Sickle cell diseases (SCDs) are a group of inherited single-gene autosomal recessive disorders caused by the sickle cell gene, which affects hemoglobin (Hb) structure. SCD includes sickle cell anemia with the SS genotype, some heterozygous conditions of the S gene, and other clinically abnormal Hbs such as beta thalassemia, HbC, HbD, and HbE among others. The primary manifestations of SCD are chronic hemolytic anemia and episodes of severe pain crises due to vasoocclusion.[1-3] Repeated vasoocclusive crises can affect multiple organ systems, and individuals with SCD have increased risks of stroke, renal dysfunction, pulmonary hypertension, retinal disease, and avascular necrosis.[2-5] Pregnant females with SCD experience these medical risks, as well as vascular effects to the gravid uterus and placenta, which creates an additional risk for the mother and fetus. In females with SCD, the underlying anemia and multiorgan dysfunction can complicate pregnancy by affecting the cardiovascular, renal, hematologic, and respiratory systems.[6-10] Improvements in medical care and treatment for individuals with SCD, coupled with advancements in neonatal care, have contributed to a decline in morbidity and mortality both for mother and fetus; however, the physiologic changes in pregnancy still carry important clinical risks for some patients with SCD.[8, 9]
Previous studies have reported that females with SCD had a higher prevalence of preeclampsia, lung disease, and heart disease during the antenatal, intrapartum, or postpartum periods compared with women without hemoglobinopathies. In addition, the odds of fetal death, preterm birth, low birthweight, and cesarean delivery were higher for females with SCD compared with those with no reported hemoglobinopathies after adjusting for maternal age, education, parity, plurality, insurance status at delivery, prenatal care utilization, smoking, and infant sex.[6-9] The maternal mortality rate was 1.6 per 1000 deliveries in patients, compared to 0.1 per 1000 in women without SCD. Pregnant women with SCD had a higher risk for preeclampsia, eclampsia, venous thromboembolism, cardiomyopathy, intrauterine fetal demise, and intrauterine growth restriction. The odds of fetal death among deliveries to women with SCD were 2.2 times greater than those without SCD. The odds of preterm delivery, low birthweight, and having babies small for gestational age were 1.5-fold greater among women with SCD.
Patients with SCD who survive childhood and who become pregnant are likely to suffer aggravated morbidity and mortality. Low- and middle-income countries generally report increased maternal and perinatal morbidity and mortality in association with SCD.[9-14] In Turkey, maternal and fetal morbidity and mortality remain a major problem in pregnant patients with SCD. This retrospective study investigates the pregnancy outcomes of SCD patients who underwent prophylactic red blood cell exchange (RBCX) procedures from January 2000 to March 2013, and results were compared with a control group.
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- Patients and Methods
- Conflict of Interest
SCD is an inherited hemoglobinopathy that affects multiple systems with increased incidence of maternal and fetal complications in pregnant women.[6, 8] These include an increased rate of urinary tract infections, as well as major complications such as septicemia, toxemia, and thrombophlebitis arising close to the expected time of delivery.[6, 8-14, 21] In Turkey, hemoglobinopathies are the most common genetic disease and prevalence studies in the Cukurova region of southern Turkey have reported a 10% incidence of sickle cell trait. Hence, SCD is an important public health problem in our country and region.[22, 23] SCDs have heterogeneous phenotype and shown to different clinical abbreviation among the communities. Despite improvements in medical management, SCD remains associated with severe morbidity and decreased survival. With the added burden of pregnancy, follow-up of these patients is difficult. We have followed two pregnant sickle cell patients and they died before the RBCX procedure from vasoocclusive crisis. We become aware of another two SCD patients who died from vasoocclusive crisis during pregnancy in a Regional Authoritative Meeting for evaluation of maternal death arranged by Ministry of Health, Adana Division of Mother and Child Health.
RBCX is an underutilized therapy for both prevention and management of SCD complications. Exchange transfusions improve the control of blood volume and viscosity, while decreasing the risk of transfusion-related hemochromatosis. Subjects with SCD who are treated with long-term transfusion programs seem to be susceptible to iron-induced toxicity, including cardiac abnormalities and death. RBCX may be a safe, simple, and efficient method for reducing iron accumulation during long-term transfusion therapy. RBCX has been shown to reduce iron overload in patients with SCD who are treated with a long-term transfusion regimen. We measured plasma ferritin level in neither group but there were no symptoms of iron overload.
Exchange transfusion is indicated as a prophylactic measure to prevent the recurrence of cerebrovascular accidents and before extensive surgery.[24-27] Studies on prophylactic transfusions in SCD patients do not reach the same conclusions: while some indicate that they do not alter the outcome of pregnancy or only decrease the number of vasoocclusive events[28-30] others indicate that they might favorably affect overall maternal and fetal health. A pragmatic approach may be to avoid routine prophylactic transfusions for an uncomplicated pregnancy, but to consider this option for women who develop severe SCD complications[29, 32, 33] or who are known to be at high risk for vasoocclusive events.
A multicenter study of pregnant patients with SCD in the United Kingdom investigated the effects of prophylactic blood transfusion on maternal and fetal outcomes and recommended exchange transfusions in all females with homozygous SCD beginning at 28 weeks of gestation to reduce the risk of maternal complications in the third trimester and puerperium. However, earlier prophylactic blood transfusion programs can be beneficial in females with poor obstetric and hematologic histories.
Some studies have shown that the use of prophylactic RBCX in pregnancy can be effective and well tolerated by the mother to be as well as the fetuses.[31, 34, 35] In particular, this procedure may lead to maternal benefits, such as a reduced number and duration of hospital admissions, a reduction in the number of simple top-up transfusions, and less need for other supportive therapy.[31, 35] Neonatal advantages are also described, since it has been proven that the number of preterm deliveries, the prevalence of low-birthweight fetuses, and the perinatal death rate are significantly lower in children of routinely transfused SCD patients.
Our study patients had end organ failures before pregnancy and they were admitted to hospital several times due to causes like painful vasoocclusive crises (n = 24), recurrent infections (n = 20), acute chest syndrome (n = 5), leg ulcers (n = 6), hepatic necrosis (n = 1), neurologic events (n = 2), and bone necrosis (n = 2) so they had undergone RBCX procedures. Our previous clinic experience also shows that automated RBCX is an effective and safe procedure in patients with SCD.[24, 36-38] Considering the aforementioned issues, we established a policy to perform RBCX for management of SCD patients during pregnancy. We performed 39 prophylactic RBCX procedures in 24 pregnant SCD patients in the second and third trimesters. Four patients who experienced vasoocclusive crisis in the first trimester and one patient who experienced vasoocclusive crisis in the third trimester received RBCX for treatment. While four out of five patients who experienced vasoocclusive crisis and who did not receive RBCX were lost in the control group, in the study group, four patients who experienced vasoocclusive crisis in the first trimester recovered from crisis as they underwent therapeutic RBCX procedure. These four patients in the study group did not experience vasoocclusive crisis during the second and the third trimesters of pregnancy as they had undergone prophylactic RBCX procedure. It should be stated that none of the patients who underwent RBCX procedure in the second and third trimesters experienced vasoocclusive crisis, whereas four out of five patients in the control group who experienced vasoocclusive crises died as they could not undergo RBCX procedure.
Maternal mortality, as well as the incidence of cesarean section, preterm labor, and pregnancy morbidity, is higher among females with SCD. More than 50% of obstetric patients with SCD will have a pain crisis during pregnancy, and the management of these can be challenging. In our study, there were no crises during pregnancy among the SCD patients who underwent prophylactic RBCX procedures. Koshy and colleagues showed that prophylactic transfusion significantly reduced the incidence of painful crisis of SCD and substantially reduced the cumulative incidence of other complications in pregnant women during gravidity. We performed RBCX procedures in four patients with an indication for vasoocclusive crisis during pregnancy. These patients completed their pregnancies without any other problems. There was no fetal, neonatal, or maternal morbidity. These results establish the RBCX procedure as a flexible and useful means of managing gravid patients with sickle hemoglobinopathies.
Our study has some limitations. First is the small number of patients in control group. Second is the missing data in control group as records of another institution had to be used for analysis. For example, we could not access amniotic fluid L/S ratio, direct or IAT results, cord blood pH, and APGAR score records in some of the patients in the control group. For this reason we could not compare these variables statistically between the two groups. Nevertheless, we may conclude that RBCX procedure during pregnancy is favorable because while four patients in control group were lost, there were no deaths in the study group and also, while there was one intrauterine loss in the control group, no intrauterine losses occurred in the study group. However, it should be stated that peripartum and neonatal complications did not occur in patients in the control group who achieved term. In terms of fetal complications during the pregnancy and even after the delivery, there was no significance between study and control groups in terms of fetal complications. However, we observed significantly higher maternal complication rates in the control group. One patient in the control group who developed vasoocclusive crisis could be successfully managed without RBCX procedure through other treatment modalities including simple transfusion, hydration therapy, antibiotic, and analgesic drugs.
Four complications were experienced in a total of 43 RBCX procedures. A minimal or mild allergic reaction was observed and treated using medications; no fever was observed. We attempted to avoid procedure-related complications by using leukoreduced cell suspensions and by achieving a postapheresis Hct value that was identical to the steady-state value. No technical problems related to cell separators were noted, so we may conclude that RBCX is a safe procedure in pregnant women due to low, tolerable, and manageable procedure-related complication rates.
The timing of delivery in pregnant SCD has not been assessed in randomized controlled trials. Observational studies show increased perinatal mortality particularly during late pregnancy, and there is also an increased risk of complications such as preeclampsia, abruption, and acute sickle pain. Most women will go into spontaneous labor, and vaginal delivery is the recommended mode of delivery.[13, 21, 32] Nevertheless, the rate of cesarean section was high in our study group (22 patients, 91.6%) and the control group (five patients, 62.5%). There were no surgical and medical complications during or after cesarean section.
Pregnant females with SCD have an increased risk of maternal and perinatal mortality and morbidity, which can be reduced by effective multidisciplinary care throughout pregnancy. Preconceptual optimization of SCD is advised, including screening for chronic disease complications and medication review. Regular antenatal review is essential and ultrasound monitoring of fetal growth, at least four times per week, beginning at 24 weeks, is recommended.[14, 40-42] Blood should be transfused for pregnant females with acute anemia, acute stroke, or acute chest syndrome, but the role of prophylactic blood transfusion is not clear and further trials are necessary.
Olujohungbe and coworkers reported alloimmunization rates as 8% to 72% in multiple transfused patients with SCD. This ratio was found as 16.6% in our study and this result was comparable with the literature. Although our study has put forward the fact that prophylactic RBCX is a safe and reliable method in pregnant women with SCD, we recommend close monitorization of these patients for alloimmunization.
Pregnant patients with SCD require close surveillance by multidisciplinary teams, which should include hematologists, obstetricians, anesthetists, and pediatricians who are experienced in the management of this disorder. Our team manages adult sickle cell patients and has great experience as we have been performing RBCX procedure for more than 10 years to treat severe cases of SCD.[24, 36-38]
In conclusion, our study demonstrates that prophylactic RBCX during pregnancy is a feasible and safe procedure for prevention of HbS-associated complications in patients with SCD. Although these results were favorable, further randomized multicenter studies are required to compare prophylactic RBCX and other treatment modalities in gravid sickle cell patients.