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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Newborn Screening for Sickle Cell Disease and
Comprehensive Clinical Care Programs, Unit of Gynecology and
Obstetrics, Faculty of Health Sciences, Cotonou, National University of
Republic of Benin (West Africa).
Sickle cell disease (SCD) is associated with an increased risk of
medical complications during pregnancy. In sub-Saharan Africa, fetal
and maternal mortality rates are particularly high. This study
evaluated the effect of an active prenatal management program on
pregnancy outcome in patients with SCD in an African setting. Pregnant
women with SCD attending the National Teaching Hospital in Cotonou (The
Republic of Benin, West Africa) were recruited before the 28th week of
gestation. Management was based on providing information and education
about SCD and improving nutritional status, malaria prevention, early
detection of bacterial infections, and restricted use of blood
transfusion. Maternal and fetal mortality rates and SCD-related
morbidity were the principal variables assessed. One hundred and eight
patients (42 SS and 66 SC) with 111 fetuses were included in the study.
Thirteen fetal deaths (from 9 SS and 4 SC mothers) were recorded and 2 deaths of SC mothers. The maternal mortality rate of 1.8% was
comparable with the overall maternal mortality rate for this maternity
unit (1.2%). Few SCD-related events were recorded. Plasmodium
falciparum malaria infection was the major cause of morbidity.
Sixty-three patients (19 SS and 44 SC) successfully completed their
pregnancy (58.3%) without requiring transfusion. Providing pregnant
SCD patients with relevant medical care based on simple cost-effective
approaches can have a positive impact on SCD-associated morbidity and
mortality in an otherwise difficult setting in Africa.
(Blood. 2000;96:1685-1689) Sickle cell disease (SCD) is associated with an
increased risk of medical complications during pregnancy. The maternal
risks include prepartum and postpartum painful crises, urinary tract infections, pulmonary complications, anemia, preeclampsia, and death.
Fetal complications include premature delivery with its associated
risks, intrauterine growth retardation (low birth weight), fetal
distress during labor, and a high rate of perinatal
mortality.1-8 The details of appropriate prenatal care and
perinatal management for these patients is still a matter for debate in
developed countries. However, studies have shown that there is a
significant improvement in pregnancy outcome and that these women are
able to complete pregnancy successfully if they are given appropriate
prenatal care.9-13 Unfortunately, no such improvement has
yet been observed in sub-Saharan countries, which have the highest
prevalence of SCD and reported rates of maternal mortality exceeding
9%.7 Between July 1, 1993 and December 31, 1993, 15 pregnant women with SCD (7 SS patients and 8 SC patients) were referred
to the Gynecology and Obstetrics Department of the National Teaching Hospital in Cotonou, the capital of the Republic of Benin (West Africa). The maternal and fetal outcomes for these patients were very
poor, with both mother and fetus dying in 4 cases (3 SS patients and 1 SC patients), and fetal deaths in 2 other cases (1 SS and 1 SC mother).
In contrast, the current overall maternal and fetal mortality rates in
this maternity unit are 1.2% and 6.3%, respectively. The prevalence
of infections (especially malaria), the frequent worsening of anemia,
the limited health care facilities, and particularly the lack of
adequate management during pregnancy are thought to be the major
factors responsible for the observed poor maternal and fetal
outcomes.5 In light of the potentially extreme
consequences of pregnancy in SCD patients in Benin, we initiated a
prospective study in February 1994 to evaluate the effect of active
prenatal management on maternal and fetal outcomes at our hospital. The data presented here indicate that providing SCD patients with relevant
medical care based on simple cost-effective approaches during their
pregnancies can have a positive impact on associated morbidity and
mortality in an otherwise hostile setting in Africa.
Patients
Study design
In terms of patient care, taking local infrastructure and environment constraints into account, we focused our attention on: (1) the provision of repeated information and education about SCD with particular emphasis on factors that may precipitate acute events; (2) suggesting ways to improve nutritional status, in particular, by drawing attention to affordable local products that have a high nutritional value but are often neglected; (3) systematic supplementation with iron, folate, and vitamins; (4) the provision of advice about maintaining hydration levels by a daily intake of fluid, to keep urine volume high; (5) Plasmodium falciparum malaria prophylaxis involving the prescription of chloroquine for intake on alternate days and advice to sleep under a mosquito net; (6) the early detection of bacterial infections (particularly urinary tract infections and pneumonia); and (7) the implementation of stringent criteria for blood transfusion indications. Patient care The staff included a senior hematologist, a gynecologist/obstetrician, and 4 specially trained midwives. On entry into the study, an exhaustive history was taken for each patient and physical/obstetric examinations were performed. Gestational age was estimated from the date of the last menstrual period or an ultrasound scan if the patient could afford to pay for it. Patients were evaluated fortnightly until the last month of their pregnancy, and weekly thereafter. At each prenatal visit, the importance of compliance and a healthy lifestyle to maternal and fetal health were emphasized. The women were advised to contact the clinicians involved in the study immediately if they experienced any unusual symptoms. Patients were admitted to the hospital when labor appeared imminent. Final evaluations were carried out 2 weeks and 6 weeks after the delivery. A friendly atmosphere was maintained throughout the follow-up, which was probably instrumental in achieving the excellent compliance observed.Laboratory studies included a complete blood cell count, a reticulocyte count, urinalysis to detect asymptomatic bacteriuria, and blood smears for P falciparum asexual parasite counts at each prenatal visit and whenever indications appeared. A chest x-ray was performed if pneumonia or any other pulmonary event was suspected and systematically at the 7th month of gestation to check for asymptomatic pulmonary events. Management of labor At the beginning of labor, the patient was hydrated by an intravenous infusion of 5% glucose (3000 mL/m2 daily) with adjustment of electrolytes and acid-base balances. Intravenous bactericidal antibiotic treatment (amoxycillin and gentamycin) and quinine were also given and the whole protocol was maintained until the second day after delivery. Fetal heart rate was monitored throughout labor. Intravenous oxytocin was given to all patients at the start of labor, to reduce the duration of labor so as to decrease the level of delivery-associated blood loss. The delivery route (vaginal or cesarean section) depended on the usual obstetric indications. In our obstetric department, the rate of deliveries by cesarean section is about 25% to 30%.Transfusion therapy Initially, our policy was to limit blood transfusions essentially to the following indications: (1) to compensate for anemia with symptoms of impending cardiac failure; (2) to provide a prophylactic "top-up" transfusion before a cesarean section; or (3) when the prelabor hemoglobin level was less than 8g/dL. However, we were forced to restrict transfusions further due to several local constraints. These included the irregular availability of safe blood products, the patient's inability to pay for transfusion, the patient's unwillingness to have a blood transfusion for fear of being infected with human immunodeficiency virus or other blood-borne organisms, and the lack of screening procedures for red blood cell antibodies. Thus, in the later phase of the study, blood transfusions were given only if anemia was not tolerated clinically, regardless of the level of hemoglobin. The blood was cross-matched before transfusion.Data analysis The number of successfully completed pregnancies, the maternal mortality rate, fetal death rate, and perinatal mortality rate were recorded. We also recorded the frequency and severity of SCD-related events, specific complications of pregnancy including spontaneous abortion (defined as spontaneous termination of the pregnancy before the 28th week of gestation), the frequency of P falciparum malaria infection, and the causes of a worsening of anemia resulting in transfusion.
Table 1 summarizes the
characteristics of the patients enrolled in this study and Table
2 presents the overall maternal and fetal
outcomes. A total of 108 pregnancies (42 homozygous SS and 66 SC)
involving 111 fetuses were followed. Overall, 86% of the pregnancies
ended in live births. Only one premature delivery, of twins, was
recorded, at a gestational age of 34 weeks (for an SC patient).
Overall, the mean birth weight of neonates from SS mothers was
significantly lower than that for neonates from SC mothers
(P = .03, Fisher exact test). However, both values were
within the 25th and 10th percentiles of mean birth weight for 1200 neonates born to healthy AS and AC mothers in the same maternity unit
over the same period. When observed, fetal death occurred at a
gestational age of 32 to 39 weeks. No fetal deaths were recorded for
patients with previous unsuccessful pregnancies. The maternal mortality
rate was 1.8%. Two SC patients with pregnancies complicated by
preeclampsia died from toxemia. No autopsy was performed in
either case.
Most of the SCD patients had not been followed as part of a specific medical care program before this study. It was, therefore, difficult to obtain a precise past medical history for these patients. However, when interviewed, patients reported numerous past SCD-related acute events, and all but 15 (all SC) had had at least one transfusion. During the course of this study, over half the 108 patients experienced painful SCD crises (24 SS patients, 57%; 35 SC patients, 53%). These crises were mild in all cases, were treated essentially with aspirin and paracetamol, and did not require narcotics. A few patients (3 SS and 2 SC) had more than 2 episodes. Two SS patients had pulmonary complications; one of these patients experienced a severe acute chest syndrome with a fever over 40°C and respiratory distress requiring partial exchange transfusion. This patient was carrying twins and one fetus died soon after the onset of this episode. Urinary tract infections, with Escherichia coli as the most frequent causative pathogen, were recorded in 7 SS patients (16.7%) and 17 SC patients (25.7%). Despite our preventive measures, P falciparum malaria was diagnosed in 16 SS patients (38.0%) and 15 SC patients (22.7%). Atypically, we found that many patients presented with high parasitemia and severe anemia (hemoglobin levels > 40% below the steady-state level) but without fever (rectal temperature, 37.5°C). Indeed, 40.9% of the episodes of P falciparum malaria infection were not associated with fever (11 episodes of 25 in SS patients, 44.0%; 7 episodes of 19 in SC patients, 36.8%). Forty-five patients (41.7%) had a blood transfusion during the study
period (23 SS patients, 54.8%; 22 SC patients, 33.3%). All except 2 SS patients and 1 SC patient had transfusions before enrollment. One SS
patient had an emergency partial exchange transfusion because of severe
pneumonia. In the initial phase of the study, scheduled partial
exchange transfusions were given once each to 2 SS patients and twice
to another patient as recommended in the literature. Similarly,
systematic "top-up" transfusions in case of cesarean section or
prelabor transfusion for a hemoglobin level lower than 8 g/dL were
given to 3 SS patients and to 4 SC patients. These 10 patients with
scheduled transfusions also had transfusions during pregnancy for
worsening of anemia. For all the other cases, in the later phase of the
study, transfusion was administrated only when anemia was not tolerated
clinically. Table 3 lists the different
etiologies associated with the worsening of anemia in these patients.
The 2 maternal deaths involved women belonging to that group. It is
noteworthy that in 45.6% of the transfusions given to SS patients,
P falciparum malaria was the causative factor. No immediate
adverse reactions to transfusion were reported.
Table 4 shows the hemoglobin levels,
SCD-related complications, and maternal/fetal outcomes of the 19 SS
patients and 44 SC patients who did not receive a blood transfusion
during the study period. Overall, hemoglobin level and hematocrit
increased between inclusion and the end of the pregnancy for these
patients. The increase was particularly marked for the SS patients (1.2 g/dL and 3%, respectively). However, 4 of the SS patients who were not
given transfusions during the study period had been given 3 or more
blood transfusions before their inclusion in this study. At first
presentation, these patients had hemoglobin levels of 4.3, 5.8, 6.0, and 7.2 g/dL. Their hematocrit values were 15%, 18%, 19%, and 24%,
respectively. There was a gradual and marked increase in hemoglobin
level and hematocrit in these patients during the study, with no
further transfusions. Their final hemoglobin levels were 8.7, 8.0, 8.8, and 8.7 g/dL, respectively. Their final hematocrit values were 29%,
25%, 27%, and 28%, respectively. Finally, fewer SCD-associated
complications were observed in the group of 19 SS patients who were
never transfused during the study period than for the study population
as a whole. No maternal deaths occurred and all but 5 pregnancies (2 spontaneous abortions and 3 stillbirths) ended in live births. Only 2 of the nontransfused SS patients were found to have P
falciparum malaria.
The Republic of Benin, West Africa, has a high prevalence of
SCD. Although precise data about the incidence of pregnancies in women
with SCD are not available in Benin, it is clear that they are not by
far as frequently encountered as might be expected from a
In designing this pilot study, we focused our attention on environmental factors associated with the African setting that might seriously affect the clinical course of SCD. Other than one severe pulmonary complication in a patient bearing twins, few SCD-related events were observed and those that did occur were mild. In this respect, it is notable that the mean fetal hemoglobin level in our SS patients was only 2.1%. Thus, probably, the poor pregnancy outcomes previously reported for SCD patients in West Africa reflect inadequate management of these patients rather than the intrinsic severity of the disease. Both the women who died had SC disease. This is consistent with previous findings that women with this genotype have a relatively benign course when not pregnant but are genuinely at risk in late pregnancy.14,15 Because these patients do not normally suffer from severe acute events, they may be less concerned about the possible harmful complications of pregnancy. This may result in a lower level of compliance with the preventive measures proposed during the antenatal period. This series consisted of cases from a single institution, followed prospectively; thus, we cannot rule out some possible selection bias. However, if there were bias, it would probably result from the selection of more complicated cases because peripheral maternity hospitals generally refer eventful cases to our university hospital. Randomized studies have shown no significant beneficial effect of prophylactic blood transfusions in pregnant women with SCD,14-18 and the appropriate timing of their use is still a matter of debate. Apart from emergency transfusion for acute anemia (< 5 g/dL hemoglobin), the recommended indications for blood transfusion include toxemia, twin pregnancy, previous history of perinatal mortality, septicemia, acute renal failure, acute chest syndrome, a recent neurologic event, hypoxemia, and preparation for surgical intervention.12 Thus most pregnant women with SCD, particularly those who are homozygous (SS), receive blood transfusions during the course of their pregnancy. In this study, we set out to limit the use of blood transfusion during pregnancy. We were forced to restrict its use even further due to local constraints. We found that many patients, when closely monitored, had well-tolerated anemia, regardless of the level of hemoglobin, and that many were able to complete their pregnancy successfully without transfusion, regardless of the route of delivery. Thus, as stated by El-Shafei et al,19 a policy of restricted blood transfusions can be followed safely without compromising maternal or fetal well-being, with the additional benefit of reducing blood transfusion-associated complications. These findings have major implications in Africa where safe blood products are not always available. In this series, 23 SS women (54.7%) and 22 SC women (33.3%) had transfusions. Analysis of the factors responsible for the worsening of anemia that led to transfusion indicated that the percentage of women transfused could probably be reduced further because P falciparum malaria, a preventable infection, was the root cause of 45.6% of the transfusions in SS women. In contrast, only 2 of the nontransfused SS women had P falciparum malaria during the pregnancy. Incidentally, fever is a major symptom of P falciparum malaria. However, we observed that several patients presented with high parasitemia and life-threatening anemia (hemoglobin < 40% of steady-state levels), but without fever. The pathophysiology of this condition is unclear, but the prevention of P falciparum malaria remains an essential goal in the management of pregnant women with SCD in environments in which this infection is endemic. The 11.9% rate of fetal loss late in pregnancy is exactly the same in this study as that reported in Jamaica5 or the United States.6 Still, it is higher than for the hospital maternity unit as a whole (6.3%). The limited laboratory facilities in our hospital have hampered attempts to investigate the causes of these fetal deaths in more detail. However, retrospective analysis suggested that at least 4 of the 13 fetal deaths (3 from SS mothers and 1 from an SC mother) might have been prevented by inducing labor earlier. These fetuses were aged over 37 weeks and all were alive during the 3 days preceding the onset of labor. It is possible that, in these patients who may have chronic organ damage, uterine blood flow and placental volume may not have been sufficient to meet the metabolic exchanges and growth requirements of the enlarging fetus, resulting in sudden fetal death as the pregnancy neared completion. An evaluation of when and how to induce labor in SCD patients is underway. In conclusion, we have shown that in an African setting, the clinical status of most SS and SC patients is not seriously affected by pregnancy if these women benefit from active prenatal management. The Republic of Benin is one of the least developed countries of sub-Saharan Africa. Its gross annual per capita income was estimated to be US $287 in 1994, with less than 5% of its budget dedicated to health services. The care regime described herein is based on simple low-cost approaches and does not require any significant increase in health care expenditure. Instead, emphasis is placed on education and frequent medical follow-up. It is therefore suitable for application in most African settings. The improvement that we have seen in maternal and fetal outcomes suggests that the widespread tradition in Benin of advising patients with SCD to avoid pregnancy requires reassessment.
We would like to thank Drs F. Guedou, E. Papiernik, R. Krishnamoorthy, and J. Elion for their help in the preparation of this manuscript.
Submitted October 4, 1999; accepted April 25, 2000.
Supported by grants from the Program CAMPUS of the Ministère Français de la Coopération (grant no. 9234106) and the European Union (grant no. TS3-CT930244).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Mohamed Cherif Rahimy, PO 01 Box 2640 RP Cotonou, The Republic of Benin (West Africa); e-mail: mrahimy{at}syfed.bj.refer.org.
1. Kobak AJ, Stein PJ, Daro AF. Sickle cell anemia in pregnancy: a review of the literature and report of six cases. Am J Obstet Gynecol. 1941;41:811.
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Charache S, Scott J, Niebyl J, Bonds D.
Management of sickle cell disease in pregnant patients.
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1980;55:407 3. Milner PF, Jones BR, Dobler J. Outcome of pregnancy in sickle cell anemia and sickle cell-hemoglobin C disease: an analysis of 181 pregnancies in 98 patients, and a review of the literature. Am J Obstet Gynecol. 1980;138:239[Medline] [Order article via Infotrieve]. 4. Tuck SM, Studd JWW, White JM. Pregnancy in sickle cell disease in the UK. Br J Obstet Gynaecol. 1983;90:112[Medline] [Order article via Infotrieve]. 5. Poddar D, Maude GH, Plant MJ, Scorer H, Serjeant GR. Pregnancy in Jamaican women with homozygous sickle cell disease: fetal and maternal outcome. Br J Obstet Gynaecol. 1986;93:727[Medline] [Order article via Infotrieve]. 6. Powars DR, Sandhu M, Niland-Weiss J, Johnson C, Bruce S, Manning PR. Pregnancy in sickle cell disease. Obstet Gynecol. 1986;67:217[Medline] [Order article via Infotrieve]. 7. Dare FO, Makinde OO, Faasuba OB. The obstetrics performance of sickle cell disease patients and homozygous C disease patients in Ile-Ife, Nigeria. Int J Gynaecol Obstet. 1992;37:163[Medline] [Order article via Infotrieve]. 8. El-Shafei AM, Dhaliwal JK, Shandhu AK. Pregnancy in sickle cell disease in Bahrain. Br J Obstet Gynaecol. 1992;99:101[Medline] [Order article via Infotrieve]. 9. Miller J, Horger E, Key T, Walker E. Management of sickle cell hemoglobinopathies in pregnant patients. Am J Obstet Gynecol. 1981;141:237[Medline] [Order article via Infotrieve]. 10. Charache S, Niebyl J. Pregnancy in sickle cell disease. Clin Haematol. 1985;14:729[Medline] [Order article via Infotrieve]. 11. Koshy M, Chisum D, Burd L, Orlina A, How H. Management of sickle cell anaemia and pregnancy. J Clin Apheresis. 1991;6:230[Medline] [Order article via Infotrieve]. 12. Koshy M. Sickle cell disease and pregnancy. Blood. 1995;9:157. 13. Smith JA, Espeland M, Bellevue R, Bonds D, Brown AK, Koshy M. Pregnancy in sickle cell disease: experience of the cooperative study of sickle cell disease. Obstet Gynecol. 1996;87:199[Abstract]. 14. Howard RJ, Tuck SM, Pearson TC. Pregnancy in sickle cell disease in the UK: results of a multicentre survey of the effect of prophylactic blood transfusion on maternal and fetal outcome. Br J Obstet Gynaecol. 1995;102:947[Medline] [Order article via Infotrieve].
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Cunningham FG, Pritchard JA, Mason R.
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1983;62:419 16. Tuck SM, James CE, Brewster EM, Pearson TC, Studd JWW. Prophylactic blood transfusion in maternal sickle cell syndromes. Br J Obstet Gynaecol. 1987;94:121[Medline] [Order article via Infotrieve]. 17. Koshy M, Burd L, Wallace D, Moawad A, Baron J. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. N Engl J Med. 1988;319:1447[Abstract]. 18. Morrison JC, Morrison FS, Floyd RC, Roberts WE, Wayne Hess L, Wiser WL. Use of continuous flow erythrocytapheresis in pregnant patients with sickle cell disease. J Clin Apheresis. 1991;6:224[Medline] [Order article via Infotrieve]. 19. El-Shafei AM, Dhaliwal JK, Shandhu AK, Al-Sharqi R, Salmaniya M. Indications for blood transfusion in pregnancy with sickle cell disease. Aust N Z J Obstet Gynaecol. 1995;35:405[Medline] [Order article via Infotrieve].
© 2000 by The American Society of Hematology.
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  L. Ross, P. Simkhada, and W. C. S. Smith Evaluating effectiveness of complex interventions aimed at reducing maternal mortality in developing countries J. Public Health Med., December 1, 2005; 27(4): 331 - 337. [Abstract] [Full Text] [PDF]
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 M. C. Rahimy, A. Gangbo, G. Ahouignan, R. Adjou, C. Deguenon, S. Goussanou, and E. Alihonou Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in a sub-Saharan African setting Blood, August 1, 2003; 102(3): 834 - 838. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
S gene frequency of about 25%. There are
several reasons for this. First, the clinical presentation is generally
severe and more than 50% of affected children do not reach their 5th
birthday. Survivors suffer rapid progressive organ damage, which
reduces life expectancy. Thus, many patients die before reaching the
reproductive age. Second, the fact that the outcome of pregnancy in
women with SCD is often poor is widely known by the population and it
is common belief that pregnancy is the main cause of death in women with SCD who have survived childhood events. Indeed, our experience before this study, with maternal and fetal mortality rates of 27% and
40%, respectively, clearly illustrates the high level of risks
associated with pregnancy in SCD patients in Benin. Thus, in many
communities, SCD women surviving to reproductive age are advised to
avoid becoming pregnant. In developed countries, improvements in the
pregnancy outcome have been achieved through a multidisciplinary approach.