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Morbidity associated with sickle cell disease in pregnancy

      Objective

      The purpose of this study was to identify morbidity that is associated with sickle cell disease (SCD) in pregnancy.

      Study Design

      The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality for the years 2000-2003 was queried for all pregnancy-related discharges with a diagnosis of SCD.

      Results

      There were 17,952 deliveries (0.1% of the total) to women with SCD. There were 10 deaths (72.4 per 100,000 deliveries). Cerebral vein thrombosis, pneumonia, pyelonephritis, deep venous thrombosis, transfusion, postpartum infection, sepsis, and systemic inflammatory response syndrome were much more common among women with SCD. They were more likely to undergo cesarean delivery, to experience pregnancy-related complications (such as gestational hypertension/preeclampsia, eclampsia, abruption, antepartum bleeding, preterm labor, and fetal growth restriction), and to have cardiomyopathy or pulmonary hypertension at the time of delivery.

      Conclusion

      Women with sickle cell disease are at greater risk for morbidity in pregnancy than previously estimated.

      Key words

      Sickle cell disease (SCD), which affects 1 in 600 African Americans, is the most common hemoglobinopathy in the United States.
      • Samuels P.
      Hematologic complications of pregnancy.
      Pregnancy in women with SCD has been associated with increased incidence of medical- and pregnancy-related complications.
      • Hassell K.
      Pregnancy and sickle cell disease.
      Because of medical advances in obstetrics and neonatology, more women with SCD are attempting pregnancy.
      • Hassell K.
      Pregnancy and sickle cell disease.
      American College of Obstetrics and Gynecology Committee on Obstetrics
      Hemoglobinopathies in pregnancy: practice bulletin no.: 78.
      • Rappaport V.J.
      • Velasquez M.
      • Williams K.
      Hemoglobinopathies in pregnancy.
      Mortality rates among pregnant women with SCD have been falling consistently since the 1970s.
      • Powars D.R.
      • Sandhu M.
      • Niland-Weiss J.
      • Johnson C.
      • Bruce S.
      • Manning P.R.
      Pregnancy in sickle cell disease.
      To date, studies that have focused on pregnancy-related events in patients with SCD have been limited by small sample sizes or to single centers.
      For Editors' Commentary, see Table of Contents
      Although most studies of SCD in pregnancy document risks to the fetus that include preterm labor and intrauterine growth restriction,
      • Sun P.M.
      • Wilburn W.
      • Raynor B.D.
      • Jamieson D.
      Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia.
      • Smith J.A.
      • Espeland M.
      • Bellevue R.
      • Bonds D.
      • Brown A.K.
      • Koshy M.
      Pregnancy in sickle cell disease: experience of the Cooperative Study of Sickle Cell Disease.
      there are limited data about maternal outcomes. The women themselves appear to be at risk for multiple pregnancy-related complications (such as pregnancy-induced hypertension, preeclampsia, and pyelonephritis). However, current research is contradictory regarding the impact of these conditions.
      • Sun P.M.
      • Wilburn W.
      • Raynor B.D.
      • Jamieson D.
      Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia.
      • Smith J.A.
      • Espeland M.
      • Bellevue R.
      • Bonds D.
      • Brown A.K.
      • Koshy M.
      Pregnancy in sickle cell disease: experience of the Cooperative Study of Sickle Cell Disease.
      • Serjeant G.R.
      • Loy L.L.
      • Crowther M.
      • Hambleton I.R.
      • Thame M.
      Outcome of pregnancy in homozygous sickle cell disease.
      Most studies fail to demonstrate an increased risk of preeclampsia or eclampsia in pregnant women with SCD.
      • Sun P.M.
      • Wilburn W.
      • Raynor B.D.
      • Jamieson D.
      Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia.
      • Serjeant G.R.
      • Loy L.L.
      • Crowther M.
      • Hambleton I.R.
      • Thame M.
      Outcome of pregnancy in homozygous sickle cell disease.
      Most deaths in pregnant women with SCD are attributable to thromboembolic events,
      • Hassell K.
      Pregnancy and sickle cell disease.
      yet the overall risk of thromboembolic events in pregnant women with SCD has never been explored fully. The consequences of infections, which may result in sepsis, have not been studied.
      The purpose of this study was to identify the association between SCD and the occurrence of adverse maternal and fetal outcomes that are associated with pregnancy in the United States.

      Materials and Methods

      The Nationwide Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality for years 2000-2003 was queried for all pregnancy-related discharges with a diagnosis of SCD. The NIS contains data from 5-8 million hospital stays from approximately 1000 hospitals and is the largest all-payer inpatient care database in the United States. The NIS is a 20% stratified sample of all discharges and allows for national estimates. Included in this sample are general hospitals and academic medical centers. Rehabilitation hospitals, long-term hospitals, psychiatric hospitals, and alcoholism or chemical-dependency treatment facilities are excluded. The hospitals are divided into strata based on ownership, bed size, teaching status, urban compared with rural location, and region. Sampling probabilities are proportional to the number of hospitals in each stratum. The sampling frame compromises 90% of all discharges from US hospitals.
      Overview of the Nationwide Inpatient Sample (NIS) 2000.
      Introduction to the Nationwide Inpatient Sample (NIS) 2002.
      Information included in the NIS is similar to that in a typical discharge abstract with safeguards to protect the privacy of individual patients, physicians, and hospitals. Data are available for the purposes of aggregate statistical reporting, analysis, and research. Although the nature of the data is limited to discharge diagnoses and demographic information, the NIS allows for the study of relatively rare conditions (such as pregnancy in women with SCD).
      Overview of the Nationwide Inpatient Sample (NIS) 2000.
      Introduction to the Nationwide Inpatient Sample (NIS) 2002.
      Records were identified in the NIS by International Classification of Diseases, Ninth Revision (ICD-9) codes for all pregnancy-related discharges for the years 2000-2003 (the latest data that were available at the inception of the study). The pregnancy-related discharge records that were included in the sample from that period were classified as to whether they were an antepartum admission, an admission at the time of delivery, or a postpartum admission. An antepartum admission was defined as any discharge record with a pregnancy-related code (ICD-9 codes 630-648) that did not also include a delivery code. An admission for delivery was defined as any discharge record that included a delivery code (ICD-9 codes 74 for cesarean section 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 660-677) and did not also include a delivery code.
      The ICD-9 codes that were used to identify discharges with SCD were 282.4 and 282.6. For comorbidities, 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.
      The sampling frame for events that are listed in Table 1 (thrombotic events, infections, transfusions, and hemorrhages) was antepartum admissions, delivery admissions, and postpartum admissions. To avoid overestimation of conditions that could be present on >1 admission, the sampling frame for the chronic medical conditions that are listed in Table 2 and pregnancy-related complications that are listed in Table 3 was limited to discharges that included a delivery code.
      TABLE 1Events that complicate antepartum, delivery, and postpartum periods among women with SCD
      DiagnosisICD-9 codesOR95% CIP value
      Stroke431, 434, 436, 674.02.00.6-6.9.25
      Cerebral vein thrombosis325, 671.54.92.2-10.9<.001
      Myocardial infarction4100
      Pneumonia480, 481, 482, 483, 486, 487.19.88.0-12.0<.001
      Pyelonephritis590.1, 590.81.31.0-1.8.05
      Pulmonary embolus673.2, 415.11.70.9-3.1.08
      Deep venous thrombosis671.3, 671.4, 451.1, 451.22.51.5-4.1<.001
      TransfusionsCPT codes 9900, 9902, 9904, 990722.518.7-27.0<.001
      Postpartum infection670, 6721.41.1-1.7<.001
      Postpartum hemorrhage666, 669.10.50.3-0.6<.001
      Sepsis790.7, 0386.84.4-10.5<.001
      Systemic inflammatory response syndrome995.9212.62.1-13.6.01
      Villers. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008.
      TABLE 2Medical conditions present at time of delivery in patients with SCD
      DiagnosisICD-9 codesOR95% CIP value
      Hypertension401, 4050.60.4-1.0.06
      Cardiomyopathy4253.71.8-7.5<.001
      Pulmonary hypertension4166.32.1-18.8<.001
      Renal failure639.3, 584, 585, 5863.50.8-14.9.09
      Anemia648.2, 280, 28190.177.9-104.2<.001
      Obesity278.00.90.6-1.2.41
      Smoking305.1, V15.820.60.4-0.8<.001
      Substance abuse648.3, 305.0, 305.2, 305.3, 305.4, 305.5, 305.6, 305.71.00.8-1.1.92
      Villers. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008.
      TABLE 3Pregnancy-related complications present at time of delivery in patients with SCD
      DiagnosisICD-9 codesOR95% CIP value
      Gestational hypertension and preeclampsia642.0, 642.1, 642.2, 642.3, 642.4, 642.5, 642.7, 642.91.21.1-1.3.01
      Eclampsia642.63.21.8-6.0<.001
      Abruption641.21.61.2-2.1<.001
      Antepartum bleeding640.0, 640.8, 640.9, 641.1, 641.3, 641.8, 641.91.71.2-2.2<.001
      Preterm labor6441.41.3-1.6<.001
      Intrauterine growth restriction656.52.21.8-2.6<.001
      Intrauterine fetal death656.41.10.8-1.7.62
      Gestational diabetes mellitus648.81.00.8-1.2.74
      Asymptomatic bacteruria646.56.83.1-14.9<.001
      Genitourinary tract infection646.62.31.9-2.7<.001
      Villers. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008.
      The analysis accounted for the cluster sampling that was used by the NIS. Data were weighted by the strata's primary sampling units (hospitals) and sampling weights based on the NIS sampling design. STATA software (version 8.0; Stata Corp LP, College Station, TX) and the SVY (survey data) commands with these weights were used for both descriptive and inferential analyses. Two-way chi-square tests generated cell frequencies and standard deviations for demographics, events, medical conditions, and pregnancy-related complications. Multivariable logistic regression produced odds ratios (ORs) and 95% CIs.
      The protocol was reviewed and approved by the Duke University Medical Center Institutional Review Board.

      Results

      From 2000-2003, there were 18,345,538 pregnancy-related discharges. Of these discharges, 25,612 were to patients with SCD. There were 17,952 deliveries among women with SCD and 16,756,944 deliveries among women without SCD. There were 7775 discharges with a diagnosis of sickle cell crisis. Ten pregnant women were diagnosed with acute chest syndrome. Women with SCD (mean age, 27.8 years) were slightly older than all other women, whose mean age was 27.5 years. The difference, although small, was statistically significant.
      Women with SCD had a higher rate of cesarean delivery, 31% vs 25%, compared with other women (P < .001).
      There were 10 deaths in the sickle cell group, which was approximately 1% of all maternal deaths. The mortality rate for women with SCD was 72.4 deaths per 100,000 deliveries, compared with a mortality rate of 12.7 deaths per 100,000 deliveries for women without SCD.
      As shown in Table 1, compared with women without SCD, women with SCD were more likely to experience infections and thromboembolic events. The following medical events were all associated with an increased likelihood of occurrence in pregnant women with SCD when compared with pregnant women without SCD: cerebral vein thrombosis (OR, 4.9; 95% CI, 2.2-10.9), pneumonia (OR, 9.8; 95% CI, 8.0-12.0), pyelonephritis (OR, 1.3; 95% CI, 1.0-1.8), deep vein thrombosis (OR, 2.5; 95% CI, 1.5-4.1), transfusions (OR, 22.5; 95% CI, 18.7-27.0), postpartum infection (OR, 1.4; 95% CI, 1.1-1.7), sepsis (OR, 6.8; 95% CI, 4.4-10.5), and systemic inflammatory response syndrome (SIRS; OR, 12.6; 95% CI, 2.1-13.6). Women with SCD may have been more likely to experience stroke and pulmonary embolus, but the odds ratios were not significant. There were no cases of myocardial infarctions among pregnant women with SCD. The risk for postpartum hemorrhage was actually reduced in women with SCD (OR, 0.5; 95% CI, 0.3-0.6).
      Table 2 depicts medical conditions that were present at the time of delivery among women with SCD. Subjects in this cohort were more likely to experience cardiomyopathy (OR, 3.7; 95% CI, 1.8-7.5) and pulmonary hypertension (OR, 6.3; 95% CI, 2.1-18.8). An association between systemic hypertension or renal failure with pregnancy in SCD was not observed. Additionally, women with SCD were no more likely to have a diagnosis of obesity or substance abuse, and they were less likely to smoke (OR, 0.6; 95% CI, 0.4-0.8).
      Pregnancy-related complications that were present among women with SCD are presented in Table 3. With the exception of intrauterine fetal death and gestational diabetes mellitus, all pregnancy-related complications that were studied were significantly more likely to be present among women with SCD. Pregnancy-related complications that were associated significantly with SCD included gestational hypertension and preeclampsia (OR, 1.2; 95% CI, 1.1-1.3), eclampsia (OR, 3.2; 95% CI, 1.8-6.0), abruption (OR, 1.6; 95% CI, 1.2-2.1), antepartum bleeding (OR, 1.7; 95% CI, 1.2-2.2), preterm labor (OR, 1.4; 95% CI, 1.3-1.6), fetal growth restriction (OR, 2.2; 95% CI, 1.8-2.6), asymptomatic bacteruria (OR, 6.8; 95% CI, 3.1-14.9), and genitourinary tract infection (OR, 2.3; 95% CI, 1.9-2.7).

      Comment

      This study raises new concerns about SCD in pregnancy. Women with SCD are known to have high-risk pregnancies mainly because of fetal risks; this study documents the variety and extent of the maternal risks that these women face. Women with SCD are at an increased risk to experience both medical complications (such as infections and thromboembolic events) and pregnancy-related complications (such as preeclampsia, eclampsia, preterm labor, placental abruption, and fetal growth restriction). The risk for experiencing these complications is significantly higher than in other women. SCD complicated 0.1% of pregnancies but accounted for 1% of all maternal deaths.
      Occurrence of gestational hypertension and preeclampsia is increased in women with SCD. Also, these women are more than 3 times as likely to undergo an eclamptic seizure than are women who do not have SCD.
      Thromboembolic events have been implicated in maternal death from SCD. Women with SCD are more likely to have cerebral vein thrombosis or deep vein thrombosis. Another study that evaluated venous thromboembolism in SCD found a preponderance of pulmonary embolism over deep vein thrombosis.
      • Stein P.D.
      • Beemath A.
      • Meyers F.A.
      • Skaf E.
      • Olson R.E.
      Deep vein thrombosis and pulmonary embolism in hospitalized patient with sickle cell disease.
      We found the opposite. Perhaps this is due to the general preponderance of deep vein thrombosis (which accounts for 80% of venous thromboembolism) over pulmonary embolism (which accounts for 20% of venous thromboembolism) in pregnancy.
      • James A.H.
      • Jamison M.G.
      • Brancazio L.R.
      • Myers E.R.
      Venous thromboembolism during pregnancy and the postpartum period.
      Noteworthy, women in this study were less likely to have a postpartum hemorrhage, perhaps because of smaller fetal size or to hypercoagulability that is associated with SCD.
      Data in this study showed that women with SCD are more likely to experience pneumonia, pyelonephritis, postpartum infection, sepsis, and SIRS than women without SCD. At the time of delivery, women with SCD were more likely to have asymptomatic bacteruria and genitourinary infections. Our findings support findings from previous studies,
      • Hassell K.
      Pregnancy and sickle cell disease.
      but this study adds information that suggests that women with SCD may be at significantly higher risk of the development of catastrophic infections that include sepsis and SIRS.
      Pregnancy has been shown to exacerbate sickle cell pain crises
      American College of Obstetrics and Gynecology Committee on Obstetrics
      Hemoglobinopathies in pregnancy: practice bulletin no.: 78.
      and to increase the rate of hospitalizations. A large number of antepartum admissions are due to pain crises. Acute chest syndrome, although uncommon during pregnancy, is another cause of antepartum admissions. SCD worsens during pregnancy and is responsible for morbidity during pregnancy.
      Pulmonary hypertension is acknowledged increasingly as a complication of SCD. It has been described in up to 30% of this population and is associated with a high mortality rate.
      • Ataga K.I.
      • Sood N.
      • De Gent G.
      • et al.
      Pulmonary hypertension in sickle cell disease.
      The statistically significant presence of pulmonary hypertension at delivery supports the previous observation and warrants the need for appropriate evaluation and management. Obstetricians must work closely with hematologists to prevent further complications and associated death.
      In the present study, cesarean deliveries were more likely to be performed for pregnant women with SCD than for those women without SCD. Cesarean deliveries are likely undertaken because of fetal compromise. Closer fetal monitoring and a lower threshold to tolerate nonreassuring fetal heart rate patterns may contribute to this trend. An increased risk of intrauterine fetal death was not found in this study. This may be attributed to improved fetal monitoring and the increased likelihood of intervention.
      The nature of this database limits the number of conclusions that can be drawn about adverse pregnancy outcomes and SCD because data for this study were drawn exclusively from discharge record abstractions. It is known that complications in patients with SCD vary with the genotype (hemoglobin SS, hemoglobin SC and hemoglobin S-beta + thal) and with the degree of anemia.
      • Rappaport V.J.
      • Velasquez M.
      • Williams K.
      Hemoglobinopathies in pregnancy.
      • Seoud M.A.
      • Cantwell C.
      • Nobles G.
      • Levy D.L.
      Outcome of pregnancies complicated by sickle cell and sickle-C hemoglobinopathies.
      Before 2004, the ICD-9 code 282.4 lacked specificity. Although most of the discharges with an ICD-9 code of 282.4 were S-beta + thal, the code also included discharges with a diagnosis of thalassemia. The more precise ICD-9 codes for S-beta + thal, 282.41 and 282.41, were not introduced until 2004. Detailed information is not available from a dataset of this type, which means that the pregnancy-related risks may be underestimated for certain subsets of this population and overestimated for others. Also, this study was not able to quantify other risks that women with SCD face (such as occurrence of spontaneous first-trimester abortions), because this condition usually is managed in the outpatient setting, these data were not captured.
      Discharge databases inherently are open to questions regarding accuracy of coding. A recent investigation of an obstetric discharge database confirmed that the diagnoses that are generated are generally accurate and provide reliable information.
      • Yasmeen S.
      • Romano P.S.
      • Schembri M.E.
      • Keyzer J.M.
      • Gilbert W.M.
      Accuracy of obstetric diagnoses and procedures in hospital discharge data.
      Despite the limitations of the database that was used in this study, the design of our study allowed for the examination of large numbers of patients to estimate maternal mortality rates and odds ratios for various events, medical conditions, and pregnancy-related conditions that would otherwise have been hard to quantify.
      Good, committed obstetric care has no doubt reduced the risks that are faced by women with SCD. Interventions and therapies that did not exist 30 years ago are now available to pregnant women on a routine basis. Intensive fetal surveillance likely has contributed to the finding that intrauterine death was not a significant adverse outcome in this study. However, the maternal mortality rate for women with SCD is 6 times greater than the mortality rate for women without SCD. Despite the potential promise of prophylactic red-cell transfusions, a randomized trial in pregnant women with SCD failed to demonstrate a significant reduction in maternal or fetal complications.
      • 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.
      Although there have been many remarkable improvements in the survival of women with SCD during pregnancy, they are still at a significantly increased risk of morbidity and death compared with other women. Understanding the events, medical conditions, and pregnancy-related complications that women with SCD experience will allow opportunities for prevention and intervention.

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