Volume 199, Issue 2 , Pages 127.e1-127.e6, August 2008
A national study of the complications of lupus in pregnancy
Article Outline
Objective
This study was undertaken to determine the risk of rare complications during pregnancy for women with systemic lupus erythematosus.
Study Design
By using the Nationwide Inpatient Sample from 2000-2003, we compared maternal and pregnancy complications for all pregnancy-related admissions for women with and without systemic lupus erythematosus.
Results
Of more than 16.7 million admissions for childbirth over the 4 years, 13,555 were to women with systemic lupus erythematosus. Maternal mortality was 20-fold higher among women with systemic lupus erythematosus. The risks for thrombosis, infection, thrombocytopenia, and transfusion were each 3- to 7-fold higher for women with systemic lupus erythematosus. Lupus patients also had a higher risk for cesarean sections (odds ratio: 1.7), preterm labor (odds ratio: 2.4), and preeclampsia (odds ratio: 3.0) than other women. Women with systemic lupus erythematosus were more likely to have other medical conditions, including diabetes, hypertension, and thrombophilia, that are associated with adverse pregnancy outcomes.
Conclusion
Women with systemic lupus erythematosus are at increased risk for serious medical and pregnancy complications during pregnancy.
Key words: maternal mortality, preeclampsia, pregnancy, systemic lupus erythematosus
As the treatment of systemic lupus erythematosus (SLE) improves, more women with this disease are able to become pregnant. Pregnancy outcomes have improved dramatically over the last 40 years, with the pregnancy loss rate falling from 43% in the 1960s to 17% by 2000.1 The risks for maternal complications from SLE pregnancies, however, are not well documented. As each previously reported cohort has ranged from 25-265 pregnancies, reliable data for rare complications has not been available. Though lupus is no longer a contraindication to pregnancy, the extent of risk to a woman has been difficult to assess.
For Editors' Commentary, see Table of Contents
In this study, we have reviewed the Nationwide Inpatient Sample (NIS), a large database that includes detailed information on 20% of all hospitalizations throughout the United States. By using this database, we sought risk estimates for more rare, but potentially devastating, maternal complications, including thrombosis, infection, and maternal death.
Materials and Methods
The research protocol used in this study was reviewed and approved by the Duke University Medical Center Institutional Review Board. The NIS, from the Healthcare Cost and Utilization Project (HCUP) of the Agency for Healthcare Research and Quality (AHRQ), was queried for all pregnancy-related discharge codes for the years 2000-2003. The NIS contains data from approximately 1000 hospitals and is the largest all-payer inpatient care database in the United States. It is a 20% stratified sample from a sampling frame that comprises 90% of all US hospital discharges. Included in the sample are general hospitals and academic medical centers.2, 3, 4, 5 The hospitals are divided into strata based on ownership, bed size, teaching status, urban vs rural location, and region. Sampling probabilities are proportional to the number of hospitals in each stratum.
The NIS has been used to analyze pregnancy outcomes by several investigators to identified risks for myocardial infarction, stroke, and thrombosis, as well as cesarean section rates.4, 5, 6, 7, 8
Information included in the NIS is what can be derived from a typical discharge abstract, with safeguards to protect the privacy of individual patients, physicians, and hospitals. These data include diagnoses and procedures; admission and discharge status; demographic information such as gender, age, race and median income for ZIP code; and hospital characteristics. Although the data are limited, the NIS is the most reliable source of data on hospital admissions and discharges. Reliability is supported by agreement between the NIS, a telephone survey, and the National Health Interview Survey (a national, door-to-door survey). Invalid or inconsistent diagnostic codes are flagged.2, 3, 5
The pregnancy-related discharge records included in the sample from 2000-2003 were identified by using the International Classification of Diseases Ninth Revision (ICD-9) and were classified as to whether they were an admission during pregnancy or postpartum. A pregnancy admission was defined as any discharge record with a pregnancy-related code (ICD-9 codes 630-648) or delivery code (ICD-9 codes 74 for cesarean delivery and 72, 73, 75, v27, or 650-659 for vaginal delivery). A postpartum admission was defined as any discharge record that included a postpartum diagnosis (ICD-9 codes 670-677) and did not also include a delivery code.
The ICD-9 code used for Systemic Lupus Erythematosus was 710.0. Women were identified as having a hypercoagulable condition by using codes 286.5, 289.9, 795.79, 273.8, 286.9, 289.91. There is no designated ICD-9 code for antiphospholipid syndrome (APS), but we believe that women with this syndrome will be included in this hypercoagulable group. For other comorbidities and complications, both the ICD-9 code for a particular condition in pregnancy and the general ICD-9 code for that condition were used. If the pregnancy-related code was not specific, it was not used.
Data were analyzed based on the NIS sampling design, a multistaged sampling frame consisting of 3 stages. The 3 stages are strata (geographic region, urban vs rural location, teaching status, type of ownership, and bed size), hospitals within the strata, and individual discharges weighted by population counts and controlled for missing data. STATA 9.0 (Stata Corp LP, College Station, TX) with its SVY (survey data) commands using these 3 stages were used for all analyses, both descriptive and inferential. Two-way χ2 analyses were performed, accounting for the complex survey design of the NIS. The 2-way weighted χ2analyses yielded cell frequencies and their proportions. Logistic regression analyses were used to compute odds ratios (OR) with 95% confidence intervals (CI) for medical conditions and obstetric complications. Logistic regression models adjusted for age for comorbidities, pregnancy complications and medical computations yield new adjusted odds ratios with 95% CI.
Results
There were more than 16.7 million deliveries between 2000 and 2003: 13,555 of which were to women with a diagnosis of SLE. These pregnancies resulted in 18.3 million pregnancy-related hospitalizations: 17,263 of which were to women with a diagnosis of SLE.
The demographic make-up of the SLE pregnancies was different from the non-SLE pregnant population (Table 1). Women with SLE were, on average, older than women without SLE. A larger proportion of SLE pregnancies were to African American women, consistent with the demographic distribution of this disease. According to this database, 0.08% of white deliveries, 0.12% of African American deliveries, and 0.06% of Hispanic deliveries were to women with SLE.
TABLE 1. Demographics and modifiable risk factors
| Demographic and risk factors | SLE pregnancies | Non-SLE pregnancies | P-value |
|---|---|---|---|
| Mean age (y) | 30.0 | 27.5 | <.001 |
| Age at delivery ≥35 | 21.2% | 14.2% | <.001 |
| Ethnicity | |||
 White | 55% | 53% | .05 |
| African American | 20% | 14% | <.001 |
| Hispanic | 17% | 23% | <.001 |
| Other | 8% | 10% | <.001 |
| Obesity | 1.2% | 1% | .39 |
| Tobacco use | 2.9% | 2.9% | .97 |
| Alcohol and substance abuse | 0.8% | 1% | .30 |
The modifiable lifestyle risk factors for poor pregnancy outcome were not statistically different for women with SLE (Table 1). A similar proportion of women with SLE were reported to be obese, smoked tobacco, or abused alcohol or drugs during pregnancy, compared with the non-SLE population. These risk factors were rare, with only 3% of women smoking during pregnancy.
Women with SLE have more comorbid conditions that place their pregnancies at higher risk than other women (Table 2). Diabetes mellitus and hypertension diagnosed before pregnancy were both more common among women with SLE; however, when adjusted for maternal age, the OR for pregestational diabetes was no longer statistically significant for SLE and non-SLE populations (OR: 1.1; 95% CI, 0.9-1.3). Pulmonary hypertension and renal failure, both signs of advanced connective tissue disease and relative contraindications to pregnancy, were rare but more common among women with SLE. After adjusting for the older maternal age among women with SLE, the OR of pulmonary hypertension (OR: 2.6; 95% CI, 1.7-3.6) and renal failure (OR: 3.7; 95% CI, 2.8-4.6) remained elevated, though not as high as when unadjusted. Thrombophilia, diagnosed in this study by using a broad spectrum of ICD-9 codes that included women with APS and other hypercoagulable states, more frequently complicated SLE pregnancies. Thrombophilia remained elevated (OR: 20.9; 95% CI, 13.5-32.4) when adjusted for the older age of women with SLE.
TABLE 2. Comorbid illnesses in women with SLE
| Comorbid illness | Percentage of SLE deliveries with the condition | Percentage of non-SLE deliveries with the condition | OR | 95% CI | P value |
|---|---|---|---|---|---|
| Pregestational diabetes | 5.6% | 4.2% | 1.7 | 1.2-2.2 | <.001 |
| Hypertension | 3.9% | 0.7% | 5.5 | 4.5-6.8 | <.001 |
| Pulmonary hypertension | 0.2% | 0.01% | 10.9 | 3.9-30.0 | <.001 |
| Renal failure | 0.2% | 0.002% | 36.9 | 25.0-52.3 | <.001 |
| Thrombophilia | 4.0% | 0.04% | 34.7 | 27.7-43.4 | <.001 |
Pregnancy complications
Women with SLE had a 2- to 4-fold increased rate of pregnancy complications than the non-SLE population (Table 3). More than one-third of women with SLE had a cesarean section and one-fifth were admitted with preterm labor. Preeclampsia was diagnosed in 22.5% of women with SLE. When adjusted for the increased maternal age of the women with SLE, the risks for preeclampsia, preterm labor, and intrauterine growth rate (IUGR) remained unchanged. Intrauterine or fetal growth restriction occurred in 5.6% of SLE pregnancies, but the database did not contain the birthweight, so we cannot comment on the frequency of small-for-gestational-age infants.
TABLE 3. Pregnancy complications in SLE pregnancies
| Pregnancy complication | Percentage of SLE deliveries with the complication | Percentage of non-SLE deliveries with the complication | OR | 95% CI | P value |
|---|---|---|---|---|---|
| Cesarean section | 36.6% | 25.0% | 1.7 | 1.6-1.9 | <.001 |
| Preterm labora | 20.8% | 8.1% | 2.4 | 2.1-2.6 | <.001 |
| Intrauterine (fetal) growth restriction | 5.6% | 1.5% | 2.6 | 2.2-3.1 | <.001 |
| Preeclampsia | 22.5% | 7.6% | 3.0 | 2.7-3.3 | <.001 |
| Eclampsia | 0.5% | 0.09% | 4.4 | 2.7-7.2 | <.001 |
aPreterm labor indicates women admitted for preterm labor but is not an accurate proxy for preterm birth. |
Medical complications
Women with SLE also had more medical complications during pregnancy than healthy women (Table 4). The risk of maternal death (325/100,000 live births) was more than 20-fold higher than the non-SLE population. The actual rate of death was 0.32% among all SLE pregnancies, which averages to about 11 maternal deaths per year in the United States. When adjusted for maternal age, the risk of maternal death remained markedly elevated for women with SLE (OR: 17.8; 95% CI, 7.2-44).
TABLE 4. Medical complications in SLE pregnancies
| Medical complication | Percentage of SLE pregnancies with the complication | Percentage of non-SLE pregnancies with the complication | OR | 95% CI | P value |
|---|---|---|---|---|---|
| Thrombotic complications | |||||
| Stroke | 0.32% | 0.03% | 6.5 | 2.8-10.3 | <.001 |
| Pulmonary Embolus | 0.4% | 0.04% | 5.5 | 2.8-10.8 | <.001 |
| DVT | 1.0% | 0.01% | 7.9 | 5.0-12.6 | <.001 |
| Infectious complications | |||||
| Sepsis | 0.5% | 0.1% | 3.5 | 2.0-6.0 | <.001 |
| Pneumonia | 1.7% | 0.2% | 4.3 | 3.1-5.9 | <.001 |
| Hematologic complications | |||||
| Transfusion | 2.7% | 0.5% | 3.6 | 2.8-4.2 | <.001 |
| Postpartum hemorrhage | 4.5% | 3.3% | 1.2 | 1.0-1.5 | .01 |
| Antepartum bleeding | 2.0% | 0.4% | 1.8 | 1.3-2.4 | <.001 |
| Anemia at delivery | 12.6% | 6.8% | 1.9 | 1.7-2.2 | <.001 |
| Thrombocytopenia | 4.3% | 0.4% | 8.3 | 6.8-10.1 | <.001 |
The risk for sepsis and pneumonia was several fold higher among women with SLE, though the absolute risk of infection remained low. Postpartum infections occurred slightly more commonly among women with SLE (OR: 1.4, P < .001).
Hematologic complications are common among lupus patients and so not surprisingly among lupus pregnancies. Anemia was diagnosed in more than 12% of SLE pregnancies at the time of delivery. Thrombocytopenia, a common manifestation of lupus, was identified 8 times as often in SLE as in non-SLE pregnancies. These hematologic abnormalities, perhaps, combined to increase the risk for transfusion 3-fold among women with SLE. Interestingly, the rate of postpartum hemorrhage was only slightly higher than in the remainder of the population (OR: 1.2, P < .001).
The risk for venous thromboembolism was 5- to 8-fold higher and the risk of stroke was 6.5-fold higher for women with SLE compared with other women. Even when adjusted for the older age of women with SLE, the risk for thrombosis (deep vein thrombosis, pulmonary embolism, or cerebrovascular accident) remained more than 10-fold higher for women with SLE.
Comment
When compared with other women, SLE patients are at increased risk for maternal death, preeclampsia, preterm labor, thrombosis, infection, and hematologic complications during pregnancy. These elevated risks make clear the need for close monitoring by both maternal-fetal medicine physicians and rheumatologists during pregnancy.
Women with SLE in the NIS cohort had several demographic and medical risk factors for adverse pregnancy outcomes, beyond the diagnosis of SLE. Women with SLE were older and more were African American compared with the non-SLE population. As would be expected given the natural history of SLE, women with this disease had a higher incidence of comorbid conditions, including diabetes, hypertension, pulmonary hypertension, and renal failure.9 Treatment with corticosteroids during pregnancy can increase the risk for diabetes and hypertension. Pulmonary hypertension and renal failure are both life-threatening complications of severe SLE.10 Many would consider both conditions relative contraindications to pregnancy; the low number of pregnancies is evidence that this message is reaching these women.
Reliable maternal mortality rates for women with SLE have not been previously available. In the Hopkins Lupus Cohort, 3 maternal deaths occurred in 265 pregnancies, leading to a rate of 1100 per 100,000 births.11 This cohort is from a quaternary care referral center and would be expected to include women at higher risk of death than the general SLE population. In the NIS, we found that the maternal mortality rate of 325 per 100,000 live births (0.325%) to women with SLE is more than 20-fold higher than the mortality rate for the non-SLE population. This statistic is alarming and should heighten the level of vigilance that we use for SLE pregnancies. However, the rate is not surprising given the annual mortality rate for women with SLE. Among studies published since 1995, the annual mortality rate for nonpregnant SLE patients range between 790 and 3208 deaths per 100,000 patient-years (0.79-3.2%).12, 13, 14, 15, 16 Though it is not ideal to compare mortality rates between different types of studies, the maternal mortality rate found in this study is at least several folds lower than expected in the nonpregnant SLE patient.
Nonpregnant women with SLE are at increased risk for venous and arterial thrombosis with an estimated 2% having a thrombotic event during each year of disease.17, 18, 19 Pregnancy also increases the risk of thrombosis by about 3-fold, even in otherwise healthy women. In this study, however, we found that the risk for thrombosis increased even further among women with SLE, by 10-fold when adjusted for maternal age. This led to 1.7% of SLE pregnancies having a thrombotic complication. Given this elevated risk, women with SLE who complain of possible thrombotic symptoms should be evaluated carefully. In addition, further thrombotic risk factors, such as thrombophilia (in particular antiphospholipid antibodies), hypertension, tobacco use, and immobility should be addressed prophylactically in women with SLE during pregnancy.
Women with SLE are at increased risk for infection caused by both disease-related immune dysregulation and immunosuppressive therapy. This is reflected in the increased risk for pneumonia and sepsis found in this study. In a prospective cohort of SLE patients, sepsis occurred in 0.24 of every 100 patient years and pulmonary infection 1.4/100 patient years.20 The frequency of sepsis and pneumonia found in this pregnancy study is similar to that expected in non-pregnant SLE patients.
Prior cohort studies have demonstrated increased rates of pregnancy complications in women with SLE, but this is the largest to date to describe the risk for cesarean birth, preterm labor, and preeclampsia. The NIS database does not, however, include data on the gestational age at birth or birthweight. Data on early fetal loss that was managed as an outpatient is also not included in the database.
This study confirms prior reports of cesarean section rates, with more than one-third of pregnancies delivered surgically. Prior reports of SLE pregnancies found similar percentages of cesarean deliveries: 38.2% in a population based study in California in 1993-4, and between 26-38% in tertiary care center cohorts.21, 22, 23
Though 20.8% of SLE pregnancies in this cohort had a diagnosis of preterm labor at the time of childbirth, this is not an accurate estimate of the rate of preterm birth. Women with premature rupture of membranes, pharmacologically induced labor, or a cesarean section for medical indications may deliver prematurely, but without preterm labor. In a literature review of SLE pregnancy cohorts, one-third of all SLE pregnancies were delivered preterm.1 Risk factors associated with preterm birth in these cohorts include increased SLE activity before and during pregnancy, preeclampsia and hypertension, use of prednisone, and low complement.11, 24
This study confirms that preeclampsia is a significant problem in SLE pregnancies. We included ICD-9 codes for hypertension in pregnancy, mild, and severe preeclampsia in this category. Distinguishing between preeclampsia and lupus nephritis (proteinuria, active urine sediment, and hypertension) can be difficult and sometimes impossible. The distinction is important clinically as the treatment for preeclampsia (delivery) and lupus nephritis (immunosuppression) are different. We expect that some patients labeled as having preeclampsia in this study actually had lupus nephritis. Even with this bias, it is still notable that one-fifth of pregnancies are complicated by significant hypertension or preeclampsia. In prior SLE cohorts, 2.7-30% of pregnancies were complicated by preeclampsia, a rate up to 5.7-fold higher than expected.23, 24, 25
The main strength of this study lies in the size of the NIS cohort. The NIS reflects a 20% stratified sample from a sampling frame that comprises 90% of all hospitalizations in the United States and has been demonstrated to be representative of all pregnancies. Prior studies of SLE pregnancies have relied on cohorts of pregnancies collected at single institutions; the largest study included 265 pregnancies.11 The small size of prior SLE pregnancy cohorts precluded the assessment of rare complications such as maternal death. Prior studies were based in referral centers and administered by rheumatologists with special interest and expertise in SLE pregnancies, and were therefore biased toward the sickest SLE patients. The NIS cohort represents women admitted to all types of hospitals, collecting data on women with all severities of SLE. This makes the NIS lupus cohort more representative of the lupus patients seen by community obstetricians.
Because of the large size of this dataset, we were able to perform a multivariate analysis by using maternal age. Unfortunately, data on race are not available for 29% of the pregnancies, as several states did not report this, precluding inclusion of race in the multivariate analysis. After adjusting for age, the OR for pregnancy complications did not change. However, several comorbid illnesses, including pregestational diabetes, renal failure, and pulmonary hypertension, appear to be highly dependent on maternal age.
The primary drawback to this study is the inability to confirm the SLE diagnoses included in the NIS. We selected 710.0, the ICD-9 code for SLE, because it is the most precise code available for this condition. We suspect that some women with a positive antinuclear antibody titer, but not meeting the American College of Rheumatology criteria for SLE, were included in this cohort. However, by virtue of the fact that the diagnosis was included in the discharge paperwork, the SLE generally must have been sufficiently symptomatic to warrant mention.
The NIS does not include the gestational age at delivery nor data about the infant, such as APGAR scores, birthweight, newborn intensive care unit admission, or congenital abnormalities. The data are deidentified and do not allow for matching of women to infants. Therefore, we are unable to comment on the rate of preterm birth, low birthweight, or other complications in the infant.
Because of the nature of the database, sequential hospital admissions for the same woman cannot be linked together. Undoubtedly, some women had multiple admissions during their pregnancy, and these admissions are counted separately. Similarly, some medical complications that occur during pregnancy (ie, an infection) may not be recorded at the time of hospitalization for childbirth. We have taken this into account by including all hospital admissions associated with pregnancy when counting the medical complications (events) included in Table 4. The comorbid conditions listed in Table 2, which typically continue throughout pregnancy, were only counted at the time of delivery to avoid recounting these persistent conditions.
This is the largest study to date of SLE pregnancies and provides a nationwide assessment of pregnancy complications. This study demonstrates that the majority of women with SLE can have a successful pregnancy. However, as has previously been reported, pregnancy can be risky for women with SLE, resulting in more cesarean births, preeclampsia, infections, thromboses, and maternal deaths than pregnancy in other women. We also found that medical complications, including thrombosis, infection, and hematologic abnormalities are more common for patients with SLE. When compared with risks endured by nonpregnant SLE patients, however, the risks during pregnancy are not elevated. This comparison demonstrates that, though pregnancy can pose a risk to a woman with SLE, this risk may not be higher than any other year of this woman's life.
Prior cohort studies have identified risk factors, such as increased lupus activity before and during pregnancy, lupus nephritis, and hypertension, that place a woman with SLE and her pregnancy at particularly high risk. Further large-scale cohorts are required to stratify the risk for rare events based on these factors to provide more individualized counseling to SLE patients contemplating pregnancy.
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- . Overview of the Nationwide Inpatient Sample (NIS) 2000. Rockville, MD: The Agency for Healthcare Research and Quality; 2002;
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Cite this article as: Clowse MEB, Jamison M, Myers E, et al. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127.e1-127.e6.
Drs Clowse and James are funded by NIH grant 5K12-HD-043446
PII: S0002-9378(08)00276-7
doi:10.1016/j.ajog.2008.03.012
© 2008 Mosby, Inc. All rights reserved.
Volume 199, Issue 2 , Pages 127.e1-127.e6, August 2008
