Objective
We sought to investigate whether patients with a history of recurrent pregnancy loss (RPL) have an increased risk for future maternal atherosclerotic morbidity.
Study Design
A population-based study compared the incidence of long-term atherosclerotic morbidity (renal and cardiovascular) in a cohort of women with and without a diagnosis of RPL. Patients had a mean follow-up duration of more than a decade. Women with known atherosclerotic disease were excluded from the study. Cardiovascular morbidity was divided into 4 categories according to severity and type including simple and complex cardiovascular events and invasive and noninvasive cardiac procedures. Kaplan-Meier survival curves were used to estimate cumulative incidence of cardiovascular and renal hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios for cardiovascular and renal morbidity.
Results
During the study period 99,285 patients were included; of these 6.7% (n = 6690) had a history of RPL. Patients with RPL had higher rates of renal and cardiovascular morbidity including cardiac invasive and noninvasive diagnostic procedures, simple as well as complex cardiovascular events, and hospitalizations due to cardiovascular causes. Using Kaplan-Meier survival curves, patients with a previous diagnosis of RPL had a significantly higher cumulative incidence of cardiovascular but not renal hospitalizations. Using a Cox proportional hazards model, adjusted for confounders such as preeclampsia, diabetes mellitus, obesity, and smoking, a history of RPL remained independently associated with cardiovascular hospitalizations (adjusted hazard ratio, 1.6; 95% confidence interval, 1.4–1.8; P = .001).
Conclusion
RPL is an independent risk factor for long-term maternal cardiovascular complications.
Recurrent pregnancy loss (RPL) is defined as ≥2 consecutive pregnancy losses and affects approximately 1-2% of woman.
Several etiologies were linked to RPL, including immunologic factors; thrombophilia; vascular/placental, genetic, and uterine malformations; and environmental causes.
In recent years there is growing interest regarding the link between common pregnancy complications and the future risk for atherosclerotic diseases including cardiovascular and renal morbidity.
The most studied pregnancy complications are preeclampsia and gestational diabetes mellitus, and findings have led to recent recommendations published by the American Heart Association that included these complications in the guidelines for the preliminary risk evaluation for cardiovascular disease in women. Nevertheless, preeclampsia and diabetes mellitus are not the only complications studied and data regarding other pregnancy complications has been demonstrated. An increased risk for future cardiovascular morbidity and mortality has been found in patients with history of obstetric complications that might have a vascular component such as preterm delivery, intrauterine growth restriction, and placental abruption.
The association between RPL and subsequent risk for atherosclerotic morbidity such as cardiovascular and renal morbidity has not been previously studied extensively. Only 2 studies examined this association. One study investigated the pathophysiological link between endothelial dysfunction in patients with RPL and postulated that it leads to an increased risk for future cardiovascular disease later in life. The second study found patients with a history of RPL to be at approximately 9 times increased risk for myocardial infarction. Nevertheless, it is not yet clearly understood whether there is a true association between RPL and future risk for atherosclerotic morbidity or that rather this increased risk is due to other comorbidities such as hypertensive disorders.
The aim of the present population-based study was to investigate the association between a history of RPL and a woman’s future long-term risk for atherosclerotic morbidity.
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, serving 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 between the years 1988 through 2012. Excluded were: multifetal pregnancies (eg, twins, triplets), patients with a known cardiovascular and renal disease before or during the index pregnancy, and patients with known congenital cardiac or renal malformations.
Study design
A population-based retrospective cohort study was conducted. The exposure was a history of diagnosis of RPL, which was defined as ≥2 consecutive pregnancy losses. The index pregnancy was defined as the first pregnancy after the diagnosis, meaning after ≥2 consecutive pregnancy losses. Patients who for the entire period of follow-up were not diagnosed with RPL comprised the comparison group. For this group the index pregnancy was randomly selected. A retrospective follow-up of hospitalizations due to atherosclerotic morbidity up to 24 years after the index birth was performed. Atherosclerotic morbidity was defined as hospitalizations for any cardiovascular and renal reasons at the first atherosclerotic-related hospitalization at the Soroka University Medical Center. Cardiovascular morbidity was divided into 4 categories according to severity and type, including 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, Ninth Revision ( ICD-9 ) codes for each subtype of cardiovascular and renal morbidity are presented in the Appendix (Supplementary Tables 1 and 2) .
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 prior to entering it into the database. Coding was performed after assessing 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 using software (SPSS package 17 ed; IBM Corp, Armonk, NY). Statistical significance was calculated using the χ 2 test for differences in qualitative variables and the Student t test for differences in continuous variables.
Kaplan-Meier survival curve was used to compare cumulative incidence of atherosclerotic hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for long-term atherosclerotic hospitalizations. P < .05 was considered statistically significant.
Results
During the study period 99,285 patients were included. Of these 6.7% (n = 6690) had a history of RPL. Patients had a mean follow-up duration of more than a decade (11.2 years).
Table 1 summarizes characteristics of patients with and without a diagnosis of RPL. Patients in the RPL group were significantly older, had a higher birth order, and were more obese than the comparison group. In addition, patients with a history of RPL had higher rates of diabetes mellitus. The mean number of years of follow-up to the cardiovascular-related hospitalization was significantly shorter in the RPL as compared with the comparison group.
| Characteristic | RPL (n= 6690) | No RPL (n= 92,595) | P value |
|---|---|---|---|
| Maternal age at index birth, y ± SD | 31.3 ± 6 | 28.7 ± 6 | .001 |
| Ethnicity | .001 | ||
| Jewish | 56.6% | 67.8% | |
| Bedouin | 43.4% | 32.2% | |
| Smoking | 1.9% | 2.1% | .001 |
| Drug abuse | 0.1% | 0.1% | .053 |
| Postpartum anemia (hemoglobin <10 g/dL) | 29.0% | 28.9% | .889 |
| Preeclampsia | 4.9% | 4.9% | .870 |
| Chronic hypertension | 1.6% | 3.1% | .001 |
| Diabetes mellitus (gestational and pregestational) | 10.7% | 6.3% | .001 |
| Small for gestational age | 4.8% | 5.0% | .512 |
| Obesity (pregestational BMI >30 kg/m 2 ) | 1.2% | 1.0% | .032 |
| Parity at index birth, median (mode) | 6.3 ± 3 | 3.1 ± 2 | .001 |
| Mean time from index pregnancy to cardiovascular hospitalization, y ± SD | 11.8 ± 6.3 | 12.3 ± 6.1 | .001 |
| Mean time from index pregnancy to renal hospitalization, y ± SD | 12.7 ± 4.9 | 12.8 ± 6.8 | .954 |
Table 2 presents a comparison of cardiovascular and renal morbidity and total related hospitalizations during the follow-up period. Patients with RPL had higher rates of renal as well as cardiovascular morbidity including cardiac invasive and noninvasive diagnostic procedures, simple as well as complex cardiovascular events, and hospitalizations due to cardiovascular causes.
| Variable | RPL (n= 6690) | No RPL (n= 92,595) | OR | 95% CI | P value |
|---|---|---|---|---|---|
| Cardiac noninvasive diagnostic procedures | 1.8% | 0.9% | 1.9 | 1.6–2.3 | .001 |
| Cardiac invasive diagnostic procedures | 0.8% | 0.4% | 2.1 | 1.6–2.8 | .001 |
| Simple cardiovascular events | 2.3% | 1.3% | 1.8 | 1.5–2.2 | .001 |
| Complex cardiovascular events | 3.2% | 1.6% | 1.9 | 1.7–2.3 | .001 |
| Total cardiovascular hospitalizations | 5.8% | 3.1% | 1.9 | 1.7–2.2 | .001 |
| Hospitalizations due to renal causes | 0.2% | 0.1% | 1.8 | 1.01–3.07 | .043 |
The Figure presents a Kaplan-Meier survival curve for the cumulative incidence of cardiovascular and renal hospitalizations in both study groups (with or without a history of RPL). Patients with a previous diagnosis of RPL had a significantly higher cumulative incidence of cardiovascular-related ( Figure , A) but not renal-related ( Figure , B) hospitalizations during the whole follow-up period.
Cox proportional hazards models were used to estimate the adjusted HR and 95% CI for long-term cardiovascular and renal hospitalizations. Controlling for recognized confounders related to the metabolic syndrome such as diabetes, preeclampsia, and obesity as well as antiphospholipid syndrome and thrombophilia, RPL remained independently associated with cardiovascular hospitalizations ( Table 3 ). Even after adding several other confounders such as ethnicity, parity, chronic hypertension, drug abuse, and smoking, RPL remained independently associated with cardiovascular hospitalizations ( Table 4 ). In this model RPL was entered as a dummy variable including 2 consecutive losses and ≥3 pregnancy losses. In both categories RPL was independently associated with cardiovascular disease. The HR was higher in the ≥3 losses group (adjusted HR, 1.6; 95% CI, 1.4–1.8; P < .001) as compared with 2 consecutive losses (adjusted HR, 1.3; 95% CI, 1.1–1.5; P < .001).
| Variable | Adjusted HR | 95% CI | P value |
|---|---|---|---|
| Recurrent pregnancy loss | 1.6 | 1.4–1.8 | .001 |
| Preeclampsia | 2.4 | 2.2–2.6 | .001 |
| Gestational diabetes mellitus | 2.5 | 1.9–3.1 | .001 |
| Obesity (pregestational BMI >30 kg/m 2 ) | 1.9 | 1.7–2.1 | .001 |
| Antiphospholipid syndrome | 2.9 | 1.2–7.0 | .020 |
| Thrombophilia | 3.3 | 1.8–6.1 | .001 |
| Variable | Adjusted HR | 95% CI | P value |
|---|---|---|---|
| Recurrent pregnancy loss, 2 consecutive | 1.3 | 1.1–1.5 | .004 |
| Recurrent pregnancy loss, ≥3 | 1.6 | 1.4–1.8 | .001 |
| Preeclampsia | 1.7 | 1.5–1.9 | .001 |
| Gestational diabetes mellitus | 2.0 | 1.8–2.2 | .001 |
| Obesity (pregestational BMI >30 kg/m 2 ) | 2.5 | 2.0–3.0 | .001 |
| Parity | 1.17 | 1.15–1.19 | .001 |
| Ethnicity | 0.84 | 0.77–0.91 | .001 |
| Drug abuse | 5.8 | 3.0–11.0 | .001 |
| Smoking | 2.2 | 1.9–2.5 | .001 |
When performing these models regarding renal-related hospitalizations controlling for parity and diabetes mellitus, RPL has not been found to be independently associated to renal hospitalizations (adjusted HR, 1.3; 95% CI, 0.8–2.3; P = .301) ( Table 5 ).
| Variable | Adjusted HR | 95% CI | P value |
|---|---|---|---|
| Recurrent pregnancy loss | 1.3 | 0.8–2.3 | .301 |
| Parity | 1.2 | 1.17–1.29 | .001 |
| Gestational diabetes mellitus | 2.5 | 1.6–3.9 | .001 |
Results
During the study period 99,285 patients were included. Of these 6.7% (n = 6690) had a history of RPL. Patients had a mean follow-up duration of more than a decade (11.2 years).
Table 1 summarizes characteristics of patients with and without a diagnosis of RPL. Patients in the RPL group were significantly older, had a higher birth order, and were more obese than the comparison group. In addition, patients with a history of RPL had higher rates of diabetes mellitus. The mean number of years of follow-up to the cardiovascular-related hospitalization was significantly shorter in the RPL as compared with the comparison group.
| Characteristic | RPL (n= 6690) | No RPL (n= 92,595) | P value |
|---|---|---|---|
| Maternal age at index birth, y ± SD | 31.3 ± 6 | 28.7 ± 6 | .001 |
| Ethnicity | .001 | ||
| Jewish | 56.6% | 67.8% | |
| Bedouin | 43.4% | 32.2% | |
| Smoking | 1.9% | 2.1% | .001 |
| Drug abuse | 0.1% | 0.1% | .053 |
| Postpartum anemia (hemoglobin <10 g/dL) | 29.0% | 28.9% | .889 |
| Preeclampsia | 4.9% | 4.9% | .870 |
| Chronic hypertension | 1.6% | 3.1% | .001 |
| Diabetes mellitus (gestational and pregestational) | 10.7% | 6.3% | .001 |
| Small for gestational age | 4.8% | 5.0% | .512 |
| Obesity (pregestational BMI >30 kg/m 2 ) | 1.2% | 1.0% | .032 |
| Parity at index birth, median (mode) | 6.3 ± 3 | 3.1 ± 2 | .001 |
| Mean time from index pregnancy to cardiovascular hospitalization, y ± SD | 11.8 ± 6.3 | 12.3 ± 6.1 | .001 |
| Mean time from index pregnancy to renal hospitalization, y ± SD | 12.7 ± 4.9 | 12.8 ± 6.8 | .954 |
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