http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(6): 685–689 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.928855
ORIGINAL ARTICLE
Pregnancy in patients with sickle cell disease: maternal and perinatal outcomes Vanessa Maria Fenelon Costa, M.D., M.Sc1,2, Marcos Borato Viana, M.D., Ph.D.3, and Regina Ame´lia Lopes Pessoa Aguiar, M.D., Ph.D.2,3 1
Hospital Odilon Behrens, Belo Horizonte, Brasil, 2Programa de Po´s-graduac¸a˜o em Sau´de da Mulher, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil, and 3Nu´cleo de Ac¸o˜es e Pesquisa em Apoio Diagno´stico (NUPAD), Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil Abstract
Keywords
Objective: To compare obstetrical, hematological and neonatal outcomes of pregnant women with or without sickle cell disease (SCD). Methods: A prospective study of 60 pregnancies of 58 women with SCD (29 SCD-SS and 29 SCDSC) compared with 192 pregnancies in 187 healthy pregnant women was carried out from January 2009 to August 2011. Results: Compared to controls, the SCD group had higher rate of preterm delivery (p50.001, OR ¼ 4.96, 95% CI 2.57–9.59), higher cesarean rate (p50.001, OR ¼ 5.00, CI 2.65–9.45), more frequent deep vein thrombosis (p ¼ 0.003), and urinary infection (p ¼ 0.001, OR ¼ 3.31, CI 1.63– 6.73), higher prevalence of small for gestational age babies (p ¼ 0.019, OR ¼ 2.66, CI 1.15–6.17), and more frequent baby admissions to progressive care unit (p50.001, OR ¼ 4.89, CI 2.26–10.6). Maternal death rate was also higher among women with SCD (p ¼ 0.056). All adverse events were more frequent in the SS subgroup. Babies from the SS subgroup had the lowest weight at birth (2080 g) compared to SC (2737 g; p50.001) and controls (3035 g). A multivariate analysis confirmed painful episodes and SS genotype as factors contributing to preterm delivery. Conclusion: SCD pregnant women – especially those in the SS subgroup – are more prone to experience perinatal and maternal complications in comparison with pregnant women without SCD.
Acute chest syndrome, albuminuria, hemoglobin SC, preterm delivery, sickle cell anemia
Introduction Sickle cell disease (SCD) is an inherited disease in which the predominant presence of sickle hemoglobin (HbS) in red blood cells leads to sickling, vaso-occlusion, and chronic hemolytic anemia. This results in decreased delivery of oxygen to tissues and causes acute and chronic tissue and organ injury. SCD is associated with high mortality rates, especially in young children. It is usually diagnosed in childhood, ideally through newborn screening. Affected infants typically become symptomatic after four months of life [1,2]. Pregnant women with SCD may experience hematological and obstetrical complications, such as preeclampsia, severe anemia, frequent painful crises and infections [3]. Placental ischemia and endothelial damage may be risk factors for those complications. Retrospective data suggest higher mortality rate in SCD pregnant women when compared to the general population [4–6]. The spontaneous abortion rate is variable. It was 35.7% for SS patients against a 10.4% in a control group [3].
History Received 6 March 2014 Accepted 25 May 2014 Published online 26 June 2014
Peripartum complications are more common in SS patients than in those who are AA or SC [1,4,6,7]. SCD complications requiring blood transfusion seemed to be associated with increased risk of prematurity and pre-eclampsia [5,6]. The rate of perinatal mortality in SCD pregnant women used to be as high as 53% [3]. It has reduced, however, to below 5% owing to improved obstetric and neonatal care provided over the last three decades [4,5,8]. Low birth weight and intrauterine growth retardation (IUGR) may be the result of chronic anemia and placental vaso-occlusion, but recent studies have not found significant correlation between weight at birth and the degree of anemia of mothers with SCD [9,10]. This study aimed to compare the clinical course of pregnancies in women with SCD with that of a control group. It focused on maternal and perinatal outcomes and risk factors associated with preterm delivery. In addition, clinical outcome was compared between SS and SC subgroups.
Methods Address for correspondence: Regina Ame´lia Lopes Pessoa Aguiar, M.D., Ph.D., Nu´cleo de Ac¸o˜es e Pesquisa em Apoio Diagno´stico (NUPAD), Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil. E-mail: [email protected]
This prospective cohort study was approved by the Ethics Committees of the partner institutions. All patients signed informed consent forms.
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J Matern Fetal Neonatal Med, 2015; 28(6): 685–689
The pregnant women were followed at the maternity departments of Odilon Behrens Municipal Hospital and Hospital of UFMG (Federal University of Minas Gerais), both in the city of Belo Horizonte, Brazil, from January 2009 to August 2011. They were divided into two groups: a control group and a study group, subdivided according to genotype into SS or S-b0 thal, and SC. SS (n ¼ 27) and S-b0 thal (n ¼ 2) patients were grouped together due to similar severity of clinical manifestations. The Study Group comprised 60 pregnancies in 58 women with SCD (29 women and 30 pregnancies in each subgroup, SS or SC) that presented for prenatal care before completing 20 weeks of gestation. Two patients (one SS and one SC) had two consecutive pregnancies each. Two SC patients had twin pregnancies. The total number of fetuses is, therefore, 62. The Control Group included 192 pregnancies in 187 healthy women that were delivered immediately after the delivery of each of the pregnancies of women with SCD and whose profiles matched those of the Study Group by maternal age, maternal parity and newborn’s sex. Only one Control woman had a twin pregnancy. Maternal complications were considered to be related to the pregnancy if they happened within 6 weeks after delivery. Maternal blood transfusions were not prophylactically administered and clinical indications for transfusion in acutely ill pregnant women included hematocrit decrease to 80% from the basal value for a given patient and acute chest syndrome, irrespective of hematocrit basal value. In this setting, manual blood exchange was always the therapeutic option. Patients were tested for albuminuria before the 20th week of pregnancy in the absence of urinary infection and concomitant pain episode. Tests were repeated in each visit for both the Control and Study groups. Asymptomatic bacteriuria was screened for at the first prenatal care visit for both groups. If positive (100 000 CFU), patients were
treated with antibiotics and urine culture was repeated every month. If the initial screening was negative, the Control Group was not further tested unless specific urinary symptoms were reported. For the Study Group urine culture was repeated every 3 months, except for patients with macroalbuminuria (4300 mg/24 h) in whom tests were repeated every month after its detection. Progressive Care Unit (PCU) admission for babies means care units for those who needed close monitoring without resorting to intensive care units. Data analyses We compared the following parameters between the Study and Control Groups: urinary infection, pre-eclampsia, spontaneous preterm labor, deep vein thrombosis, type of delivery, preterm delivery, postnatal or postabortion infection, maternal death, stillbirth, small for gestational age baby (SGA), admission to PCU, and neonatal death (Table 1). Painful episodes, pulmonary complications, blood transfusion, maternal hospital admissions, preterm delivery, SGA baby and PCU admission were compared between the SS and SC subgroups (Table 2). SPSS 17.0Õ (New York, NY) was used to run the following statistical analyses: Pearson’s chi-square test or Fisher’s exact test, whichever was appropriate, for qualitative variables; unpaired Student’s t-test or Mann–Whitney for continuous variables with or without Gaussian distribution, respectively. Differences in results with p 0.05 were considered significant. Confidence intervals were established at 95% level. A multivariate logistic regression was carried out to assess the variables that could be associated with preterm delivery in the group with SCD. In this analysis, twin pregnancies in the SC subgroup (n ¼ 2) were excluded because twin gestation usually associates with preterm delivery.
Table 1. Maternal and perinatal results in 60 pregnancies of women with sickle cell disease and in 192 controls. Results Urinary tract infection Pre-eclampsia* Spontaneous preterm labor Deep vein thrombosis Type of delivery* Cesarean Vaginal Post-natal or post-abortion infection Maternal death Preterm delivery* Stillbirthy SGA babyy PCU admissionz Neonatal deathô
Study group pregnancies
Control group pregnancies
p value
Odds ratio
95% CI
a
18/60 5/58 3/58 4/60
(30.0) (8.6) (5.2) (6.7)
22/192 21/192 11/192 0/192
(11.5) (10.9) (5.7) (0.0)
0.001 0.612a 1.000b 0.003b
3.31 0.77 0.89 –
1.63–6.73 0.28–2.13 0.242–3.33 –
40/58 18/58 2/60 2/60 26/58 1/60 11/60 17/58 2/59
(69.0) (31.0) (3.3) (3.3) (44.8) (1.7) (18.3) (29.3) (3.4)
59/192 133/192 5/192 0/192 27/192 4/192 15/193 15/189 2/189
(30.7) (69.3) (2.6) (0.0) (14.1) (2.1) (7.8) (7.9) (1.1)
0.000a
5.00
2.65–9.45
0.527b 0.056b 50.001a 1.000b 0.019a 50.001a 0.241b
1.29 – 4.96 0.80 2.66 4.89 3.28
0.24–6.82 – 2.57–9.59 0.09–7.30 1.15–6.17 2.26–10.6 0.45–23.82
CI, confidence interval; SGA, small for gestational age; PCU, progressive care unit. *Two abortions (20 weeks of pregnancy) in SS patients were excluded from the total of pregnancies. yTwo aborted fetuses (20 weeks of pregnancy) in SS patients were excluded from the total of 62 fetuses (twin pregnancies in two SC patients); one twin pregnancy adds to 191 pregnancies in Controls for SGA baby calculation. zTwo aborted fetuses, one stillbirth and one neonatal death were excluded from the total of 62 fetuses; 4 stillbirth were excluded for the PCU admission calculation in the Control Group. ôTwo aborted fetuses and one stillbirth were excluded from the total of 62 fetuses in the Study Group; 4 stillbirth fetuses were excluded from the total of 193 fetuses (one twin pregnancy in the Control Group). a Pearson’s chi-square test. b Fisher’s exact test.
Pregnancy in sickle cell disease
DOI: 10.3109/14767058.2014.928855
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Table 2. Maternal and perinatal results in sickle cell disease pregnancies, according to genotype (30 SS and 30 SC). Results Painful episodes Pulmonary complications Blood transfusion Maternal hospital admissions* Preterm deliveriesy SGA babyz Neonatal PCU admissionô
SS pregnancies 25/30 05/30 25/30 22/30 20/28 6/28 11/26
(83.3) (16.7) (83.3) (73.3) (71.4) (21.4) (42.3)
SC pregnancies 18/30 06/30 09/30 15/30 4/28 5/32 6/32
(60.0) (20.0) (30.0) (50) (21.4) (15.6) (18.8)
p value
Odds ratio
95% CI
0.045 0.739 50.001 0.06 50.001 0.562 0.05
3.33 0.80 11.62 2.75 14.9 1.47 3.17
0.99–11.11 0.22–2.98 3.39–40.0 0.93–8.3 3.94–58.8 0.40–5.46 0.97–10.3
CI, confidence interval; SGA, Small for gestational age; PCU, Progressive Care Unit; p value, Pearson’s chi-squared test or Fisher’s exact test. *At least one and not including admissions for uncomplicated delivery. yTwo abortions in SS pregnancies and two twin pregnancies in SC subgroup were excluded. zTwo abortions in SS pregnancies were excluded; two twins were included in SC pregnancies. ôTwo aborted fetuses, one stillbirth and one neonatal death were excluded from the SS pregnancies; two twins were included in SC pregnancies.
Results The results showed a significant difference in gestational age at delivery between the Control Group (median 39 weeks) and the SCD Group (median 37 weeks) (p50.001). The difference was found to be ascribable to the SS subgroup (32–37 weeks), in contrast with SC (37–38.5 weeks). Pregnant women with SCD were found to be 5 times more likely to require cesarean section than healthy women (p50.001; Table 1). Urinary tract infection was 3 times more frequent among women with SCD (p ¼ 0.001), while the frequencies of pre-term labor (p ¼ 1.00), pre-eclampsia (p ¼ 0.61) and postnatal infection (p ¼ 0.53) were neither significantly different between the SCD Group and the Control Group (Table 1), nor between the SS and SC subgroups. In the Study Group, 37 pregnancies required hospital admission. Hematologic issues were the most frequent reason for the admissions (Table 2). Four pregnant women (6.7%), all from SS subgroup, had deep venous thrombosis. Two maternal deaths (3.3%) occurred in the SS subgroup. Painful episodes were reported in 43 of the 60 SCD pregancies (71.7%), more frequently in the SS than in SC subgroup (p ¼ 0.045). A total of 11 events of painful episodes happened within 6 weeks after birth. Pulmonary complications were found in 11 pregnancies (18.3%), with similar frequency in both SS and SC subgroups (p ¼ 0.74). Pregnancies in women with SS needed significantly more blood transfusions than those in women with SC (OR ¼ 11.6, 95% Cl 3.4–40.0) (Table 2). Preterm delivery, neonatal PCU admission and SGA newborns were more frequent in the SCD Group than in the Control Group (Table 1). Babies from the SS subgroup had the lowest weight at birth (2080 g; interquartile range 727 g) compared to SC (2,737 g; interquartile range 698 g) and controls (3035 g; interquartile range 633 g). Both differences between the SCD group versus controls and SS versus SC subgroups were statistically significant (p50.001). Pregnancies in women with SCD were almost 5 times more likely to either deliver pretermly or give birth to a child that needed PCU admission than those without SCD. SGA newborns, a consequence of IUGR, were 2.7 more frequent in SCD pregnancies than in those of Controls (95% CI 1.2– 6.2; Table 1). Five-minute Apgar scores were similar for
Table 3. Final multivariate logistic model for risk of preterm delivery in 56 pregnancies of women with sickle cell disease*. Risk of preterm delivery
95% confidence interval
p value
2.622
13.76
3.28–57.64
50.001
2.137
8.48
1.39–51.57
0.02
–
–
–
Coefficient Genotype (SS relative to SC) Painful episode (yes versus no) Constant
3.373
*Number of pregnancies: SS ¼ 28; SC ¼ 28. Two abortions in SS subgroup and two twin pregnancies in SC subgroup were excluded from this analysis (see Data analyses in Methods).
both groups. No statistically significant differences in neonatal and fetal death rates were found between Study and Control Groups. The analysis of neonatal outcome in the SCD subgroups showed significant differences between the SS and the SC subgroups in preterm delivery prevalence and PCU admissions. The likelihood of preterm delivery was 15 times greater in the SS group than in the SC group (95% CI: 3.9–58.8; Table 2). The univariate analysis of factors that might be associated with preterm delivery, adjusted for the differences between subgroups SS and SC, showed statistically significant associations with: painful episodes during pregnancy (p ¼ 0.011), acute chest syndrome (ACS) (p ¼ 0.043), pre-eclampsia (p50.001), high baseline white cell count (p ¼ 0.019), and high baseline platelet count (p50.001). ACS was significantly associated with painful episodes: all patients with ACS had concomitant or previous pain episode and 26% of those who had a pain episode developed ACS (p ¼ 0.02). Pregestational morbidity, nephropathy, urinary infection, deep vein thrombosis, maternal age, baseline total or relative fetal HbS concentration, and mean total HbS concentration during pregnancy were not significantly associated with preterm delivery. In the final multivariate analysis (Table 3), only the SS genotype and the occurrence of painful crises (‘‘yes’’ or ‘‘no’’) remained statistically significant. The preterm delivery risk was approximately 14 times higher in SS pregnancies compared to SC pregnancies (95% CI, 3.3–57.6; p50.001)
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and 8.5 times higher in pregnancies of women who experienced at least one painful episode (95% CI, 1.4–51.6; p ¼ 0.02).
Discussion Pregnant women with SCD have higher rates of maternal and fetal morbidity and mortality than women who do not have the disorder. Because it is a multisystemic disorder, SCD can cause chronic damage in many body systems that influence the course of pregnancy, such as: severe anemia, renal dysfunction, pulmonary hypertension, stroke, gallstones, femoral avascular necrosis, bone marrow fat embolism, and lower-limb ulceration. Functional asplenia makes them more susceptible to encapsulated bacterial infections. Splenomegaly may cause thrombocytopenia, which has to be monitored during pregnancy [11,12]. Consistent with those reported in the literature, this study found some maternal and fetal complications which were more common in the SCD Group than in the Control Group [13–15]: cesarean section, deep vein thrombosis, urinary infection, IUGR, and PCU admissions for newborns. Comparison of maternal and fetal outcomes according to maternal genotype showed that in SS pregnancies, the occurrence of at least one painful episode, need for blood transfusion, and preterm delivery were more frequent. Painful episodes were the main reason for hospital admission among the patients included in this study. The rate of these episodes was higher than those from retrospective studies that have ranged from 25.3% to 47% [14,15]. Possible explanations for the increase in pain episodes in pregnancy include increased metabolic demand, stress, cell adhesion molecule activity and pro-coagulant state. The fact that this is a prospective study based on data collected in reference centers may have contributed to identifying events more accurately, instead of relying exclusively on potentially biased memory recalls or review of medical records, as done in retrospective studies. In the present study, the rate of non-prophylactic blood transfusion for hematologic and/or obstetric reasons was higher than those reported in the literature (32–48.9% [15,16]). Two SS patients had their chronic tranfusion schedule maintained for secondary stroke prophylaxis. As mentioned before, blood transfusion was given to patients if specific circumstances such as ACS, worsening of anemia, and labor preparation occurred. It should be recognized that the number of cesarean sections in this study may have increased the rate of blood transfusion. The cesarean delivery rate in this study was higher than others reported in the literature, e.g. 19% and 43% [15,16]. Statistically significant differences between cesarean and vaginal delivery rates were not found, however, by others when SCD patients were compared to AA women [3]. In the present study, cesarean sections were carried out electively when previous femoral head avascular necrosis was present. Fetal distress due to maternal complications was the main reason for pregnancy interruption. It should be recognized that criteria for cesarean section in SCD patients was not really uniform because clinical judgement by obstetricians is
J Matern Fetal Neonatal Med, 2015; 28(6): 685–689
obviously heterogenous, although they have previously discussed the general criteria for it. Among the complications assessed in this study, nine (8 SS and 1 SC) had macroalbuminuria before the 20th week of pregnancy. This finding suggests the importance of assessing renal function, including 24-h urinary protein tests, in the early stages of SCD pregnancy, in order to prevent wrong diagnosis of pre-eclampsia as well as to identify renal impairment and subsequently provide women with treatment to prevent pre-eclampsia. Diagnosing pre-eclampsia in pregnant women with SCD is not simple, because high blood pressure and increased liver enzymes may be associated with acute vaso-occlusive events, which may be misinterpreted as severe pre-eclampsia or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Therefore, pre-eclampsia among SCD women should be diagnosed carefully and in the absence of acute vaso-occlusive events. Systematic proteinuria tests were performed for all patients in the first half of pregnancy. This may explain the low rate of pre-eclampsia found in this study, a rate similar to that of the Control Group. Such screening contributed to more accurate diagnosis of pre-eclampsia, yielding results similar to those reported by others [3,17]. Universal screening for asymptomatic bacteriuria has been indicated for patients with SCD with the objective of preventing sepsis from the urinary tract. The rate of urinary infection and asymptomatic bacteriuria was higher than usually reported [12] and may be the result of including patients with asymptomatic bacteriuria in the study, which is less common in other reports. This intensive and thorough monitoring may also have contributed to the decreased rate of puerperal infection. Only two pregnant women with SCD had puerperal infection, which is a rate substantially lower than that of 17.6% reported in the literature [12]. Systematic investigation and treatment of infections and asymptomatic bacteruria, delivery assistance by a specialized team, accurate techniques and reduced surgical duration of both cesarean section and vaginal delivery are proven approaches to reduce puerperal infections. A recent study has shown that pregnant women with SCD are 7–11 times more likely to die than those without the disorder [18]. In the present study, two maternal deaths were recorded following ACS. This justifies the need of following these pregnant women in specialized SCD centers with the objective of early diagnosis and treatment of SCD-related and obstetrical complications. Acute chest syndrome is the main cause of death among pregnant women, accounting for rates that range from 11–20% [3,13]. It is characterized by a recent radiologically proved pulmonary infiltration associated with fever, cough and hypoxemia. Reducing the percentage of red blood cells containing HbS by exchange transfusion and providing adequate antibiotic-based treatment, oxygen supplementation, and intensive respiratory physiotherapy are needed to prevent death [19]. Some patients with SC subtype in the present study had their first-ever painful crisis and ACS during pregnancy. This suggests that women with SC subtype require the same thorough obstetrical and hematological follow-up as that provided for patients with SS. ACS was also the main
Pregnancy in sickle cell disease
DOI: 10.3109/14767058.2014.928855
reason for intensive care unit admission in the present study, similar to results reported by others who found a rate of 17.3% of intensive care unit admission for pregnant women with SCD [12]. Preterm delivery was the outcome for 44.8% of the pregnancies in women with SCD. The prevalence was higher among SS patients, a finding that corroborates previous results [3]. The mean gestational age was lower in the SS subgroup compared to the SC subgroup. Mean gestational ages of 34 and 37 weeks were reported by others [3,17] in SS patients. In the present study, most preterm deliveries (96.2%) occurred after 34 weeks of pregnancy. That probably reflects the effect of intensive prenatal care that allowed early diagnosis of fetal complications secondary to acute manifestations of maternal SCD. Our specialized, prospective and early-monitoring system of prenatal care appears to have changed the pattern of spontaneous abortion and stillbirth into a pattern of late prematurity, without increasing neonatal death. In SCD mothers, perinatal mortality rate usually ranges from 7.8% to 18.7% [13,14] and that of stillbirth from 4.9% to 7.1% [3,13]. However, one of the cited studies [3] included the number of spontaneous abortions in the denominator of pregnancies in calculating the stillbirth rate. If spontaneous abortions (30 in total) were excluded, the stillbirth rate would increase to 11.1%. In the present study, the stillbirth rate was 1.7% (just one case), neonatal mortality was 3.4% (two cases), and the perinatal mortality rate was 5%. The lower rate of perinatal mortality in our study compared to the literature is probably due to intensive surveillance of fetal growth and well-being. Prematurity is still a common cause of neonatal mortality in SCD. It is also a major determinant of neurocognitive impairment during childhood. The main obstetrical indication for early pregnancy interruption in both the Control and Study Group was the decrease of fetal vitality. Analyses of preterm delivery were, therefore, carried out aimed at identifying associated risk factors in the Study Group. After multivariate logistic regression, SCD genotype and painful episodes were the two variables that remained statistically significant in the final model. Pregnant women with SS were 13 times more likely than those with SC to have preterm delivery. For those who had painful episodes during pregnancy the associated risk of having preterm delivery was 8.5 times higher compared to pregnant women without these episodes. It is known that respiratory distress and ACS frequently come along or after pain episodes in SCD, as demonstrated in this report. Maternal hypoxemia can lead to decreased fetal vitality and urgent need for pregnancy interruption. This suggests that both SS and SC patients with painful episodes should be treated as early as possible with effective approaches to pain control in order to reduce early pregnancy interruption and prematurity. No association was found between preterm delivery and fetal growth retardation. This finding suggests that growth disturbance did not impact the rate of preterm babies since fetal growth was preserved. In conclusion, our results clearly show that pregnancy in women with SCD, both SS and SC, is complicated by maternal and perinatal complications. Specialized care and close monitoring of the pregnant woman with SCD are critical
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to reduce all the potentially harmful effects of SCD on the health of the mother and child.
Acknowlegements Our thanks to all members of Project Aninha, in special to Milza Januario, MD, Jose´ Nelio Januario, MD, and Patricia Resende Cardoso, MD; to English translator Kelen Lima, and to Professor Kwaku Ohene-Frempong for his kind revision of the article.
Declaration of interest This study was financially supported by the Ministry of Health, Project Aninha. The authors report no conflicts of interest.
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ORIGINAL ARTICLE
Pregnancy in patients with sickle cell disease: maternal and perinatal outcomes Vanessa Maria Fenelon Costa, M.D., M.Sc1,2, Marcos Borato Viana, M.D., Ph.D.3, and Regina Ame´lia Lopes Pessoa Aguiar, M.D., Ph.D.2,3 1
Hospital Odilon Behrens, Belo Horizonte, Brasil, 2Programa de Po´s-graduac¸a˜o em Sau´de da Mulher, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil, and 3Nu´cleo de Ac¸o˜es e Pesquisa em Apoio Diagno´stico (NUPAD), Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil Abstract
Keywords
Objective: To compare obstetrical, hematological and neonatal outcomes of pregnant women with or without sickle cell disease (SCD). Methods: A prospective study of 60 pregnancies of 58 women with SCD (29 SCD-SS and 29 SCDSC) compared with 192 pregnancies in 187 healthy pregnant women was carried out from January 2009 to August 2011. Results: Compared to controls, the SCD group had higher rate of preterm delivery (p50.001, OR ¼ 4.96, 95% CI 2.57–9.59), higher cesarean rate (p50.001, OR ¼ 5.00, CI 2.65–9.45), more frequent deep vein thrombosis (p ¼ 0.003), and urinary infection (p ¼ 0.001, OR ¼ 3.31, CI 1.63– 6.73), higher prevalence of small for gestational age babies (p ¼ 0.019, OR ¼ 2.66, CI 1.15–6.17), and more frequent baby admissions to progressive care unit (p50.001, OR ¼ 4.89, CI 2.26–10.6). Maternal death rate was also higher among women with SCD (p ¼ 0.056). All adverse events were more frequent in the SS subgroup. Babies from the SS subgroup had the lowest weight at birth (2080 g) compared to SC (2737 g; p50.001) and controls (3035 g). A multivariate analysis confirmed painful episodes and SS genotype as factors contributing to preterm delivery. Conclusion: SCD pregnant women – especially those in the SS subgroup – are more prone to experience perinatal and maternal complications in comparison with pregnant women without SCD.
Acute chest syndrome, albuminuria, hemoglobin SC, preterm delivery, sickle cell anemia
Introduction Sickle cell disease (SCD) is an inherited disease in which the predominant presence of sickle hemoglobin (HbS) in red blood cells leads to sickling, vaso-occlusion, and chronic hemolytic anemia. This results in decreased delivery of oxygen to tissues and causes acute and chronic tissue and organ injury. SCD is associated with high mortality rates, especially in young children. It is usually diagnosed in childhood, ideally through newborn screening. Affected infants typically become symptomatic after four months of life [1,2]. Pregnant women with SCD may experience hematological and obstetrical complications, such as preeclampsia, severe anemia, frequent painful crises and infections [3]. Placental ischemia and endothelial damage may be risk factors for those complications. Retrospective data suggest higher mortality rate in SCD pregnant women when compared to the general population [4–6]. The spontaneous abortion rate is variable. It was 35.7% for SS patients against a 10.4% in a control group [3].
History Received 6 March 2014 Accepted 25 May 2014 Published online 26 June 2014
Peripartum complications are more common in SS patients than in those who are AA or SC [1,4,6,7]. SCD complications requiring blood transfusion seemed to be associated with increased risk of prematurity and pre-eclampsia [5,6]. The rate of perinatal mortality in SCD pregnant women used to be as high as 53% [3]. It has reduced, however, to below 5% owing to improved obstetric and neonatal care provided over the last three decades [4,5,8]. Low birth weight and intrauterine growth retardation (IUGR) may be the result of chronic anemia and placental vaso-occlusion, but recent studies have not found significant correlation between weight at birth and the degree of anemia of mothers with SCD [9,10]. This study aimed to compare the clinical course of pregnancies in women with SCD with that of a control group. It focused on maternal and perinatal outcomes and risk factors associated with preterm delivery. In addition, clinical outcome was compared between SS and SC subgroups.
Methods Address for correspondence: Regina Ame´lia Lopes Pessoa Aguiar, M.D., Ph.D., Nu´cleo de Ac¸o˜es e Pesquisa em Apoio Diagno´stico (NUPAD), Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil. E-mail: [email protected]
This prospective cohort study was approved by the Ethics Committees of the partner institutions. All patients signed informed consent forms.
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The pregnant women were followed at the maternity departments of Odilon Behrens Municipal Hospital and Hospital of UFMG (Federal University of Minas Gerais), both in the city of Belo Horizonte, Brazil, from January 2009 to August 2011. They were divided into two groups: a control group and a study group, subdivided according to genotype into SS or S-b0 thal, and SC. SS (n ¼ 27) and S-b0 thal (n ¼ 2) patients were grouped together due to similar severity of clinical manifestations. The Study Group comprised 60 pregnancies in 58 women with SCD (29 women and 30 pregnancies in each subgroup, SS or SC) that presented for prenatal care before completing 20 weeks of gestation. Two patients (one SS and one SC) had two consecutive pregnancies each. Two SC patients had twin pregnancies. The total number of fetuses is, therefore, 62. The Control Group included 192 pregnancies in 187 healthy women that were delivered immediately after the delivery of each of the pregnancies of women with SCD and whose profiles matched those of the Study Group by maternal age, maternal parity and newborn’s sex. Only one Control woman had a twin pregnancy. Maternal complications were considered to be related to the pregnancy if they happened within 6 weeks after delivery. Maternal blood transfusions were not prophylactically administered and clinical indications for transfusion in acutely ill pregnant women included hematocrit decrease to 80% from the basal value for a given patient and acute chest syndrome, irrespective of hematocrit basal value. In this setting, manual blood exchange was always the therapeutic option. Patients were tested for albuminuria before the 20th week of pregnancy in the absence of urinary infection and concomitant pain episode. Tests were repeated in each visit for both the Control and Study groups. Asymptomatic bacteriuria was screened for at the first prenatal care visit for both groups. If positive (100 000 CFU), patients were
treated with antibiotics and urine culture was repeated every month. If the initial screening was negative, the Control Group was not further tested unless specific urinary symptoms were reported. For the Study Group urine culture was repeated every 3 months, except for patients with macroalbuminuria (4300 mg/24 h) in whom tests were repeated every month after its detection. Progressive Care Unit (PCU) admission for babies means care units for those who needed close monitoring without resorting to intensive care units. Data analyses We compared the following parameters between the Study and Control Groups: urinary infection, pre-eclampsia, spontaneous preterm labor, deep vein thrombosis, type of delivery, preterm delivery, postnatal or postabortion infection, maternal death, stillbirth, small for gestational age baby (SGA), admission to PCU, and neonatal death (Table 1). Painful episodes, pulmonary complications, blood transfusion, maternal hospital admissions, preterm delivery, SGA baby and PCU admission were compared between the SS and SC subgroups (Table 2). SPSS 17.0Õ (New York, NY) was used to run the following statistical analyses: Pearson’s chi-square test or Fisher’s exact test, whichever was appropriate, for qualitative variables; unpaired Student’s t-test or Mann–Whitney for continuous variables with or without Gaussian distribution, respectively. Differences in results with p 0.05 were considered significant. Confidence intervals were established at 95% level. A multivariate logistic regression was carried out to assess the variables that could be associated with preterm delivery in the group with SCD. In this analysis, twin pregnancies in the SC subgroup (n ¼ 2) were excluded because twin gestation usually associates with preterm delivery.
Table 1. Maternal and perinatal results in 60 pregnancies of women with sickle cell disease and in 192 controls. Results Urinary tract infection Pre-eclampsia* Spontaneous preterm labor Deep vein thrombosis Type of delivery* Cesarean Vaginal Post-natal or post-abortion infection Maternal death Preterm delivery* Stillbirthy SGA babyy PCU admissionz Neonatal deathô
Study group pregnancies
Control group pregnancies
p value
Odds ratio
95% CI
a
18/60 5/58 3/58 4/60
(30.0) (8.6) (5.2) (6.7)
22/192 21/192 11/192 0/192
(11.5) (10.9) (5.7) (0.0)
0.001 0.612a 1.000b 0.003b
3.31 0.77 0.89 –
1.63–6.73 0.28–2.13 0.242–3.33 –
40/58 18/58 2/60 2/60 26/58 1/60 11/60 17/58 2/59
(69.0) (31.0) (3.3) (3.3) (44.8) (1.7) (18.3) (29.3) (3.4)
59/192 133/192 5/192 0/192 27/192 4/192 15/193 15/189 2/189
(30.7) (69.3) (2.6) (0.0) (14.1) (2.1) (7.8) (7.9) (1.1)
0.000a
5.00
2.65–9.45
0.527b 0.056b 50.001a 1.000b 0.019a 50.001a 0.241b
1.29 – 4.96 0.80 2.66 4.89 3.28
0.24–6.82 – 2.57–9.59 0.09–7.30 1.15–6.17 2.26–10.6 0.45–23.82
CI, confidence interval; SGA, small for gestational age; PCU, progressive care unit. *Two abortions (20 weeks of pregnancy) in SS patients were excluded from the total of pregnancies. yTwo aborted fetuses (20 weeks of pregnancy) in SS patients were excluded from the total of 62 fetuses (twin pregnancies in two SC patients); one twin pregnancy adds to 191 pregnancies in Controls for SGA baby calculation. zTwo aborted fetuses, one stillbirth and one neonatal death were excluded from the total of 62 fetuses; 4 stillbirth were excluded for the PCU admission calculation in the Control Group. ôTwo aborted fetuses and one stillbirth were excluded from the total of 62 fetuses in the Study Group; 4 stillbirth fetuses were excluded from the total of 193 fetuses (one twin pregnancy in the Control Group). a Pearson’s chi-square test. b Fisher’s exact test.
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Table 2. Maternal and perinatal results in sickle cell disease pregnancies, according to genotype (30 SS and 30 SC). Results Painful episodes Pulmonary complications Blood transfusion Maternal hospital admissions* Preterm deliveriesy SGA babyz Neonatal PCU admissionô
SS pregnancies 25/30 05/30 25/30 22/30 20/28 6/28 11/26
(83.3) (16.7) (83.3) (73.3) (71.4) (21.4) (42.3)
SC pregnancies 18/30 06/30 09/30 15/30 4/28 5/32 6/32
(60.0) (20.0) (30.0) (50) (21.4) (15.6) (18.8)
p value
Odds ratio
95% CI
0.045 0.739 50.001 0.06 50.001 0.562 0.05
3.33 0.80 11.62 2.75 14.9 1.47 3.17
0.99–11.11 0.22–2.98 3.39–40.0 0.93–8.3 3.94–58.8 0.40–5.46 0.97–10.3
CI, confidence interval; SGA, Small for gestational age; PCU, Progressive Care Unit; p value, Pearson’s chi-squared test or Fisher’s exact test. *At least one and not including admissions for uncomplicated delivery. yTwo abortions in SS pregnancies and two twin pregnancies in SC subgroup were excluded. zTwo abortions in SS pregnancies were excluded; two twins were included in SC pregnancies. ôTwo aborted fetuses, one stillbirth and one neonatal death were excluded from the SS pregnancies; two twins were included in SC pregnancies.
Results The results showed a significant difference in gestational age at delivery between the Control Group (median 39 weeks) and the SCD Group (median 37 weeks) (p50.001). The difference was found to be ascribable to the SS subgroup (32–37 weeks), in contrast with SC (37–38.5 weeks). Pregnant women with SCD were found to be 5 times more likely to require cesarean section than healthy women (p50.001; Table 1). Urinary tract infection was 3 times more frequent among women with SCD (p ¼ 0.001), while the frequencies of pre-term labor (p ¼ 1.00), pre-eclampsia (p ¼ 0.61) and postnatal infection (p ¼ 0.53) were neither significantly different between the SCD Group and the Control Group (Table 1), nor between the SS and SC subgroups. In the Study Group, 37 pregnancies required hospital admission. Hematologic issues were the most frequent reason for the admissions (Table 2). Four pregnant women (6.7%), all from SS subgroup, had deep venous thrombosis. Two maternal deaths (3.3%) occurred in the SS subgroup. Painful episodes were reported in 43 of the 60 SCD pregancies (71.7%), more frequently in the SS than in SC subgroup (p ¼ 0.045). A total of 11 events of painful episodes happened within 6 weeks after birth. Pulmonary complications were found in 11 pregnancies (18.3%), with similar frequency in both SS and SC subgroups (p ¼ 0.74). Pregnancies in women with SS needed significantly more blood transfusions than those in women with SC (OR ¼ 11.6, 95% Cl 3.4–40.0) (Table 2). Preterm delivery, neonatal PCU admission and SGA newborns were more frequent in the SCD Group than in the Control Group (Table 1). Babies from the SS subgroup had the lowest weight at birth (2080 g; interquartile range 727 g) compared to SC (2,737 g; interquartile range 698 g) and controls (3035 g; interquartile range 633 g). Both differences between the SCD group versus controls and SS versus SC subgroups were statistically significant (p50.001). Pregnancies in women with SCD were almost 5 times more likely to either deliver pretermly or give birth to a child that needed PCU admission than those without SCD. SGA newborns, a consequence of IUGR, were 2.7 more frequent in SCD pregnancies than in those of Controls (95% CI 1.2– 6.2; Table 1). Five-minute Apgar scores were similar for
Table 3. Final multivariate logistic model for risk of preterm delivery in 56 pregnancies of women with sickle cell disease*. Risk of preterm delivery
95% confidence interval
p value
2.622
13.76
3.28–57.64
50.001
2.137
8.48
1.39–51.57
0.02
–
–
–
Coefficient Genotype (SS relative to SC) Painful episode (yes versus no) Constant
3.373
*Number of pregnancies: SS ¼ 28; SC ¼ 28. Two abortions in SS subgroup and two twin pregnancies in SC subgroup were excluded from this analysis (see Data analyses in Methods).
both groups. No statistically significant differences in neonatal and fetal death rates were found between Study and Control Groups. The analysis of neonatal outcome in the SCD subgroups showed significant differences between the SS and the SC subgroups in preterm delivery prevalence and PCU admissions. The likelihood of preterm delivery was 15 times greater in the SS group than in the SC group (95% CI: 3.9–58.8; Table 2). The univariate analysis of factors that might be associated with preterm delivery, adjusted for the differences between subgroups SS and SC, showed statistically significant associations with: painful episodes during pregnancy (p ¼ 0.011), acute chest syndrome (ACS) (p ¼ 0.043), pre-eclampsia (p50.001), high baseline white cell count (p ¼ 0.019), and high baseline platelet count (p50.001). ACS was significantly associated with painful episodes: all patients with ACS had concomitant or previous pain episode and 26% of those who had a pain episode developed ACS (p ¼ 0.02). Pregestational morbidity, nephropathy, urinary infection, deep vein thrombosis, maternal age, baseline total or relative fetal HbS concentration, and mean total HbS concentration during pregnancy were not significantly associated with preterm delivery. In the final multivariate analysis (Table 3), only the SS genotype and the occurrence of painful crises (‘‘yes’’ or ‘‘no’’) remained statistically significant. The preterm delivery risk was approximately 14 times higher in SS pregnancies compared to SC pregnancies (95% CI, 3.3–57.6; p50.001)
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and 8.5 times higher in pregnancies of women who experienced at least one painful episode (95% CI, 1.4–51.6; p ¼ 0.02).
Discussion Pregnant women with SCD have higher rates of maternal and fetal morbidity and mortality than women who do not have the disorder. Because it is a multisystemic disorder, SCD can cause chronic damage in many body systems that influence the course of pregnancy, such as: severe anemia, renal dysfunction, pulmonary hypertension, stroke, gallstones, femoral avascular necrosis, bone marrow fat embolism, and lower-limb ulceration. Functional asplenia makes them more susceptible to encapsulated bacterial infections. Splenomegaly may cause thrombocytopenia, which has to be monitored during pregnancy [11,12]. Consistent with those reported in the literature, this study found some maternal and fetal complications which were more common in the SCD Group than in the Control Group [13–15]: cesarean section, deep vein thrombosis, urinary infection, IUGR, and PCU admissions for newborns. Comparison of maternal and fetal outcomes according to maternal genotype showed that in SS pregnancies, the occurrence of at least one painful episode, need for blood transfusion, and preterm delivery were more frequent. Painful episodes were the main reason for hospital admission among the patients included in this study. The rate of these episodes was higher than those from retrospective studies that have ranged from 25.3% to 47% [14,15]. Possible explanations for the increase in pain episodes in pregnancy include increased metabolic demand, stress, cell adhesion molecule activity and pro-coagulant state. The fact that this is a prospective study based on data collected in reference centers may have contributed to identifying events more accurately, instead of relying exclusively on potentially biased memory recalls or review of medical records, as done in retrospective studies. In the present study, the rate of non-prophylactic blood transfusion for hematologic and/or obstetric reasons was higher than those reported in the literature (32–48.9% [15,16]). Two SS patients had their chronic tranfusion schedule maintained for secondary stroke prophylaxis. As mentioned before, blood transfusion was given to patients if specific circumstances such as ACS, worsening of anemia, and labor preparation occurred. It should be recognized that the number of cesarean sections in this study may have increased the rate of blood transfusion. The cesarean delivery rate in this study was higher than others reported in the literature, e.g. 19% and 43% [15,16]. Statistically significant differences between cesarean and vaginal delivery rates were not found, however, by others when SCD patients were compared to AA women [3]. In the present study, cesarean sections were carried out electively when previous femoral head avascular necrosis was present. Fetal distress due to maternal complications was the main reason for pregnancy interruption. It should be recognized that criteria for cesarean section in SCD patients was not really uniform because clinical judgement by obstetricians is
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obviously heterogenous, although they have previously discussed the general criteria for it. Among the complications assessed in this study, nine (8 SS and 1 SC) had macroalbuminuria before the 20th week of pregnancy. This finding suggests the importance of assessing renal function, including 24-h urinary protein tests, in the early stages of SCD pregnancy, in order to prevent wrong diagnosis of pre-eclampsia as well as to identify renal impairment and subsequently provide women with treatment to prevent pre-eclampsia. Diagnosing pre-eclampsia in pregnant women with SCD is not simple, because high blood pressure and increased liver enzymes may be associated with acute vaso-occlusive events, which may be misinterpreted as severe pre-eclampsia or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Therefore, pre-eclampsia among SCD women should be diagnosed carefully and in the absence of acute vaso-occlusive events. Systematic proteinuria tests were performed for all patients in the first half of pregnancy. This may explain the low rate of pre-eclampsia found in this study, a rate similar to that of the Control Group. Such screening contributed to more accurate diagnosis of pre-eclampsia, yielding results similar to those reported by others [3,17]. Universal screening for asymptomatic bacteriuria has been indicated for patients with SCD with the objective of preventing sepsis from the urinary tract. The rate of urinary infection and asymptomatic bacteriuria was higher than usually reported [12] and may be the result of including patients with asymptomatic bacteriuria in the study, which is less common in other reports. This intensive and thorough monitoring may also have contributed to the decreased rate of puerperal infection. Only two pregnant women with SCD had puerperal infection, which is a rate substantially lower than that of 17.6% reported in the literature [12]. Systematic investigation and treatment of infections and asymptomatic bacteruria, delivery assistance by a specialized team, accurate techniques and reduced surgical duration of both cesarean section and vaginal delivery are proven approaches to reduce puerperal infections. A recent study has shown that pregnant women with SCD are 7–11 times more likely to die than those without the disorder [18]. In the present study, two maternal deaths were recorded following ACS. This justifies the need of following these pregnant women in specialized SCD centers with the objective of early diagnosis and treatment of SCD-related and obstetrical complications. Acute chest syndrome is the main cause of death among pregnant women, accounting for rates that range from 11–20% [3,13]. It is characterized by a recent radiologically proved pulmonary infiltration associated with fever, cough and hypoxemia. Reducing the percentage of red blood cells containing HbS by exchange transfusion and providing adequate antibiotic-based treatment, oxygen supplementation, and intensive respiratory physiotherapy are needed to prevent death [19]. Some patients with SC subtype in the present study had their first-ever painful crisis and ACS during pregnancy. This suggests that women with SC subtype require the same thorough obstetrical and hematological follow-up as that provided for patients with SS. ACS was also the main
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reason for intensive care unit admission in the present study, similar to results reported by others who found a rate of 17.3% of intensive care unit admission for pregnant women with SCD [12]. Preterm delivery was the outcome for 44.8% of the pregnancies in women with SCD. The prevalence was higher among SS patients, a finding that corroborates previous results [3]. The mean gestational age was lower in the SS subgroup compared to the SC subgroup. Mean gestational ages of 34 and 37 weeks were reported by others [3,17] in SS patients. In the present study, most preterm deliveries (96.2%) occurred after 34 weeks of pregnancy. That probably reflects the effect of intensive prenatal care that allowed early diagnosis of fetal complications secondary to acute manifestations of maternal SCD. Our specialized, prospective and early-monitoring system of prenatal care appears to have changed the pattern of spontaneous abortion and stillbirth into a pattern of late prematurity, without increasing neonatal death. In SCD mothers, perinatal mortality rate usually ranges from 7.8% to 18.7% [13,14] and that of stillbirth from 4.9% to 7.1% [3,13]. However, one of the cited studies [3] included the number of spontaneous abortions in the denominator of pregnancies in calculating the stillbirth rate. If spontaneous abortions (30 in total) were excluded, the stillbirth rate would increase to 11.1%. In the present study, the stillbirth rate was 1.7% (just one case), neonatal mortality was 3.4% (two cases), and the perinatal mortality rate was 5%. The lower rate of perinatal mortality in our study compared to the literature is probably due to intensive surveillance of fetal growth and well-being. Prematurity is still a common cause of neonatal mortality in SCD. It is also a major determinant of neurocognitive impairment during childhood. The main obstetrical indication for early pregnancy interruption in both the Control and Study Group was the decrease of fetal vitality. Analyses of preterm delivery were, therefore, carried out aimed at identifying associated risk factors in the Study Group. After multivariate logistic regression, SCD genotype and painful episodes were the two variables that remained statistically significant in the final model. Pregnant women with SS were 13 times more likely than those with SC to have preterm delivery. For those who had painful episodes during pregnancy the associated risk of having preterm delivery was 8.5 times higher compared to pregnant women without these episodes. It is known that respiratory distress and ACS frequently come along or after pain episodes in SCD, as demonstrated in this report. Maternal hypoxemia can lead to decreased fetal vitality and urgent need for pregnancy interruption. This suggests that both SS and SC patients with painful episodes should be treated as early as possible with effective approaches to pain control in order to reduce early pregnancy interruption and prematurity. No association was found between preterm delivery and fetal growth retardation. This finding suggests that growth disturbance did not impact the rate of preterm babies since fetal growth was preserved. In conclusion, our results clearly show that pregnancy in women with SCD, both SS and SC, is complicated by maternal and perinatal complications. Specialized care and close monitoring of the pregnant woman with SCD are critical
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to reduce all the potentially harmful effects of SCD on the health of the mother and child.
Acknowlegements Our thanks to all members of Project Aninha, in special to Milza Januario, MD, Jose´ Nelio Januario, MD, and Patricia Resende Cardoso, MD; to English translator Kelen Lima, and to Professor Kwaku Ohene-Frempong for his kind revision of the article.
Declaration of interest This study was financially supported by the Ministry of Health, Project Aninha. The authors report no conflicts of interest.
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