Major Sickle Cell Disease in Pregnant Women at University Teaching Hospital of Cocody in Cote d’Ivoire, a Low Resources Country

Background : Sickle cell disease (SCD) is one of the most prevalent genetic disorders, including major SCD and SC Trait (SCT) genotypes. Many studies have shown a negative association between major SCD and pregnancy. However, they are underestimated in Cote d’Ivoire statistics. To provide consistent data on SCD in pregnancy, we compare outcomes between women with normal hemoglobin (Hb) genotype and major SCD. Methods : A retrospective, and case-control study in the University Hospital of Cocody, from 2015 to 2018, analyzed maternal and fetal outcomes, comparing the Cases Group: major SCD (HbSS, HbSC) and Control Group: normal hemoglobin (Hb) genotype A. Only pregnancies with gestations longer than 28 weeks were included. No cases of thalassemia or variant of hemoglobin were found. Local protocols recommended systematic use of vasodilators or analgesics, folic acid, and high concentrations of inhaled oxygen during labor, associated with fluid and/or blood transfusion. We excluded sickle cell trait (SCT) genotype AS (HbAS), and incomplete data. A logistic regression was exploited to gauge the risk factors. We used SPSS version 19 (IBM Corp., Armonk, NY, USA) for statistical analysis, and calculate the adjusted odds ratio and 95% confidence interval. Results : We registered 156 major SCD (0.92%), compared to 312 HbAA. In Cases Group 27.6% were multigravidas ( > 4), young aged ( ≤ 20) (16.0%), and well-educated (43.6%). Major SCD were HbSC (33.3%) and HbSS (66.7%). The commonest maternal antenatal complication in major SCD was anemia ( p < 0.0001), vaso occlusive crisis ( p < 0.0001), and pregnancy-induced hypertension ( p < 0.0001). Blood transfusions were significant in the SCD group ( p < 0.0001). No significant difference between the groups regarding stillbirths ( p = 0.3150) was recorded. Moreover, a significant risk in the major SCD genotype was low birth weight (LBW) ( p < 0.0001), negative Apgar in the 5th minute ( p < 0.0001), vaso-occlusive crisis (VOC) ( p < 0.0001), and acute chest syndrome (ACS) ( p < 0.0019). Conclusions : The findings of the survey suggest better fetal and maternal prognosis in HbAA compared to major SCD. Multidisciplinary team management is necessary to improve those outcomes. Patient awareness and education, and early and effective prenatal care are useful to avoid those risks.


Introduction
Normal human hemoglobin (Hb) (HbAA) allows oxygen transfer in blood.Its chemical structure normally includes one pair of heme molecules (2α-type) and globin chains (2β-type) [1].Globin represents the protein fraction in which many mutations can occur, leading to structural and physiological function alterations [1,2].Abnormal hemoglobin corresponds to sickle (S) cell disease (SCD) and may be in the form of a homozygous or heterozygous genotype.Sickle cell disease (SCD) is the most prevalent genetic disorder in developing Sub-Saharan Africa, South America, Central America, Saudi Arabia, India, and Mediterranean countries [3][4][5][6][7][8][9].This disorder is caused by a β-globin subunit gene mutation [3][4][5][6][7][8][9] and can be divided into 2 groups: major and minor SCD.Genotypically, homozygous hemoglobin S (SS) and heterozygous form (hemoglobin SC, hemoglobin Sβ+-thalassemia, and Sβ0-thalassemia) were predominant and considered major SCD.Infrequent forms include hemoglobin C, or even hemoglobin E (thalassemia β), or genotypes SD and SE [1][2][3][4].Women with hemoglobin HbAS or SC trait (SCT) genotype suffer from minor diseases [5][6][7].These abnormal structural variations result in oxygen delivery alterations, Hb molecule instability, and low oxidation resistance [1,4].SCD is the most common hemoglobinopathy among humans, affecting approximately 5% of the world's population, and 7% of pregnant women [1,4].The condition promotes susceptibility to severe infections, chronic inflammation, hypercoagulability disorders, damage to vital organs, renal and respiratory disorders, or bone marrow suppression [1,[5][6][7].Empirical evidence suggests that major SCD is negatively correlated with poor maternal and perinatal health outcomes [5][6][7][8][9].Few studies in Cote d'Ivoire, have studied the negative outcomes of SCD in pregnancy [8,9].These negative repercussions include maternal complications, such as chronic anemia, infection, painful vaso-occlusive crisis (VOC), preeclampsia, premature labor, and increased cesarean section (CS) rates [5][6][7][8][9][10][11][12].On the other side, adverse perinatal outcomes include intrauterine growth restriction (IUGR), premature infants, and in-utero fetal distress or death (IUFD).High rates of maternal and fetal mortality were reported during pregnancy in major SCD compared to the general population [8][9][10][11][12].This condition required better quality of management to improve the mother and child's prognosis [9].There is a paucity of information about SCD making appropriate ante, prenatal and postnatal care challenging.In developing countries, lack of education in women, low access to prenatal care, lack of medical coverage, and low technical-level health facilities are obstacles to efficient management.Moreover, the development of guidelines for providing complete prenatal care to women with SCD has yet to be developed.The implementation of better management modalities should be instituted and would require a multidisciplinary team decision (MTD) of obstetricians, hematologists, pediatricians, anesthesiologists, and midwives.This study was conducted to report consistent data on the prevalence of this major hemoglobin disease, to evaluate prenatal and postnatal care, and to determine the maternal and fetal prognosis in a reference health center located in Cocody.

Material and Methods
We conducted a retrospective cross-sectional and retrospective case-control study of all hemoglobinopathies at the obstetrics department of the University Hospital of Cocody (Cote d'Ivoire), between January 2015 and December 2018 (4 years).We have obtained the approval of Felix Houphouet Boigny University for the publication of the results of this study.This study compared ante, intra and postnatal outcomes of women with major SCD (Cases Group), to those with normal hemoglobin genotype or HbAA (Control Group).The inclusion criteria are listed as following: Cases Group included the major SCD genotypes (HbSS, HbSC), and the Control Group consisted of pregnant women with HbAA.The exclusion criteria are listed as following: incomplet files lost of followup and non consent women.The genotype was specified by hemoglobin electrophoresis performed during antenatal care or known before pregnancy.We analyzed maternal and fetal outcomes.The Cases Group included the major SCD genotypes (HbSS, HbSC), and the Control Group consisted of pregnant women with HbAA.No cases of quantitative sickle cell disorders of globin chains (thalassemia), qualitative disorders of globin structure, or structural variant of hemoglobin (S-ßthalassemia, HbSF, HbSD, HbSO) were found in the population.In the same way, we did not find hemoglobin with decreased stability, and Hemoglobin with altered oxygen affinity as our laboratories are lim-ited.We obtained consent from 468 pregnant women for this comparative retrospective study: 156 women with major SCD belonging (Cases Group); 312 pregnant women with HbAA genotype (Control Group).The comparison involved ante, intra, and postpartum data, and the selection of the patient pool was based on matching age, gravidity, and similar socioeconomic status.Emphasis was on obstetrical history and significant history of the underlying disease symptomatology.Preterm labor was considered as the onset of labor before 37 completed weeks of gestation (WG), while anemia was identified when the hemoglobin concentration level was below 110 g/dL.The World Health Organization (WHO) defined severe anemia as Hb <70 g/L in children under 5 years of age and Hb <80 g/L in all other age groups, though other definitions, including Hb <50 g/L, are used of particular importance clinically, as it can result in high-output heart failure and death.Pregnancyinduced hypertension (PIH) was a blood pressure higher than 140/90 mmHg in two instances six hours apart.Early neonatal death was determined as death within seven days of birth, whereas low birth weight (LBW) was defined as birth weight below 2500 grams.IUGR was diagnosed when the birth weight was lower than the 10th percentile of the average for gestational age.The patient's prenatal care was provided in conjunction with hematologists on an alternating bimonthly basis.Pregnant women's care was delivered under the aegis of MTD management, led by an experienced hematologist, neonatologist, nephrologist, pain management experts, and obstetricians.Local protocols recommended for major forms of hemoglobinopathies in pregnant women, systematic use of vasodilators (Trimetazidine Dihydrochloride 5 mg coated tablet daily, manufactured by Rakshit Pharmaceuticals Limited in Ahmedabad, Gujarat, India) or analgesic (manufactured by Sanofi-Aventis, Paris, France) three times per day (in case of painful crises), Folic acid tablet 5 mg daily 5 (manufactured by Versalya Pharma, Milan, Italia) until the postpartum period.High concentrations of inhaled oxygen were administered to prevent HbS polymerization during labor associated with fluid and blood transfusion if the hemoglobin level was less than 7 g/dL.We excluded women with HbAS, any other electrophoretic profile, and history of renal disease, pre-existing diabetes, incomplete data, and abortion as we only included pregnancy over 28 WG.A logistic regression was exploited to gauge the risk of pregnancy outcomes.Pregnant women with abnormal hemoglobin were compared (i.e., pregnant women with SCD versus SCT).Odds ratios were calculated by comparing SCT with SCD.We employed SPSS version 19 (IBM Corp., Armonk, NY, USA) for statistical analysis.The adjusted odds ratio (AOR) and 95% confidence interval (CI) were obtained with logistic regression in multivariate analyses adjusted for age, parity, and other variables in the study.The level of significance for the p value was set as 0.05 (p < 0.05).

General Data of Pregnant Women
Over a 4-year-period, we recorded 16,924 deliveries, with 156 cases of major SCD (HbSS, 104; HbSC, 52) corresponding to a prevalence of 0.92%.Major SCD forms included heterozygous genotype (HbSC, 33.3%) and homozygous forms (HbSS, 66.7%).The mean gestational age at delivery was 36 ± 4 weeks.CS represents 52.6% in both Groups (n = 246), and included 246 in the Cases Group (84.6%).No twin pregnancies were recorded in HbAA either in major SCD.These major SCDs correspond to the Cases Group (n = 156), and were compared to 312 pregnant women without SCD (normal hemoglobin genotype, Control Group) (Table 1).The Control Group included women between the ages of 15 and 44 years (mean 26.9 ± 3.9).As for the Cases Group, the youngest and oldest were 16 and 40 years, respectively (mean 27.7 ± 4.1).The majority of women in the two groups were of the reproductive age, range between 21 and 35 years old.All women included in the Cases Group were below 40 years old Amongst the 468 women, 143 were primigravidas (30.6%), followed by 199 multigravida (>4) (42.5%) (Table 1).These data on pregnant general characteristics are highlighted in Table 1.

Intrapartum and Neonatal Data
Logistic regression analysis did not confirm a statistically significant association between the major SCD group and HbAA, concerning CS (p < 0.0001) and intrapartum hemorrhage (p = 0.0002; Table 2).The occurrence of maternal death (MD) was not significant in the Cases Group (OR = 0.20, 95% CI [0.04-0.84];p = 0.0320; Table 2).Emergency CS was realized for acute fetal distress (AFD) in major SCD (80.0%).The mean birth weight was 2825 g in the Control Group, while in the major Cases Group it was 1876.79 g.No significant association was observed between both Groups, regarding perinatal mortality (p = 0.2110), stillbirths (p = 0.3150), acute fetal distress (p = 0.9308), Intrauterine fetal death (p = 0.7194), and neona- tal infection (p = 0.1600; Table 3).Moreover, major SCD genotypes were significantly associated high risk of low birth weight (LBW; p < 0.0001) and an Apgar score of less than 7 in the 5th minute (p < 0.0001; Table 3).

Limitations
There are some limitations in the present study.This was a retrospective study based on patients' data collected at a hospital and further analyzed.Our study did not cover women with SCD who delivered at home or other health care facilities in the territory, as well as the cause of the perinatal mortality rate of 4.4% observed in the Control Group (p = 0.50).Therefore, the findings of this study may not be generalized to all the women in Cote d'Ivoire.Prospective data collection could increase the quality and credibility of the presented results.Nevertheless, our results were reported according to statistical standards that would minimize potential bias.Also, we did not perform a statistical comparison between data of the different sickle cell genotypes which could have allowed us to determine prognostic factors.This will soon be done in a prospective cohort multi-centric study.

Conclusions
The findings of the present survey suggest better fetal and maternal prognosis in HbAA, than in major SCD.The latter is associated with maternal complications, such as severe anemia, low birth weight, and prematurity.Multidisciplinary team management is required during these pregnancies to improve maternal and fetal prognosis.Patient awareness and education, and early and effective prenatal care are useful to avoid those risks.