, unspecified
4280
Unspecified hypertensive heart and kidney disease
404
Unspecified hypertensive heart and kidney disease without heart failure or chronic kidney disease
4049
Cardiac arrest
4275
Acute pulmonary heart disease
415
Acute cor pulmonale
4150
4: cardiac invasive diagnostic procedures
Insertion of 1 vascular stent
Z0045
Insertion of 2 vascular stents
Z0046
Percutaneous insertion of intracranial vascular stent(s)
Z0065
Insertion of 3 vascular stents
Z0047
Right heart cardiac catheterization, cardiac catheterization, nos
Z3721
Cardiac catheterization, nos
Z37211
Left heart cardiac catheterization
Z3722
Combined right and left heart cardiac catheterization
Z3723
Angiocardiography of right heart structures
Z8852
Angiocardiography of left heart structures
Z8853
Combined right and left heart angiocardiography
Z8854
Coronary arteriography with 2 catheters
Z8855
Coronary arteriography with 2 catheters
Z8856
Other and unspecified coronary arteriography
Z8857
Aortocoronary bypass for heart revascularization, nos
Z3610
Other bypass anastomosis for heart revascularization
Z3619
nos, not otherwise specified.
Kessous. PTD and future risk for cardiovascular disease. Am J Obstet Gynecol 2013.
The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth.
Maternal risk of ischemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750,350 single tone pregnancies.
Cite this article as: Kessous R, Shoham-Vardi I, Pariente G, et al. An association between preterm delivery and long-term maternal cardiovascular morbidity. Am J Obstet Gynecol 2013;209:368.e1-8.
00530-9&id=gr1.jpg){kind=link}