1. INTRODUCTION

Sickle cell anemia (SCA) is a condition brought on by faulty mutant hemoglobin production that leads to tissue ischemia and infarction throughout the body in SCA patients. SCA is the most prevalent hemoglobinopathy during pregnancy that might cause prematurity and low birth weight (LBW).1,2 Other maternal factors, such as dietary status, smoking, and drug use, as well as fetal and placental factors, such as genetic makeup, affect fetal growth and add more risks and adverse neonatal outcomes in mothers with SCA.3,4 In addition, SCA mothers experience an aggravation of the physiological changes of pregnancy, such as an increase in metabolic demand, blood viscosity, and hyper-coagulability, which increases the risk of complications like a vaso-occlusive crisis and thrombo-embolic events.5

The most frequent pathophysiologic cause of fetal growth retardation in a healthy pregnancy is placental insufficiency, which occurs when the fetus cannot grow to its total capacity due to decreased placental function.6,7 As a consequence of SCA, vaso-occlusion in the placenta causes villous fibrosis, necrosis, and infarction, impairs uteroplacental circulation, and results in prolonged fetal hypoxia and unfavorable fetal outcomes.8,9 Previous research on the prognosis of pregnancy in women with SCA showed an almost universally unfavorable outcome for mothers and children. However, preconception care and other advances in medical care have significantly improved the situation.2 Additionally, gestational diabetes is another maternal risk that is observed to be highly related to pregnancy in SCA; also, these mothers have an increased risk of spontaneous miscarriages and stillbirths due to micro-vascular damage and reduced uteroplacental circulation.10

The prevalence of SCA in Saudi Arabia varies wildly in different parts of the country, with the highest prevalence in the Eastern province, followed by the southwestern provinces.11 According to the Saudi Premarital Screening Program, the adult population has a sickle cell gene prevalence of 4.2% for sickle cell trait and 0.26% for sickle cell disease.12,13 The current study aimed to assess neonatal maturity and birth weight as outcomes in neonates delivered to mothers with SCA in the Jazan region and to assess the association between demographic variables of the mothers affected with SCA and neonatal outcomes.

2. METHODS 2.1. Context of the study

A case-control study was conducted and targeted both women, with SCA (case group) and non-SCA (control group), after delivery and newborn babies in three hospitals (Sabia, Sametah, Abu Arish General Hospital) in the Jazan region, reflecting the population in north, east, and west region of Jazan region respectively. Jazan region lies in southwestern Saudi Arabia, north of Yemen, with a population of 1.6 million.14

2.2. Data collection tool

The data collection tool included a semi-structured questionnaire within the context of a direct interview. The questionnaire was designed in Arabic to enable a more straightforward data collection process from the targeted population. It was designed to assess maternal data and neonatal birth outcomes. The demographic data included the mother’s age, educational level, occupation, and residence. In addition, the mother’s other maternal risk factors were considered, like hypertension, diabetes mellitus, smoking, and using medications during pregnancy. Also, questions to assess antenatal care were included in the form of easy access to service and the frequency of visits. Finally, data related to neonatal birth outcomes were collected to evaluate the mode of delivery, gestational age, baby gender, and birth weight. Some case definitions were used in this study and should be mentioned in this context: maturity is defined as birth after the completion of 37 weeks of gestation.15LBW was represented as a birth weight of <2500 g, while high birth weight was defined as a birth weight of more than 4000 g.16,17

2.3. Data collection process and the participants

This study targeted women with a history of SCA in the Jazan region compared with non-SCA women who delivered in the same hospitals and region. All Saudi mothers delivered in the target hospitals were included in this study; the mothers who refused to participate were excluded. In order to determine the sample size, a case-control ratio of 1:4 was used. In other words, we included approximately four mothers of control babies for every mother of a case group. The data were collected through personal interviews using a self-developed questionnaire after verbal informed consent was obtained before the interviews were initiated. Data were collected from the participants under a guarantee of anonymity—no identification data were gathered. Interviews were performed in private settings to ensure the privacy of participating women. Then the weight of the delivered newborn was obtained in kilograms (kg) using the weight scales in the delivery rooms shortly after delivery. A comparison group of 149 women with an AA phenotype hemoglobin, matched as closely as possible regarding maternal age and the delivery date, was included in the study, along with 38 singleton-delivered women with SCA (diseased: SS phenotype and trait: SA phenotype).

2.4. Data analysis

Data were analyzed via the Statistical Package for Social Sciences software, version 23.0 (IBM SPSS Inc., Chicago, IL). All information was gathered via a questionnaire and coded into variables. Categorical variables were shown as numbers and ratios, while continuous variables were shown as mean and standard deviation. Comparing proportions was done using the chi-square test; means were compared using the Student t-test. To estimate the relationship between the two variables, the odds ratio with a 95% confidence interval was generated. A value of less than 0.05 was considered significant for the probability value. To find the linked factors with the most significant power and to get rid of the ones that confused, logistic regression was used.

3. RESULTS

During the study period, there were 38 deliveries of pregnant SCA women. More than half of them aged ranged between 20 and 30 years old. Thirty-five percent were university educated, 78 percent were non-workers, and about 75 percent of the women came from rural areas. Eighty-six percent of the study sample diagnosed sickle cell trait with hemoglobin phenotype SA. Compared to 149 non-SCA women, the control group matched the SCA group in age and residence with almost a percentage distribution of age, residence, and education variables.

Regarding the variables in the two groups, 2.6% of SCA groups were smokers, 7.9% were diabetic, and 5.3% were hypertensive. These compared to 2% smokers, 6.7% diabetic, and 6.7% hypertensive in the control group. The antenatal care was adequate in two groups, constituting 89% in the case group and 75 % in the control group, as shown in Table 1. The mode of delivery was vaginal deliveries in more than 70% of the case and control groups, while the birth weight was 2.95 ± 0.40 kg and 2.99 ± 0.55 kg in the case group and control group, respectively. However, the LBW babies constitute 31% of the delivered babies in the SCA group with a weight of 2.33 ±.16 kg and 15% of the control group with a mean weight of 2.16 ± 0.30 kg. In addition, the gestational age was 39.36 ± 1.02 weeks in the case group compared to 39.5 ± 1.17 weeks in the control group, as demonstrated in Table 2.

Table 1 - Sickle cell anemia patients and control group characteristics SCA group (n = 38) Control group (n = 149) Variables Frequency % Frequency % Mother age 20-30 21 56.8 96 64.4 31-40 13 35.1 49 32.9 41-50 4 8.1 4 2.7 Mother’s education Not educated 8 21.1 37 24.8 Primary 7 18.4 18 12.1 intermediate 1 2.6 14 9.4 Secondary 9 23.7 34 22.8 University 13 34.2 46 30.9 Mother’s occupation Non-worker 30 78.9 127 85.2 Worker 8 21.1 22 14,8 Region Sabya 3 7.9 19 12.8 Samtah 10 26.3 50 33.6 Abu Arish 4 10.5 40 26.8 Alardah 10 26.3 6 4.0 Ahed Almsarha 3 7.9 7 4.7 Damad 3 7.9 3 2.0 Jazan 1 2.6 2 1.3 others 4 10.5 22 14.8 Residence Urban 9 23.7 30 20.1 Rural 29 76.3 119 79.8 If the mother smoke Yes 1 2.6 3 2.0 No 37 97.4 146 98.0 If the mother diagnosed with hypertension Yes 2 5.3 10 6.7 No 36 94.7 139 93.3 If the mother diagnosed with diabetes mellitus Yes 3 7.9 10 6.7 No 35 92.1 139 93.3 The type of sickle cell anemia SCD 5 13.2 13.5 - SCT 33 86.8 100.0 - If the mother receive medications during pregnancy Yes 16 40.5 37 31.1 No 22 59.5 112 24.8 Regular antenatal visits Yes 34 89.5 128 75.2 No 4 10.5 21 14.1

SCD = sickle cell disease; SCT = sickle cell trait.

Table 2 - Neonatal outcomes in sickle cell anemia patients and control groups Outcomes SCA group (n =38) Control group (n = 149) Mean

±

SD Minimum Maximum Mean

±

SD Minimum Maximum Birth weight (kg) 2.9474

±

0.40 2.00 3.90 2.99

±

0.55 1.00 5.00 LBW 2.33

±

0.16 kg N: 12 (31.6%) 2.16

±

0.3 kg N: 23 (15.44%) Gestational age (weeks) 39.36

±

1.02 37.00 40.00 39.5

±

1.17 34.00 42.00 Gestational age < 37 weeks N: 0 (0%) N: 1 (0.67%) Mode of delivery Vaginal 29 (76.3%) Vaginal 105 (70.5%) Cesarean 9 (23.7%) Cesarean 44 (29.5%) Gender Male 22 (57.9%) Male 81 (54.4%) Female 16 (42.1%) Female 68 (45.6)

Using the correlation tests as shown in Table 3 to assess the influence of the different variables on the birth weight, there is a significant influence of maternal age and if the mother diagnosed with high blood pressure on the birth weight in the SCA group compared to the influence of the diabetes mellitus on the birth weight in the control group. In addition, Table 4 shows a significant correlation between the mother diagnosed with diabetes mellitus and the gestational age in the control group. At the same time, there is no significant correlation between the variables and the gestational age in the case group.

Table 3 - Correlation between variables and birth weight in SCA group and control group variables SCA group (n = 38) Control group (n =149) Value df Significance (2-sided) Value df Significance (2-sided) Mother age 339.537 260 0.001 707.627 672 0.165 Mother education 41.246 52 0.880 97.270 95 0.445 Mother occupation 8.919 13 0.779 28.169 24 0.253 Region 77.527 91 0.842 195.863 168 0.070 If have regular antenatal care visits 19.714 13 0.103 151.50 24 0.916 If the mother smoke 8.730 13 0.793 28.058 24 0.258 If the mother diagnosed with hypertension 38.000 13 0.000 14.260 24 0.941 If the mother diagnosed with diabetes mellitus 19.663 13 0.104 43.678 24 0.008 If the mother had any other chronic illness 5.477 13 0.963 72.932 48 0.012 If the mother receive any medication during the pregnancy 12.654 13 0.475 23.078 24 0.515 If the mother SCA diseased or carrier 16.121 13 0.243 - - -
Table 4 - Correlation between variables and gestational age in SCA group and control group variables SCA group (n = 38) Control group (n = 149) Value df Significance (2-sided) Value df Significance (2-sided) Mother age 76.752 60 0.071 196.642 168 0.065 Mother education 19.484 12 0.078 16.369 24 0.874 Mother occupation 2.903 3 0.407 4.825 6 0.566 Region 33.630 21 0.040 39.308 42 0.590 If have regular antenatal care visits 2.537 3 0.469 6.298 6 0.391 If the mother smoke 0.534 3 0.911 5.386 6 0.495 If the mother diagnosed with hypertension 1.098 3 0.778 3.123 6 0.793 If the mother diagnosed with diabetes mellitus 1.649 3 0.638 14.791 6 0.022 If the mother had any other chronic illness 0.534 3 0.911 6.192 12 0.906 If the mother receive any medication during your last pregnancy 5.241 3 0.155 7.104 6 0.311 If the mother SCA diseased or carrier 2.241 3 0.430 - - -
4. DISCUSSION

In this study, most participant mothers in the SCA group were sickle cell trait (86.8%), 15.7% of the group was considered to have additional risk factors as 7.9% had diabetes mellitus, 5.3% were hypertensive, and 2.6% were smokers as in Table 1. The overall birth weight distribution was average compared to the control group, which showed 2.95 ± 0.40 kg and 2.99 ± 0.55 kg in the case and control groups, respectively. However, the percentage of LBW is considerably increased in the SCA group (31%) compared to the control group, as shown in Table 2. It is well documented that the lower birth weight in babies of mothers with SCA is significantly associated with lower gestational age and placental weight.18,19 The study findings suggest that infants born to mothers with SCA have a higher chance of LBW than infants born without SCA. This result can be attributed to factors such as placental insufficiency due to vaso-occlusion, which impairs uteroplacental circulation and leads to fetal hypoxia. Other complications associated with SCA, such as pre-eclampsia, infections, and intrauterine growth retardation, can also contribute to adverse neonatal outcomes.19–21 The result of our study agreed with the studies that reported that newborns born to mothers with the sickle cell trait were significantly smaller than babies born to mothers in a similar group with normal hemoglobin genotype.22,23 Although most participants in the study had sickle cell trait rather than sickle cell disease, there were still a significant proportion of LBW infants in the SCA group. The impact of the sickle cell trait on birth weight and gestational maturity remains debatable, as some investigations indicate that babies born to mothers with the trait may develop normally.24,25

Antenatal care is essential to maternal and newborn well-being, specifically in SCA mothers. In this study, although there was no direct correlation between antenatal care and birth weight or gestational maturity, the mothers demonstrated a good percentage of regular visits during their pregnancy. Ideally, a thorough evaluation needs to be done during the initial prenatal appointment, and the mothers should be informed of the importance of routine antenatal care; throughout the first two trimesters, Because these women are more likely to have pre-eclampsia and have a more increased risk of developing infections.26,27 Also, mothers should be warned about the dangers of over-exertion, dehydration, and exposure to severe temperatures, which can lead to sickle cell crises. Moreover, women with a higher risk of developing pre-eclampsia should take low-dose aspirin during pregnancy.28,29

The current study emphasizes the importance of addressing maternal risk factors, such as hypertension and diabetes mellitus, in managing SCA pregnancies. These factors significantly influenced birth weight in the SCA group, while diabetes mellitus was correlated with gestational age in the control group. Managing these co-morbidities is essential for optimizing pregnancy outcomes. These results agreed with the other studies that showed evidence that pregnancy complications were substantially correlated with diabetes mellitus and hypertension, regardless of the diagnosis of pre-eclampsia in the affected mothers, and this supports the causal effects that link hypertension, body mass index and diabetes mellitus to reduced birth weight in mothers.30,31

Concerning gestational maturity, there is no significant difference between the SCA mothers and the control group; also, there is no significant correlation between the gestational maturity of the delivered babies and the mothers’ variables. Our result is consistent with one study that concluded that after adjusting for other related risk factors for preterm delivery, women with sickle cell trait had an 85% lower risk of premature delivery at less than 32 weeks gestation. Interestingly, pregnancy plurality appeared to affect the decrease in preterm birth, with a more substantial impact in women with multiple pregnancies.32

Despite the significant presence of SCA in Saudi Arabia’s southwestern region, this is the first investigation into how SCA affects newborn birth weight and gestational maturity, which can be considered a strength. However, this study’s limitation arises from the case-control design, as there was still a chance of being affected by selection bias. In addition, data collection was challenged by the small sample size during the study period. Moreover, we could not examine every medical record in the database to corroborate further information about the participant mothers. Further research with a larger sample and more comprehensive medical record analysis would provide additional insights into the impact of SCA on pregnancy outcomes.

In conclusion, with the advancement in the management of SCA in pregnant mothers and newborns, including immunizations, newborn screening, and antibiotic prophylaxis beginning at birth, newborn survival rates and overall illness outcomes have significantly decreased, as well as maternal and neonatal mortality rates. However, compared to the general population, pregnancy with SCA is still linked to increased clinical and obstetric problems. This study indicates that SCA in pregnant mothers influences LBW. Additionally, the study spotlights the effect of other maternal factors and co-morbidities like maternal age and hypertension on pregnancy outcomes. Therefore, a multidisciplinary strategy must monitor these risky pregnancies well to sidestep avoided neonatal outcomes.

SCA in pregnant women can increase the risk of LBW in infants. Adequate antenatal care, management of maternal risk factors, and a multidisciplinary approach are necessary to minimize complications and ensure better outcomes for both mother and baby in SCA pregnancies.

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