Systemic sclerosis, primary pulmonary hypertension, and sickle cell disease are chronic diseases that are associated with noninflammatory vasculopathy and can be associated with significant morbidity and mortality.1–4 In the past, pregnancy was contraindicated in these patients due to a high incidence of maternal and fetal death.5–7 With improvements in diagnosis, follow-up, and treatment of these diseases and with careful and enhanced prenatal care in the past several years, increasing numbers of women are proceeding with pregnancy. Recent reports have demonstrated more favorable pregnancy outcomes in women with these diseases.8,9 Because these diseases are relatively rare, published studies of pregnancy outcomes have been limited by small numbers of patients and long periods of observation during which temporal trends in medical therapy had changed significantly. Most past studies were retrospective, performed at single, tertiary-care centers, and may not accurately reflect pregnancy outcomes throughout the United States. We used a large inpatient-care database that is representative of care provided in U.S. community hospitals to assess 1) obstetric hospitalizations and deliveries and 2) pregnancy outcomes and their predictors in patients with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease.
MATERIALS AND METHODS
We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project10 for the years 2002–2004. The Nationwide Inpatient Sample, established in 1988, is the largest all-payer inpatient care database that is publicly available in the United States and contains clinical and demographic information available from discharge abstracts. The database contains information from all inpatient hospitalizations in 995 hospitals, which were sampled to approximate a 20% stratified sample of community hospitals in the United States. The 2002 sample was drawn from hospitals in 35 states: California, Colorado, Connecticut, Florida, Georgia, Hawaii, Illinois, Iowa, Kansas, Kentucky, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, Nebraska, Nevada, New Jersey, New York, North Carolina, Ohio, Oregon, Pennsylvania, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, and Wisconsin. In addition, the 2003 sample included Indiana and New Hampshire, and the 2004 database included Arkansas. The Nationwide Inpatient Sample includes all the nonfederal short-stay hospitals listed by the American Hospital Association. These hospitals were divided into 60 strata based on region, location, teaching status, bed size category, and ownership. Within each stratum, a systematic random sample of hospitals was drawn, equal in size to 20% of that stratum. Detailed information on the design of the survey and the magnitude of sampling errors associated with the estimates is available in the technical documentation.11
Information available from discharge abstracts included maternal age, length of hospital stay, principal diagnosis, up to 14 secondary diagnoses, principle procedure, and up to 14 secondary procedures. Data on race and ethnicity were collected in all but 11 states; categories included white, black, Hispanic, Asian and Pacific Islander, Native American, and other. We collapsed Native Americans into the “other” category due to the small number of observations. Diagnoses and procedures were coded by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.12 Because unique patient identifiers were not provided to protect individual privacy in this publicly available data set, we used hospitalization, rather than patient, as the unit of analysis. Additionally, the lack of unique patient identifiers precluded linking of maternal to infant discharge records. Thus, data on neonatal outcomes were not available.
All obstetric hospitalizations were included in the analysis. Hospitalizations were ascribed to the diagnosis (systemic sclerosis [ICD-9-CM 710.1], primary pulmonary hypertension [416.0], and sickle cell disease [includes HB-SS, HB-SC, HB-SD, and HB-SE disease, ICD-9-CM 282.60–282.69]) found among discharge diagnoses. Patients with sickle cell trait were excluded from all analyses. The control group was defined as any obstetric hospitalization in women who did not have a diagnosis of systemic sclerosis, primary pulmonary hypertension, or sickle cell disease. Hospitalizations that were associated with delivery of an infant were defined as any hospitalization with procedure codes for cesarean delivery and other procedures for inducing or assisting delivery, or ICD-9-CM codes for normal delivery and delivery with complications. All other hospitalizations were considered antenatal hospitalizations that did not result in delivery. Comorbid conditions of interest included diabetes mellitus, antiphospholipid antibody syndrome, and renal failure.
Because systemic sclerosis and primary pulmonary hypertension are rare diseases and pregnancy is uncommon among these patients, we combined data from 3 years for all three diseases of interest to ascertain enough cases amenable for analysis. Hospital and discharge weights were applied to the sample data to estimate the total number of obstetric hospitalizations, delivery-associated hospitalizations, and cesarean delivery for women with systemic sclerosis, primary pulmonary hypertension, sickle cell disease, and the general obstetric population for the years 2002–2004. National estimates and 95% confidence intervals (CIs) were calculated.
For each group of patients (systemic sclerosis, primary pulmonary hypertension, sickle cell disease, and control), the maternal age and length of stay were calculated, and differences in means were compared using analysis of variance with the Dunnett test for multiple comparisons with a control group. The proportion of hospitalizations for each group with the following pregnancy outcomes was calculated: antenatal hospitalizations, hypertensive disorders including preeclampsia, premature rupture of membranes, cesarean delivery, and intrauterine growth restriction (IUGR). As for diagnosis of underlying vasculopathic disease, all obstetric outcomes were obtained using ICD-9 codes. Hypertensive disorders of pregnancy include blood pressure greater than 140/90 mm Hg and fall into the following categories: gestational hypertension, preeclampsia, eclampsia, and superimposed preeclampsia13; premature rupture of membranes is generally defined as rupture of amniotic sac before the onset of labor14; and IUGR is defined as weight less than 10 percentile of gestational age.15 Chi-square and Fisher exact tests were applied as appropriate to compare differences in rates between each group and the control population.
For each dichotomous outcome of interest (antenatal hospitalization, hypertensive disorders, IUGR, and cesarean delivery), logistic regression was performed for each disease using maternal age as a covariate. For length of stay (in days), linear regression was performed. Multivariable analyses were then performed for each outcome using maternal age, race or ethnicity, and other clinically important variables, including the antiphospholipid antibody syndrome, diabetes mellitus, and renal failure. Missing values were considered missing at random. Except for antenatal hospitalizations, all analyses were performed on the subset of hospitalizations that resulted in delivery of an infant to eliminate bias from multiple hospitalizations of sicker patients.
All analyses were performed using STATA 8.0 software (Stata, College Station, TX). An institutional review board waiver was obtained to use this publicly available, deidentified data.
There were 2,893,904 obstetric hospitalizations in the Nationwide Inpatient Sample database between 2002 and 2004. Of these, 149 occurred in women with a discharge diagnosis of systemic sclerosis, 85 in women with primary pulmonary hypertension, and 2,478 in women with sickle cell disease. One hospitalization carried diagnoses of both systemic sclerosis and primary pulmonary hypertension, and four patients received diagnoses of both systemic sclerosis and sickle cell disease. These pregnancies were excluded from further analysis. After application of sampling weights, there were an estimated 14 million total obstetric hospitalizations over the 3 years of study: approximately 695 hospitalizations in women with systemic sclerosis, 407 in women with primary pulmonary hypertension, and 11,928 in women with sickle cell disease (Table 1). Of these hospitalizations, we estimated approximately 11.2 million total deliveries (95% CI 10.6–11.8 million) over the 3 years: 3.72 (3.36–4.07) million in 2002, 3.66 (3.31–4.01) million in 2003, and 3.83 (3.46–4.20) million in 2004. Estimates for deliveries by diagnosis group were 504 in women with systemic sclerosis, 182 with primary pulmonary hypertension, and 4,352 with sickle cell disease. The distribution of patients among hospitals with small, medium, and large bed sizes was similar among all groups. Thirty-one percent to 40% of patients with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease were admitted to nonteaching hospitals (data not shown).
The mean age for all obstetric hospitalizations is 27.5 years (standard deviation [SD] 6.2), and mean age for women delivering an infant was 27.5 (SD 6.2) years (Table 2). Women with systemic sclerosis were an average of 2.0 years (95% C1 0.7–3.3, P<.05) older, and women with primary pulmonary hypertension were an average of 4.3 years (95% CI 2.6–6.0, P<.05) older than controls. In contrast, women with sickle cell disease were an average of 2.9 years (95% CI 2.6–3.2, P<.05) younger than controls.
Only 11 participating states did not report data on race or ethnicity. The distribution of race or ethnicity among patients with systemic sclerosis did not differ appreciably from the general obstetric population (Table 2). Among primary pulmonary hypertension patients, the distribution of race and ethnicity was similar among white, black, and Hispanic patients. This result is in contrast to reports of the distribution by race of patients with primary pulmonary hypertension in a national registry, where only a minority of patients were black (12.3%) or Hispanic (2.3%).16 As was expected, patients with sickle cell disease were almost exclusively black, with a low proportion of patients of other ethnicities.
The proportion of obstetric admissions that were not associated with delivery (antenatal hospitalizations) in the control group was 19.6%. In comparison, 26.3% of systemic sclerosis admissions were for complications of pregnancy not associated with delivery (P=.03 compared with controls), and more than half of admissions for patients with primary pulmonary hypertension (55.3%) and sickle cell disease (63.4%) did not result in the delivery of an infant (P<.001). Additional pregnancy outcomes for hospitalizations associated with delivery by diagnosis group are shown in Table 3.
Women in all three disease groups had significantly increased length of stay and rates of hypertensive disorders that were twofold to fourfold higher than the control population. Rates of IUGR were significantly higher in women with systemic sclerosis and sickle cell disease, but not with primary pulmonary hypertension. Cesarean deliveries were frequent in all groups (42.2% in systemic sclerosis, 57.9% in primary pulmonary hypertension, 44.5% in sickle cell disease, and 31.1% in controls; P<.05 compared with controls). There were too few events to compare rates of maternal death or fetal demise in this data set.
Results of multivariable analyses examining the risk of adverse outcomes in obstetric hospitalizations are shown in Table 4. Except for antenatal hospitalizations, all analyses were performed on the subset of hospitalizations associated with delivery. Systemic sclerosis was independently associated with an increased risk of hypertensive disorders (odds ratio 3.71, 95% CI 2.25–6.15), IUGR (odds ratio 3.74, 95% CI 1.51–9.28), and increased length of stay (β 2.50, 95% CI 2.07–2.95). A diagnosis of primary pulmonary hypertension was associated with a fivefold increase in the odds of an antenatal hospitalization and hypertensive disorders of pregnancy. Similarly, primary pulmonary hypertension was associated with a markedly prolonged length of stay. An elevated odds of IUGR was noted, but the 95% confidence intervals were wide and crossed the null. A diagnosis of sickle cell disease was associated with increased odds of antenatal hospitalization, hypertensive disorders, and IUGR, with a modest increase in the length of stay.
As demonstrated in other studies of perinatal outcomes, black race was associated with slightly, but statistically significant, elevated odds of all adverse outcomes of interest, independent of the disease group.17,18 In contrast, parturients of Hispanic or Asian ethnicity had lower rates of all adverse outcomes, irrespective of diagnosis, with the exception of IUGR among Asian women.17–19
Systemic sclerosis, primary pulmonary hypertension, and sickle cell disease are all vasculopathic disorders that can occur in women during the childbearing years. In past decades, women were strongly advised to avoid pregnancy because of poor perinatal outcomes for both mother and infant.5–7 More recently, pregnancies have become slightly more common among women with these underlying diseases.5,20,21 Despite this, studies have been limited by small numbers of patients collected at tertiary care medical centers and changes in perinatal care over long periods of accrual. Using data available from the Nationwide Inpatient Sample from the years 2002–2004, we compared pregnancy outcomes among women with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease with those in the general obstetric population. The numbers of live births in the control group for each year is similar to those reported by vital statistics for each year and is encompassed within our confidence intervals.22–24 We estimated nearly 4,400 deliveries among women with sickle cell disease during the 3 years of observation, compared with a much smaller number of approximately 504 deliveries in women with systemic sclerosis and 182 in women with primary pulmonary hypertension. In addition, we found women with systemic sclerosis and primary pulmonary hypertension were significantly older than the control group. This result is consistent with an older age of diagnosis of these diseases, in addition to the possibility that women diagnosed with these diseases may delay pregnancy because of medication use or other disease-related factors. We found significantly increased rates of antenatal hospitalization, hypertensive disorders of pregnancy, IUGR, and cesarean delivery among women with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease compared with the general obstetric population. The increased risk of developing these pregnancy complications persisted after adjustment for maternal age, race or ethnicity, and comorbid conditions, including diabetes mellitus, renal failure, and the antiphospholipid antibody syndrome.
Systemic sclerosis is a rare female-predominant autoimmune disease of unclear etiology that is characterized by progressive fibrosis of the skin and internal organs and a noninflammatory vasculopathy.25,26 The mean age of onset is in the fifth decade, and 10-year survival has improved from 54% in the 1970s to 66% in the later 1990s.25,26 Previous studies of pregnancy outcomes in women with systemic sclerosis at single tertiary care centers have shown an increased frequency of preterm births and small for gestational age infants.9,27,28 Likewise, our study showed a 3.7-fold increased risk of IUGR in systemic sclerosis–associated pregnancies compared with controls. These findings could be explained by the underlying vasculopathy associated with systemic sclerosis leading to placental insufficiency and infarction.29,30 Earlier studies did not find high rates of hypertensive disorders of pregnancy in patients with systemic sclerosis.9,27,28 In contrast, our study found a nearly fourfold increased risk for hypertensive disorders in systemic sclerosis–associated pregnancies compared with controls. It is possible that systemic sclerosis patients treated at tertiary care centers had more vigilant surveillance and treatment of hypertensive disorders than at community hospitals.
Primary pulmonary arterial hypertension consists of familial and sporadic cases without underlying connective tissue diseases, congenital heart disease, chronic veno-occlusive disease, or other causal entities. Age of onset among women is in the third and fourth decade, and the median survival without treatment is 2.8 years.31,32 Few studies have evaluated pregnancy outcomes in patients with primary pulmonary hypertension.32 These studies have reported high rates of maternal mortality associated with pregnancy, ranging from 30–50%, with the highest risk during the first month after delivery.6,21,33 Our study confirms that women with primary pulmonary hypertension have increased risks for complications during pregnancy. Although women with primary pulmonary hypertension were older than control patients, multivariable analyses demonstrated substantially worse outcomes. More than half of their hospitalizations were for nondelivery indications. In a previous study, the most common reasons for antenatal hospitalizations included increased dyspnea, hemoptysis, syncope, cyanosis, or hypertensive disorders.21 In our study, in addition to a high rate of antenatal hospitalizations, patients with primary pulmonary hypertension had an almost fivefold increase in hypertensive disorders and substantially increased length of stay for deliveries compared with controls.
The racial composition of patients in our study included a higher percentage of minority women with primary pulmonary hypertension than in a previously reported national registry.16 Although it is possible that the missing race data could explain this discrepancy, it is also possible that white patients had more consistent counseling against pregnancy than minority populations. Given the higher age-adjusted mortality rate in black women compared with white women with primary pulmonary hypertension in the absence of the physiological stressors of pregnancy,1,2 concerted efforts should be made to counsel patients with primary pulmonary hypertension from all racial groups of the high risks associated with pregnancy.
Sickle cell disease is an autosomal recessive genetic disorder to the β-globin gene affecting approximately 50,000 Americans34 without gender predominance. In the 1970s, the median survival time for this disease was 14.3 years; this has increased to nearly 50 years in recent decades, largely due to streptococcus pneumonia prophylaxis and better treatment of vaso-occlusive crises.4 Similarly, pregnancy outcomes in women with sickle cell disease in the 1970s were unacceptably high, and those women surviving to the childbearing years were strongly counseled against becoming pregnant.5 More recently, the maternal death rate has been reduced to less than 2%, and many women are electing to proceed with pregnancies.8 Previous studies of pregnancy in women with sickle cell disease have been limited by retrospective studies at single institutions, or multi-institution cooperative studies that span nearly 10 years to accumulate patients.8 A single randomized control trial of red cell transfusions during pregnancy evaluated 72 women accumulated over 5 years.35 Together, these data on pregnancies in women with sickle cell disease in the United States have shown young age at pregnancy, numerous antepartum admissions for complications of underlying sickle cell disease (pain crises, acute chest crises, infections, and symptomatic anemia), longer hospital stays, and increased rates of IUGR.36–38 Results from our study confirm these outcomes in a much larger cohort of nearly 4,400 deliveries over 3 years of observation. Risks of all adverse pregnancy outcomes under study were independently associated with sickle cell disease, suggesting that pregnancy outcomes observed at tertiary care centers may be similar to those seen across the United States. The early age of pregnancy we found is consistent with other studies of sickle cell disease patients in the United States36–38 and may be a reflection of both diagnosis of this genetic disease during childhood before the childbearing years and a concern for early mortality despite improvements in care.4
Several limitations of the study require discussion. Despite collecting data over 3 years, there were still very few pregnancies complicated by systemic sclerosis or primary pulmonary hypertension. The small numbers of women with systemic sclerosis and primary pulmonary hypertension may be a reflection of the rarity of disease, severity of disease, medication use that precludes pregnancy, diagnosis of underlying disease after childbearing is complete, or a small proportion of women who are able or willing to carry a pregnancy to delivery. Certainly, this will be a concern in any study of pregnancy in these populations. One solution to this problem is to increase the period of observation, but that may introduce bias because temporal trends in the care of these patients may not be captured within the available data.
Other limitations to this study are inherent to all large administrative databases. We were unable to verify discharge diagnoses for the underlying diseases or pregnancy outcomes under study. Discharge diagnoses were provided by the treating physicians, without standardized application of diagnostic criteria. This could lead to under- or overreporting of cases. Misclassification of cases may have resulted in the exclusion of women with very mild forms of disease without significant pregnancy complications, thereby biasing the results toward worse pregnancy outcomes. More specifically, we were unable to identify specific subsets of underlying disease, which may have important prognostic implications for pregnancy. For example, ICD-9 coding does not allow for distinctions between limited and diffuse systemic sclerosis, and there may be some misclassification between primary or secondary pulmonary hypertension.
Although the overwhelming majority of deliveries and serious perinatal complications to mother and fetus occur in hospital settings, much of obstetric care of patients occurs in the outpatient setting and is, therefore, not captured in hospitalization databases. Accordingly, we have no data on early pregnancy losses or elective termination because these are largely evaluated and treated in the outpatient setting. It is probable that we have missed important data on the incidence and potential risk factors for early pregnancy loss, as well as data on women who elect to terminate pregnancy for medical or other reasons. Similarly, administrative databases such as the Nationwide Inpatient Sample often lack data on other variables of interest, including duration and severity of underlying disease, medication use, parity, prenatal care, and tobacco or alcohol use, that are often documented in outpatient visits but not in final discharge summaries. Therefore, we were unable to control for important confounders that are known to be associated with adverse pregnancy outcomes.
Finally, the database does not have unique patient identifiers; thus, the unit of analysis is hospitalization rather than patient. To address this issue, we performed separate analyses limited to hospitalizations associated with delivery of an infant, and this did not alter the conclusions drawn from the data. It was assumed that childbirth occurs once during each pregnancy and that each delivery represents data from a separate pregnancy. Similarly, because there were no unique patient identifiers, there was no way to link maternal to infant records, so information such as birth weight, congenital anomalies, neonatal hospitalization and death, and other infant-specific outcomes could not be evaluated.
In this study we sought to estimate the numbers of women with these relatively uncommon vasculopathic conditions who deliver annually throughout the United States. Despite noted limitations, the strengths of this study rest in the large numbers of pregnancies from an ethnically diverse nationwide sample of hospitalizations available for analysis. We have confirmed previous observations of adverse pregnancy outcomes in women with underlying primary pulmonary hypertension and sickle cell disease; additionally, we have found higher rates of pregnancy complications in this population-based sample of pregnant women with systemic sclerosis than what has been reported at tertiary-care centers. Up to 40% of women in our study were treated in nonteaching hospitals. Women with these vasculopathic conditions require extensive preconceptional counseling about risks of pregnancy; and all pregnancies should be considered high risk and monitored carefully for signs of complications.
1. Lilienfeld DE, Rubin LJ. Mortality from primary pulmonary hypertension in the United States, 1979–1996. Chest 2000;117:797–800.
2. Kawut SM, Horn EM, Berekashvili KK, Garofano RP, Goldsmith RL, Widlitz AC, et al. New predictors of outcome in idiopathic pulmonary arterial hypertension. Am J Cardiol 2005;95:199–203.
3. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Circumstances of death in adult sickle cell disease patients. Am J Hematol 2006;81:858–63.
4. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease-life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–44.
5. Fort AT, Morrison JC, Diggs LW, Fish SA, Berreras L. Counseling the patient with sickle cell disease about reproduction: pregnancy outcome does not justify the maternal risk. Am J Obstet Gynecol 1971;111:324–7.
6. Bonnin M, Mercier FJ, Sitbon O, Roger-Christoph S, Jais X, Humbert M, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology 2005;102:1133–7.
7. Steen VD. Scleroderma and pregnancy. Rheum Dis Clin North Am 1997;23:133–47.
8. Hassell K. Pregnancy and sickle cell disease. Hematol Oncol Clin North Am 2005;19:903–16.
9. Chung L, Flyckt RLR, Colon I, Shah AA, Druzin M, Chakravarty EF. Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease. Lupus 2006;15:595–9.
11. Steiner C, Elixhauser A, Schnaier J. The healthcare cost and utilization project: an overview. Eff Clin Pract 2002;5:143–51.
12. Hart AC, Hopkins C. ICD-9 CM professional for physicians. 6th ed. Salt Lake City (UT): Ingenix; 2004.
13. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol 2003;102:181–92.
14. Naeye RL. Factors that predispose to rupture of the fetal membranes. Obstet Gynecol 1982;60:93–8.
15. Resnik R. Intrauterine growth restriction. Obstet Gynecol 2002;99:490–6.
16. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–23.
17. Shen JJ, Tymkow C, MacMullen N. Disparities in maternal outcomes among four ethnic populations. Ethn Dis 2005;15:492–7.
18. Caughey AB, Stotland NE, Washington AE, Escobar GJ. Maternal ethnicity, paternal ethnicity, and parental ethnic discordance: predictors of preeclampsia. Obstet Gynecol 2005;106:156–61.
19. Brown HL, Chireau MV, Jallah Y, Howard D. The “Hispanic paradox”: an investigation of racial disparity in pregnancy outcomes at a tertiary care medical center. Am J Obstet Gynecol 2007;197:e1–7.
20. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol 1999 94:15–20.
21. Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 1998;31:1650–7.
22. Arias E, MacDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics—2002. Pediatrics 2003;112:1215–30.
23. Martin JA, Kochanek KD, Strobino DM, Guyer B, MacDorman MF. Annual summary of vital statistics—2003. Pediatrics 2005;115:619–34.
24. Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital statistics—2004 [published erratum appears in Pediatrics 2006;117:2338]. Pediatrics 2006;117:168–83.
25. Mayes MD, Lacey Jr, JV Beebe-Dimmer J, Gillespie BW, Cooper B, Liang TJ, et al. Prevalence, incidence, survival and disease characteristics of systemic sclerosis in a large U.S. population. Arthritis Rheum 2003;48:2246–55.
26. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007;66:940–4.
27. Steen VD. Pregnancy in scleroderma. Rheum Dis Clin N Am 2007;33:345–58.
28. Steen VD, Conte C, Day N, Ramsey-Goldman R, Medsger Jr. TA Pregnancy in women with systemic sclerosis. Arthritis Rheum 1989;32:151–7.
29. Doss BJ, Jacques SM, Mayes MD, Qureshi F. Maternal scleroderma: placental findings and perinatal outcome. Hum Pathol 1998;29:1524–30.
30. Ackerman J, Gonzalez EF, Gilbert-Barness E. Immunological studies of the placenta in maternal connective tissue disease. Pediatr Dev Pathol 1999;2:19–24.
31. McLaughlin VV. Classification and epidemiology of pulmonary hypertension. Cardiol Clin 2004;22:327–41.
32. Simonneau G, Galie N, Lewis JR, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S–12S.
33. McCaffrey RN, Dunn LJ. Primary pulmonary hypertension in pregnancy. Obstet Gynecol Surv 1964;19:567–91.
34. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (Hb S) allele and sickle cell disease: a HuGE review. Am J Epidemiol 2000;151:839–45.
35. Koshy M, Burd L, Wallace D, Moawad A, Baron J. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease: a randomized cooperative study. N Engl J Med 1988;319:1447–52.
36. Smith JA, Espeland M, Bellevue R, Bonds D, Brown AK, Koshy M. Pregnancy in sickle cell disease: experience of the Cooperative Study of Sickle Cell Disease. Obstet Gynecol 1996;87:199–204.
37. Sun PM, Wilburn W, Raynor BD, Jamieson D. Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia. Am J Obstet Gynecol 2001;184:1127–30.
38. Seoud MA, Cantwell C, Nobles G, Levy DL. Outcome of pregnancies complicated by sickle cell and sickle-C hemoglobinopathies. Am J Perinatol 1994;11:187–91.
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