Homozygous Deletion Alpha-Thalassemia and Hereditary Persistence of Fetal Hemoglobin, Two Genetic Factors Predictive the Reduction of Morbidity and Mortality During Pregnancy in Sickle Cell Patients. A Report from the Democratic Republic of Congo
1 Center for Human Genetics, Faculty of Medicine, University of Kinshasa, Democratic Republic of Congo, DRC.
2 Division of Gynecology Obstetrics, Center for Sickle Cell Anemia, Kinshasa, DRC.
3 Division of Pediatrics, Hospital University, Faculty of Medicine, University of Kinshasa, DRC.
4 Division of Internal Medicine, Service of Immuno hemato Rheumatology, Hospital University, Faculty of Medicine, University of Kinshasa, DRC.
5 Division of Gynecology Obstetrics, Hospital University, Faculty of Medicine, University of Kinshasa, DRC.
Received: December 18, 2018
Accepted: May 22, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019039 DOI 10.4084/MJHID.2019.039
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to determine the beneficial role of Fetal Hemoglobin (FHb) and
alpha-thal on fetal and maternal morbidity during pregnancy in sickle
Patients and Methods
Operational definitions. In this study, the group of gestational Hb-SS /alpha-thal included only patients who had the deletion alpha-thalassemia homozygous (-α, -α or --, αα) and the group HbSS / HPFH the patients with an FHb level > 15%. However, all sickle cell patients with heterozygous alpha-thalassemia (-α, αα or αα, -α) or with FHb < 15% were excluded from this study.
Laboratory tests. The diagnosis of SCD was made by the technique of capillary electrophoresis; the device used was the Mini cap flex piercing (Sebia, France). This technique also made it possible to quantify the fraction of FHb and to make the diagnosis of HPFH. The diagnosis of HPFH was retained for an FHb > 15% after three dosages within three months. The diagnosis of SCD was confirmed by a molecular test based on the restriction fragment-length polymerization technique (RFLP). The diagnosis of alpha-thalassemia has been made by the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. The procedures, as well as the reagents used for both techniques (RFLP and MLPA), have been carefully described by Mikobi et al..[15,16]
Protocol for the management of sickle cell disease.
Transfusion and pain management. Our protocol advocates only therapeutic transfusions during pregnancy. Prophylactic transfusions which systematically transfuse sickle cell disease from the 24th weeks of pregnancy are not practiced in our department for two main reasons: economic and lack of consensus in the real benefit of systemic prophylactic transfusion. However, we will resort to occasional transfusion exchanges during the pregnancy when there is an indication. Vaso-occlusive pain at levels 1 and 2 was managed with analgesics according to the recommendations of the WHO. Complicated VOC with Stage 3 pain was managed with a multidisciplinary team consisting of anesthesia intensive care and hematologist.
Maternal pregnancy supplements and fetal monitoring. All pregnant women were given a systematic supplementation of iron and folic acid, and anti-oxidants (omega 3 fatty acids and magnesium pidolate) from the 12th week of amenorrhea. Prophylactic anti-malarial treatment was given between the 24th and 32nd weeks, and anti-helminthic deworming was given between 28 and 32 weeks. No patients received hydroxyurea during pregnancy. Fetal surveillance was primarily based on ultrasound scans.
Childbirth. Delivery was systematically scheduled for the 37th week of amenorrhea after the completion of the biophysical manning score.
Variables of interest for the study. In this study, the following general maternal variables were assessed: gestational age, menarche age, parity, weight gain. The pregnancy weight gain (ΔP) was calculated from the following formula: ΔP = Pf - Pi (Pf weight of the pregnant woman at the time of delivery, Pi weight before pregnancy). The evolution of the Hb rate allowed to appreciate the validity of a punctual transfusion. Maternal morbidity was assessed by the analysis of sickle cell complications: VOC and hemolysis as a function of gestational age, including pregnancy complications: preeclampsia, acute chest syndrome (ACS), parasitic infections (malaria), bacterial infections (urinary tract infections, pneumonia, sepsis) and postpartum, endometritis. Fetal morbidity was assessed by analysis of abortion rates, prematurity, low birth weight, and in utero death.
Statistical analyses. Statistical analyses were performed using SPSS version 20.0.T. (2016). We had determined the distribution of the study population, which was normal. We have determined also means and standard deviations. Mean of two groups were compared by the Student's t-test and those of three groups by the ANOVA test. The value of p <0.05 was considered the only one of significance.
Table 1 gives the general characteristics of sickle-cell pregnancies according to their genotype. The analysis in the table shows that the Hb-SS / alpha-thal and HbSS / HPFH women had their menarche before those of the HbSS genotype. In addition, these gestants (HbSS/alpha-thal and HbSS/HPFH) had a better weight gain. Statistical differences between the first two groups and the third group were highly significant (p <0.001).
|Table 1. General Characteristics of Sickle Cell Pregnancy by Genotype.|
Table 2 shows the biological variables during pregnancy. From the analysis in this table, the gestants of the HbSS genotype had higher levels of WBC, platelets, and reticulocytes than those with an alpha-thal or HPFH combination. The differences were highly significant (p<0.001). In contrast, serum iron and Hb were similar in all three groups.
|Table 2. The biological variables of the pregnant.|
Figure 1 shows the distribution of sickle cell crises during pregnancy. The chart analysis shows that VOC and hemolysis increase steadily with gestational age. They reach their maximum in the third trimester. However, the HbSS genotype is more affected than the other two groups. Statistical differences with the Hb-SS/alpha-thal group are highly significant (p<0.001).
|Figure 1. Evolution of VOC and worsening of anemia during pregnancy.|
Table 3 presents the frequencies of maternal and fetal complications. The analysis in this table shows that the frequencies of ACS and pre-eclampsia were similar in all three groups. In contrast, spontaneous abortions, prematurity, low birth weight, in utero death and maternal death have been more observed in the HbSS genotype. Statistical differences with the other two genotypes were highly significant (p <0.001).
|Table 3. Frequencies of maternal and fetal complications.|
Figure 2 shows the distribution of parasitic and bacterial infections during pregnancy. It appears that the frequencies of malaria were similar in the three groups. In contrast, bacterial infections (urinary tract infections, pneumonia, sepsis, and endometritis) were more common in the HbSS genotype. The statistical differences were highly significant (p <0.001).
|Figure 2. Distribution of parasitic and bacterial infections during pregnancy.|
Delivery route. In our series, 49% of Caesarean sections were performed in patients with the HbSS genotype. Whereas the rates of the cesarean section of pregnant women with the HbSS / alpha and HbSS / HbF genotypes were 24% and 27% respectively.
In this study, sickle cell patients with HbSS genotypes had their menarche late at 16 years of age. Puberty delay is usually observed in SCD and is proportional to the severity of the disease. The delivery was programmed at the 37th week; this attitude is the one reported by many authors.[19,20] Our study showed a significant difference in weight gain in favor of the HbSS / PHHF and HbSS / alpha-thal genotypes. The observed difference could be associated with the protective effects of HbF and alpha-thal. From the hematological variables, the HbSS genotype has a high number of WBCs, reticulocytes, and platelets. These high biological variables can explain the high morbidity of these patients during pregnancy.
VOC episodes were the leading cause of morbidity during pregnancy in SCD, as also reported by other authors. These VOC increase with gestational age and are more frequent and severe in the perinatal period. In our series, VOC seizures were more common in the HbSS group. During pregnancy, several authors report a high frequency of complications such as acute thoracic syndrome and pre-eclampsia.[23,24] Their frequencies (9 to 16%) vary from one series to another.[20,23,24] In our series, the frequencies of these two complications are similar to those reported by other authors on the one hand and similar between the three genotypes on the other hand. During pregnancy, spontaneous abortions, prematurity, hypotrophy, and in utero fetal death are the main complications found in SCD.[20,25] The frequencies are different from one series to another; they are also proportional to the severity of the disease during pregnancy. In our series, these complications are more common in the HbSS group.
Infection is ranked as the second leading cause of morbidity during pregnancy in SCD. In our series, malaria was the first parasitic infection encountered because of the geographical situation of DRC. Indeed, DRC is located in the area with the highest prevalence of malaria. This infection alone constitutes the first cause of maternal and fetal morbidity. In tropical Africa, malaria is ranked as the leading cause of fetal hypotrophy. The high morbidity of malaria during pregnancy is associated with maternal anemia that Plasmodium falciparum can cause. In our series, the frequency of malaria was similar in all three genotypes. Maternal morbidity has also been influenced by bacterial infections such as urinary tract infection, pneumonia, sepsis, and endometritis. Their frequencies are similar to those reported by other authors. However, in our series, these infections were more common in the HbSS group. The high frequency of cesarean section in SCD is related to peripartum complications. In our series, 49% of pregnant women had delivered by cesarean section. This frequency is similar to those reported by other authors. However, the group with the HbSS genotype was more exposed to cesarean section than the other two. The protective effect of HbF and alpha-thal observed in our series, is similar to that reported by other authors in the associations S/β(0) thalassemia, S/β(+) thalassemia, or other major sickle cell syndromes like SC, SD.
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