SSc, PPH, SCD 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
]. More recently, pregnancies have become slightly more common among women with these underlying diseases [5
]. 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 NIS from the years 2002–2004, we compared pregnancy outcomes among women with SSc, PPH, and SCD to 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
]. We estimated nearly 4,400 deliveries among women with SCD during the three years of observation, compared with a much smaller number of approximately 504 deliveries in women with SSc and 182 in women with PPH. In addition, we found women with SSc and PPH 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 SSc, PPH, and SCD compared with the general obstetric population. The increased risk of developing these pregnancy complications persisted after adjustment for maternal age, race/ethnicity, and co-morbid conditions including diabetes mellitus, renal failure, and the antiphospholipid antibody syndrome.
SSc is a rare female-predominant autoimmune disease of unclear etiology that is characterized by progressive fibrosis of the skin and internal organs and a non-inflammatory vasculopathy [25
]. 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
]. Previous studies of pregnancy outcomes in women with SSc at single tertiary care centers have shown an increased frequency of preterm births and small for gestational age infants [9
]. Likewise, our study showed a 3.7-fold increased risk of IUGR in SSc-associated pregnancies compared with controls. These findings could be explained by the underlying vasculopathy associated with SSc leading to placental insufficiency and infarction [29
]. Earlier studies did not find high rates of hypertensive disorders of pregnancy in patients with SSc [9
]. In contrast, our study found a nearly four-fold increased risk for HTN in SSc-associated pregnancies compared with controls. It is possible that SSc patients treated at tertiary care centers had more vigilant surveillance and treatment of HTN 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
]. Few studies have evaluated pregnancy outcomes in patients with PPH [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
]. Our study confirms that women with PPH have increased risks for complications during pregnancy. Although women with PPH were older than control patients, multivariable analyses demonstrated substantially worse outcomes. More than half of their hospitalizations were for non-delivery 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 PPH had an almost 5-fold increase in HTN and substantially increased LOS for deliveries compared with controls.
The racial composition of patients in our study included a higher percentage of minority women with PPH than in a previously reported national registry [16
]. While 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 PPH in the absence of the physiological stressors of pregnancy [1
], concerted efforts should be made to counsel PPH patients from all racial groups of the high risks associated with pregnancy.
SCD is an autosomal recessive genetic disorder to the β-globin gene affecting approximately 50,000 Americans [34
] 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 SCD 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 two percent, and many women are electing to proceed with pregnancies [8
]. Previous studies of pregnancy in women with SCD 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 SCD in the United States have shown young age at pregnancy, numerous antepartum admissions for complications of underlying SCD (pain crises, acute chest crises, infections, and symptomatic anemia), longer hospital stays, and increased rates of IUGR [36
]. Results from our study confirm these outcomes in a much larger cohort of nearly 4,400 deliveries over three years of observation. Risks of all adverse pregnancy outcomes under study were independently associated with SCD, suggesting that pregnancy outcomes observed at tertiary care centers may be similar to those seen across the US. The early age of pregnancy we found is consistent with other studies of SCD patients in the US [36
], and may be a reflection of both diagnosis of this genetic disease during childhood before the childbearing years, as well as a concern for early mortality despite improvements in care [4
Several limitations of the study require discussion. Despite collecting data over three years, there were still very few pregnancies complicated by SSc or PPH. The small numbers of women with SSc and PPH 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; however, that may introduce bias as 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 over-reporting 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 SSc; 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 obstetrical 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 as 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 NIS 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 PPH and SCD; additionally we have found higher rates of pregnancy complications in this population-based sample of pregnant women with SSc than what has been reported at tertiary-care centers. Up to 40% of women in our study were treated in non-teaching 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.