Normal human hemoglobin (Hb) (HbAA) allows oxygen transfer in blood. Its chemical structure normally includes one pair of heme molecules (2$\alpha$-type) and globin chains (2$\beta$-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 $\beta$-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 S$\beta$+-thalassemia, and S$\beta$0-thalassemia) were predominant and considered major SCD. Infrequent forms include hemoglobin C, or even hemoglobin E (thalassemia $\beta$), 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.

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 follow-up 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 limited. 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. Pregnancy-induced 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).

Sickle cell disease (SCD), first described three centuries ago in Africa [6, 11], is an autosomal recessive disorder with higher maternal and fetal risk during pregnancy [12, 13]. People who inherited one copy of the HbS allele, and one normal HbA allele (HbAS), also called sickle cell trait (SCT), are typically asymptomatic, with no serious adverse outcomes [12]. The homozygous form of the HbS gene (HbSS) characterizes sickle cell anemia, the most prevalent monogenic condition worldwide [1, 2, 13, 14, 15, 16, 17, 18]. However, other genotypes causing SCD can be identified, corresponding to the uniparental inheritance of the $\beta$S allele in concomitance with mutations for other HbA variants, such as S$\beta$0-thalassemia, S$\beta$+-thalassemia, and HbSC [1, 2, 9]. The abnormal HbSS and heterozygous variants are considered major SCD [6, 7, 12, 13, 14, 15, 16], and the leading main consequences are the formation of falciform cells [15, 16, 17] and chronic anemia [2, 6, 9, 15]. Falciform cells formation is supported by conditions like hypoxia, dehydration and acidosis, anemia, adhesion, and vasoconstriction [7, 13]. The main consequences inherent to this structural change are vascular disorders, painful crises, intercurrent infection, retinopathy or stenosis of the proximal portions of the large arteries, and cerebrovascular complications [7, 11, 15, 16, 17, 18]. A retrospective analysis conducted in Cote d’Ivoire gives new insights into the prevalence of SCD among patients suffering mild malaria, and found a national prevalence higher than these findings [18]. This study revealed limited prevalence, reflecting only hospital dimensions of the disease. These findings were consistent with published data in Sub-Saharan Africa literature, describing lower frequencies of around 1% to 2% of pregnancies [5, 6, 7, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. In Asia and North Africa, some authors reported higher prevalence rates [3, 4, 7, 12, 16]. In the current study, young women were predominant, and that was consistent with sub-Saharan African authors’ findings [6, 8, 9, 10, 13, 17, 18, 19, 20, 24], and those in high-income countries [21, 22, 28, 29, 30, 31]. The majority of African populations are characterized by early sexual activity, due to early marriage, which was in perfect adequation with customs and traditions [6, 8, 9, 10, 13, 17, 18, 19, 20, 24, 31]. Those populations lived usually in precarious socio-economic conditions, and are unaware of family planning methods [9, 13, 18, 19, 20, 23, 24, 30, 31], which can explain the low rate of antenatal monitoring reported in this study and the fact that nearly half of the pregnant women did not know their hemoglobin genotype before the antenatal screening [6, 13, 17, 18, 19, 20, 31, 32, 33]. In this study, the commonest SCD was HbSS, which was consistent with literature findings [3, 5, 7, 8, 17, 18, 19, 20, 27, 28, 29, 30, 31, 32]. In low- and middle-income countries (LMIC), the HbSS genotype was commonly associated with high rates of spontaneous miscarriage and IUFD [3, 5, 7, 10, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. The severe maternal and fetal complications of this association have been documented [3, 6, 18, 21, 22, 25, 31]. The implementation of ante, intra, and postpartum monitoring, managed by the obstetrician-led team (obstetricians, interns, and midwives) was essential [17, 27, 28, 29, 32]. The contribution of a hematologist is also required in all inpatient and outpatient pregnant women with SCD. Laboratory blood analysis, fetal Doppler ultrasound examination, fetal biometry, and Doppler velocimetry were necessary after 34 WG. A bi-weekly fetal monitoring until 34 WG, and weekly thereafter was necessary until delivery. This MTD provided all outpatient medical care for efficient care as vascular trouble during pregnancy, such as gestational thrombocytopenia, coagulation disorders and development of abnormal blood cells that can occlude blood vessels can be observed [11, 15, 17, 27, 32, 33, 34, 35, 36, 37]. According to previous studies [10, 11, 12, 19, 20, 21, 22, 23, 31, 32, 34, 37], we also found significant maternal morbidity rates associated to PIH (p = 0.0002) and VOC (p = 0.0001). As such, we considered that MTD is essential to provide efficient care, and reduced maternal and perinatal mortality rates amongst pregnant women with SCD compared to pregnant women without SCD [16, 17, 27]. Its implementation is essential [17], but depends on the country’s medical possibilities and resources. There was no standard care protocol for outpatient and inpatient, and a hematologist consult was sought using the hospital’s procedures for internal referrals [17]. As described in the literature [11, 15, 17, 32, 33, 34, 35, 36, 37, 38], we recorded severe maternal morbidity in people with SCD compared with deliveries among people without SCD, especially for severe hemolytic anemia (p 0.0001) and blood transfusions (p 0.0001). Blood transfusions were the main treatment for the HbSS genotype as consistent in the literature, and the hematologist’s contribution is essential in its monitoring [38, 39]. Additional morbidity factors have been highlighted, in particularly painful VOC, postpartum hemorrhage [13, 14, 31, 40]. Severe chronic anemia and painful VOC are commonest in HbSS compared to HbSC [10, 38, 39]. All those morbidity factors increased the rate of hospitalization [15, 26]. MTD care using blood coagulation monitoring during the antenatal period, including accurate testing and appropriate implementation, is necessary to contribute to early diagnosis and treatment [17, 27, 37]. The possibility of the appearance of disorders of the vital organs demonstrates the need for multidisciplinary management [17, 23, 27]. The crucial period of these complications’ development is during the third trimester and postpartum period [33, 34, 35, 36]. In this study, no cases of COVID-19 infection were recorded because the study was conducted before the epidemic crisis. However, it is well-known that SCD is considered to have a greater risk of severe illness and death from respiratory infections, including COVID-19, compared to normal hemoglobin. VOC in SCDs and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade [39, 40]. In this study, pregnancy in women with SCD was not associated with increased rates of MD. The same constatations have been recorded by Oppong et al. [17] regarding MD compared to Controls Group. Cardiopulmonary complications were the commonest cause of MD [33], even if more than half of the deceased women had ACS [38]. For all these reasons, it was recommended establishing multidisciplinary care to reduce maternal and perinatal mortality rates amongst pregnant women with SCD compared to pregnant women without SCD [17, 27, 39]. Our findings concerning neonatal findings, confirmed the evidence that major SCD is not significantly associated with preterm labor (p = 0.0572), IUGR (p = 0.0001), LBW (p 0.0001), and Apgar 7 at 5 min (p 0.0001). HbSS genotype had higher rates of perinatal morbidities compared to pregnant women with HbSC, as described by Oppong et al. [17]. As reported in the research literature, SCD increased the risk of adverse perinatal and maternal outcomes in both LMIC of Africa [10, 12, 15, 16, 31] or Asia [3, 5, 16], and high-income countries [33, 34, 35, 36, 37, 38]. The perinatal mortality rate was comparable in women with and without SCD (p = 0.211) but a small sample size of maternal (n = 2) and perinatal (n = 12) deaths, in both the women with and without SCD [12, 19]. HbSS had higher rates of perinatal morbidities compared to HbSC disease [19, 20, 23, 32, 38, 39, 41]. Implementation of the MTD care team significantly helps to decrease the perinatal mortality rate from 60.8 per 1000 births to 23.0 per 1000 births, representing a relative risk reduction of 62.2% (p = 0.20) [34, 39]. The authors also showed that the decline in the mortality rate was not significantly different, so additional preventive measures are probably required. According to our study, pregnancy complications can be severe, more frequently in pregnant women with major SCD compared to other genotypes [10, 20, 34, 37, 41]. Indeed, women with SCD had a higher risk of intrapartum stillbirth compared to normal hemoglobin but the real pathological mechanism is still not elucidated [40]. A few studies point out vasoconstriction in the placenta, placental infarction, and placental insufficiency due to reduced nutrient supply and poor metabolic exchange responsible for IUFD and IUGR [30, 32, 41]. Similar reports were found in the literature and suggested the implementation of common therapeutic measures during pre and postnatal care [6, 7, 8, 28, 29].

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.

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.

Data supporting the results of this study are available from the corresponding author, but restrictions apply to their availability. The data were used under license for the current study, and are therefore not publicly available. However, the data are available from the authors upon reasonable request and with permission from Mian et al.

VAA, JK, KHY contributed to the extraction and drafting this manuscript; data analysis, design and editing. DBM, VAA, CJN, JK, KNG, SB have made the final statistical analysis and manuscript revision. All authors have read and approved this final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.

The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Felix Houphouet Boigny University (N245354-CI/2020). All subjects gave their informed consent for inclusion before they participated in the study.

We acknowledge any support provided that is not covered by the authors’ contribution.

This research received no external funding.

The authors declare no conflict of interest.