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Abstract

Objectives

To determine the prevalence of antioxidant micronutrient deficiencies in pregnant women with pre-eclampsia and healthy pregnant women, and to assess the relationships between trace element deficiency in pregnancy and the severity of pre-eclampsia in Enugu, Nigeria.

Methods

We performed a secondary analysis of a cross-sectional analytical study of serum concentrations of copper, selenium, zinc, magnesium, and manganese in 81 pregnant women with pre-eclampsia and healthy pregnant women (controls) who were matched for age, gestational age, body mass index, and parity. This study was performed at the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu. Participants’ sera were analyzed with an atomic absorption spectrophotometer.

Results

Trace element deficiencies were common and similar between women with pre-eclampsia and controls. However, women with pre-eclampsia were more likely to be deficient in manganese than controls (odds ratio = 2.28, 95% confidence interval: 1.90–2.75). Among the micronutrients studied, only manganese concentrations were significantly lower in women without severe symptoms of pre-eclampsia than in those with severe symptoms of pre-eclampsia.

Conclusions

Micronutrient deficiency is common in pregnant women with pre-eclampsia and in healthy pregnant women in Enugu, Nigeria. Only manganese deficiency is higher in women with pre-eclampsia than in healthy pregnant women.

Keywords

Pre-eclampsia copper magnesium zinc manganese selenium micro-nutrient deficiency

Introduction

Pregnancy is a stressful physiological condition with many changes in the body’s nutritional homeostasis.¹ Nutritional deficiencies, especially micronutrient deficiencies, are common in pregnancy and even worse in developing countries where food with a low content of vitamins and minerals is consumed.^2–5 Many women in low-and middle-income countries who become pregnant have various forms of nutritional deficiencies and this negatively affects the outcome of these pregnancies, including the development of pre-eclampsia. Pre-eclampsia complicates pregnancy and causes mortality and morbidity to the mother and the fetus, and the etiology of this disease remains poorly understood.^6,7 Deficiencies of different trace elements are associated with mortality and morbidity in the newborn,⁸ fetal growth restriction,⁹ pre-eclampsia,¹⁰ and an increased risk of diseases, such as cardiovascular diseases and type II diabetes in adulthood.

Oxidative stress is implicated in the pathophysiology of pre-eclampsia.^11–15 Malondialdehyde, a major metabolite of lipid peroxidation, was one of the first biomarkers of lipid peroxidation found to be elevated in the plasma of women with pre-eclampsia.^13,14 Peroxynitrite, a strong oxidizing and nitrating agent, is produced in larger amounts in the placenta and systemic vasculature in women with pre-eclampsia than in those with a normal pregnancy.^16–18 Peroxynitrite can directly or indirectly cause endometrial dysfunction.¹⁹ Trace elements, such as selenium, magnesium, manganese, copper, and zinc, are important constituents of enzymes, which act as antioxidants and peroxynitrate scavengers in the serum, reducing the adverse endothelial effects of products of oxidative stress.²⁰ Therefore, the rate of deficiency of these trace elements affects the epidemiology of pre-eclampsia in different populations. Recently, the high prevalence and severity of pre-eclampsia in developing nations have mandated researchers to propose the involvement of nutrition, especially trace elements, in the etiology of this disorder.^2–4 Pre-eclampsia is more prevalent among poor women, and this has further strengthened the possibility that nutrient deficiency may be implicated in this disorder.⁹

Several reports have shown a relationship between plasma concentrations of trace elements and pre-eclampsia.^5,21–24 Although some studies suggest that low serum concentrations of trace elements are associated with the pathogenesis of pre-eclampsia,^21,24,25 other reports have shown no relationship.^5,23 Antioxidant micronutrients (copper, zinc, magnesium, selenium, and manganese) are major components of placental enzymes that help to protect the placenta from the development of oxidative stress, which is implicated in the pathogenesis of pre-eclampsia.²⁰

Consequently, this study aimed to determine deficiencies of copper, zinc, manganese, selenium, and magnesium in pregnant women with pre-eclampsia and in healthy pregnant controls in a developing country setting (where the incidence of pre-eclampsia is high), and to determine their relationship with the development and severity of pre-eclampsia. These findings could bridge the knowledge gaps on the role of micronutrient deficiencies in the development of pre-eclampsia, especially among women in developing countries where micronutrient deficiencies are common. The study will also serve as a guide to pharmaceutical companies and healthcare providers on the type, components, and quantities of these micronutrients in various hematinics recommended in pregnancy.

Materials and methods

Study design

This study was a secondary data analysis of a cross-sectional analytical study of participants who were involved in a larger study of maternal antioxidant levels in Enugu, Nigeria. The report of the primary outcome of the study has been published.²⁶ The details and protocols have been described in the published paper.²⁶ The larger study had the initial objectives published. However, owing to the relevance of micronutrient deficiencies in the etiopathogenesis of pre-eclampsia, the remaining objectives focusing specifically on micronutrient deficiencies and the severity of pre-eclampsia have not been investigated. The minimum sample size used in the current study was large enough to reach conclusions on the objectives considered in this secondary analysis.

Study setting

This study was conducted in the booking clinic, antenatal clinic, antenatal ward, and labor ward of the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla, Enugu, Nigeria, which is a major referral tertiary health facility in the southeast geo-political zone of Nigeria. The analysis of blood samples collected was conducted at the Department of Chemical Engineering, Caritas University, Amorji-Nike, Enugu, Nigeria.

Study area

The UNTH is located at Ituku-Ozalla, which is a community that is 21 km from Enugu capital city. The primary occupation of Enugu residents is subsistence farming, which is mainly carried out in rural communities. Others also engage in civil service works in the urban areas and 17 local government headquarters of the state. The state capital is located beside Udi Hills, which serve as the source of the River Nyaba and its major tributaries; the river and its tributaries drain most of the water from Enugu. The mean micronutrient contents of the river are as follows: zinc (World Health Organization [WHO] limit: 3 mg/L, dry season: 93.23 µg/L, wet season: 253.82 µg/L), copper (WHO permissible limit: 2.0 mg/L, dry season: 18.26 µg/L, wet season: 13.47 µg/L), magnesium (WHO limit: 100 mg/L, dry season: 7.19 mg/L, wet season:6.8 mg/L), manganese (WHO limit: 0.05 mg/L, dry season: 1425.9 µg/L, wet season: 3353.8 µg/L).²⁷

Study participants

This study involved pregnant women who booked to receive antenatal care at the UNTH and unbooked pregnant women who were admitted into the wards (labor ward, special care or antenatal ward) of the UNTH.

Exclusion criteria

The following women were excluded from the study: pregnant women who were taking drugs (magnesium sulfate and supplements) containing some of the elements assessed; pregnant women who were suffering from chronic illnesses, such as diabetes mellitus, human immunodeficiency virus infection, malignancies, and tuberculosis; women with multiple gestations; chronic alcoholics and smokers; and women who incidentally became pregnant with their copper-T intra-uterine contraceptive devices still present in their uterus.

Sample size calculation

The total sample size for the study was calculated using the following formula:²⁸

n = (Z₁ + Z₂)² × 2(S)²/(µ₂−µ₁)² with a 10% attrition rate, where Z₁ was 1.96 (95% confidence interval [CI]) and Z₂ was 0.84%. The mean serum concentration of copper was 1.9 µmol/L, and the power of the study of 80%.²⁴ This resulted in 166 participants who were divided into the study group and the control group.

Sample selection

The study group consisted of pregnant women with pre-eclampsia who met the study criteria, while the control group included healthy pregnant women who received care in the same hospital. The women were individually counselled and written informed consent was obtained from them. The women in the study group were consecutively recruited, while those in the control group were matched on a 1:1 ratio with those in the study group. After identifying and recruiting any eligible participants who had consented to the study in the study group, the control group was recruited from the antenatal clinic and matched for age ± 5 years, gestational age ± 4 weeks, parity, and body mass index ± 4.9 kg/m². The unbooked pregnant women with pre-eclampsia who were admitted to the wards were first recruited before being matched with the healthy pregnant women at the antenatal clinic.

Drug/diet evaluation of the subjects

A detailed history of the drug/diet history was performed to help determine pregnant women who were regularly on substances that contained any of the micronutrients that were studied. Such pregnant women were excluded from the study.

Socio-demographic characteristics and anthropometric measurements

The participants’ characteristics were collected by obtaining a detailed biodata and medical history of each participant. A simple medical examination was performed to obtain anthropometric measurements of each participant. The weight of the participants was measured to the nearest 0.5 kg and height was measured in meters using a weighing scale with a stadiometer (RGZ-160; Medfield Group Ltd., England, UK) for both parameters.⁹

A state of deficiency of the trace elements was defined as serum values less than the lower level of the normal ranges of the trace elements. The standard reference ranges of selenium, zinc, copper, magnesium, and manganese are shown in Table 1.²⁹

Table 1.

Normal reference values of antioxidant micronutrients in adults.

Micronutrient	Normal reference range
Micronutrient	SI units	Conversion	mg/L
Selenium	0.8–2.0 µmol/L	0.1266 × mg/L	0.632–1.580
Zinc	12–18 µmol/L	152.9 × mg/L	0.0784–0.1177
Copper	10–22 µmol/L	15.74 × mg/L	0.635–1.40
Magnesium	0.63–1.03 mmol/L	0.04114 × mg/L	1.531–2.504
Manganese	9–24 nmol/L	18200 × mg/L	0.000495–0.00132

Pre-eclampsia was defined in this study as the occurrence of de novo hypertension (≥140/90 mmHg) after 20 weeks’ gestation accompanied by proteinuria and/or evidence of maternal acute kidney injury, liver dysfunction, neurological features, hemolysis or thrombocytopenia, or fetal growth restriction.³⁰ The average values of two blood pressure measurements taken 4 hours apart was considered as the participant’s blood pressure. Blood pressure measurement was performed with the women in a sitting position using a mercury sphygmomanometer (Accoson, London, England, UK) after at least 10 minutes of rest. Systolic blood pressure was recorded at the appearance of sounds, and diastolic blood pressure was recorded at the muffling of sounds of Korotkoff (Korotkoff iv). Proteinuria was considered a urinary protein concentration ≥0.30 g/L (≥2+ on dipstick) in a minimum of two random urine samples collected 4 hours apart or ≥300 mg of protein in 24-hour urine.³¹

Pre-eclampsia was categorized into pre-eclampsia without severe features/severe findings (mild) and with severe features/severe findings (severe).²⁴ Pre-eclampsia without severe features (mild pre-eclampsia) was defined as a blood pressure ≥140 to 159/90 to 109 mmHg with two measurements taken 4 hours apart and proteinuria of 2+ on a dipstick in a minimum of two random urine samples collected at least 4 to 6 hours apart, or ≥0.3 g of protein in 24-hour urine, but not up to 5 g,^4,21,25 with no severe findings as listed below. Pre-eclampsia with severe findings (severe pre-eclampsia) was defined as a blood pressure ≥160/110 mmHg with proteinuria ≥5 g in 24 hours or 3+ proteinuria in two random urine samples collected at least 4 to 6 hours apart. Additionally, a diagnosis of severe pre-eclampsia was made in the presence of any of these severe features: pulmonary edema or cyanosis; oliguria (<400 mL of urine in 24 hours) or renal failure; epigastric pain and/or an impaired liver function test; and right hypochondrial pain, thrombocytopenia, oligohydramnios, decreased fetal growth syndrome, HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets), maternal neurological disturbances (e.g., phosphene signals, diffuse tendon reflexes, tinnitus, and eclampsia) persistent headaches, intrauterine growth restriction, and placental abruption.^4,21,25

Ethical approval and informed consent

Ethical approval was obtained from the Research and Ethics Committee of the UNTH, Ituku-Ozalla. An ethical certificate was obtained on 28 July 2013 (ethical certificate number: NHREC/05/01/20008B-FWA00002458-IR00002323). Written informed consent was obtained from all of the participants at the point of recruitment to participate in the study. Mothers whose age was younger than 18 years were excluded from the study.

Data and sample collection

Data collection was commenced after ethical approval. The study was conducted over 3 years (from 28 July 2013 to 28 July 2016). Using the superficial veins at the cubital fossa or in the upper limbs, a gentle venipuncture was performed. Five milliliters of blood was collected into a plane bottle and allowed to form a stable clot in a rack. The clotted blood sample was centrifugated for 10 minutes at 1968 g force to extract the serum, which was stored in a freezer at −20°C until analysis.

Biochemical analysis of the samples

The serum concentrations of selenium, zinc, magnesium, copper, and manganese were estimated using an atomic absorption spectrophotometer (210 VGP; Buck Scientific Inc., East Norwalk, CT, USA).^4,13,14 The senior laboratory scientist analyzing the samples in the participant’s groups was blinded throughout the study. To ensure quality control, commercially prepared samples were analyzed after each set of 20 samples to ensure that the same sensitivity and specificity were maintained throughout the analysis.

Outcome measures

The primary outcome measure was the prevalence of antioxidant micronutrient deficiencies in pregnant women with pre-eclampsia and healthy pregnant women. The secondary outcome measure was the relationships between trace element deficiency in pregnancy and severity of pre-eclampsia in Enugu, Nigeria.

Statistical analysis

The data collected were analyzed with IBM Statistical Package for Social Sciences (SPSS) 21.0 Evaluation version (IBM Corp., Armonk, NY, USA). The association between the proportions of categorical variables was determined with the Pearson chi-square test. Continuous variables are shown as the mean ± standard deviation and were compared using Student’s t-test. Data are presented using tables and charts as appropriate. A P value of <0.05 was considered significant at a 95% confidence level.

All patients’ details were de-identified in the analysis and reporting of the findings of this study. The STROBE guidelines were used in the reporting of this manuscript.³²

Results

Basic characteristics of the participants

A total number of 83 participants were recruited in each group in the study, and only 81 participants in each group completed the study. The remaining participants were excluded because of various reasons (spillage of samples, incomplete results, poor storage, and spoiling of samples). Figure 1 shows the details of recruiting the study participants. The mean ages of the participants were 29.53 ± 5.38 and 29.31 ± 5.22 years in the study and control groups, respectively. Most of the participants were aged 26 to 35 years and few participants were recruited at the extremes of their reproductive ages. The participants in both groups were mainly parous. There was no significant difference in age, body mass index, gestational age, or parity between the two groups. The mean systolic blood pressure in the study and control groups was 174 and 107 mmHg, and the mean diastolic blood pressure was 114 and 66 mmHg, respectively. Details of the sociodemographic and anthropometric characteristics of the participants are shown in Table 2.

Figure 1.

Flow chart showing the number of pregnant women with pre-eclampsia and healthy pregnant women who were recruited, and details of sera that were analyzed in both groups.

Table 2.

Basic characteristics of the participants.

Variable	Sub-category	Pregnant women with pre-eclampsia (n = 81)		Healthy pregnant women (n = 81)		χ²	P value
Variable	Sub-category	Number	%	Number	%	χ²	P value
Age groups (years)	15–25	18	22.2	18	22.2	0.062	0.969
	26–35	54	66.7	53	65.4
	36–45	9	11.1	10	12.3
Marital status	Single	6	7.4	1	1.2	3.733	0.117
Marital status	Married	75	92.6	80	98.8	3.733	0.117
Educational level	Secondary and below	44	54.3	28	34.6	6.400	0.011
Educational level	Above secondary	37	45.7	53	65.4
Tribe	Igbo	77	95.1	71	87.7	2.815	0.160
Tribe	Others	4	4.9	10	12.3	2.815	0.160
Religion	Christian	81	100.0	81	100.0	–	–
Religion	Others	0	0.0	0.0	0.0	–	–
Parity groups	Nulliparous	30	37.0	28	34.6	0.107	0.743
Parity groups	Parous	51	63.0	53	65.4	0.107	0.743
Body mass index groups	Normal	20	24.7	18	22.2	0.154	0.926
	Overweight	21	25.9	21	25.9
	Obese	40	49.4	42	51.9
Social class groups	High SES	34	42.0	46	56.8	4.438	0.109
	Middle SES	26	32.1	23	28.4
	Low SES	21	25.9	12	14.8

SES, socioeconomic status.

Trace element deficiency states among the participants

The participants showed deficiency in selenium, copper, and zinc, but the rates of deficiency were not different between the groups (Table 3). However, deficiency in manganese was significantly different between the groups. No participants in the control group were deficient in manganese, while approximately one quarter of women in the study group were deficient in manganese (P < 0.001, odds ratio = 2.3, 95% confidence interval: 1.90–2.75). Notably, all women in the study group were deficient in magnesium, but 93.8% (76/81) of the women in the control group were deficient in magnesium (P = 0.059).

Table 3.

Comparison of trace element deficiencies between pregnant women with pre-eclampsia and healthy pregnant women.

Trace elements	Pregnant women with pre-eclampsia (n = 81)		Healthy pregnant women (n = 81)		P value	OR (95% CI)
	Trace element deficiency		Trace element deficiency
	Yes, n (%)	No, n (%)	Yes, n (%)	No, n (%)
Copper	36 (44.4)	45 (55.6)	24 (29.6)	57 (70.4)	0.073	1.9 (0.99–3.63)
Zinc	72 (88.9)	9 (11.1)	66 (81.5)	15 (18.5)	0.269	1.82 (0.75–4.43)
Selenium	12 (14.8)	69 (85.2)	7 (8.6)	74 (91.4)	0.329	1.84 (0.68–4.94)
Manganese	18 (22.2)	63 (77.8)	0 (0.0)	81 (100.0)	<0.001	2.28 (1.90–2.75)
Magnesium	81 (100)	0 (0.0)	76 (93.8)	5 (6.2)	0.059	0.48 (0.41–0.57)

OR, odds ratio; CI, confidence interval.

Trace element deficiency by the presence of severe symptoms of pre-eclampsia

The rate of trace element deficiency was comparable between women without severe symptoms of pre-eclampsia (mild pre-eclampsia) and those with severe symptoms of pre-eclampsia (severe pre-eclampsia), except for the element manganese (Table 4). A higher proportion of women with mild pre-eclampsia were deficient in manganese than in those with severe pre-eclampsia (P < 0.05, odds ratio = 3.20, 95% confidence interval: 1.075–3.525).

Table 4.

Relationship between trace element deficiency in pregnancy and the severity of pre-eclampsia.

Micro-nutrient	Deficiency state	Severity of pre-eclampsia				P value	Odds ratio(95% CI)
		Pre-eclampsia without severe symptoms		Pre-eclampsia with severe symptoms
		Number (n = 24)	%	Number (n = 57)	%
Copper	Yes	8	33.3	28	49.1	0.227	0.518 (0.191–1.401)
Copper	No	16	66.7	29	50.9	0.227	0.518 (0.191–1.401)
Selenium	Yes	5	20.8	7	12.3	0.326	1.88 (0.531–6.649)
Selenium	No	19	79.2	50	87.7	0.326	1.88 (0.531–6.649)
Zinc	Yes	24	100.0	48	84.2	0.052	0.667 (0.566–0.785)
Zinc	No	0	0.0	9	15.8	0.052	0.667 (0.566–0.785)
Magnesium	Yes	24	100	57	100.0	–	–
Magnesium	No	0	0	0	0.0	–	–
Manganese	Yes	9	37.5	9	15.8	0.043	3.200 (1.075–3.525)
Manganese	No	15	62.5	48	84.2	0.043	3.200 (1.075–3.525)

OR, odds ratio; CI, confidence interval.

Discussion

The objectives of this study were to determine the prevalence of antioxidant micronutrient deficiencies in pregnant women with pre-eclampsia and healthy pregnant women, and to assess the relationships between trace element deficiency in pregnancy and the severity of pre-eclampsia in Enugu, Nigeria. We found that micronutrient deficiency was common in women with pre-eclampsia and healthy pregnant women in the study population and that the deficiencies were not significantly different, except for manganese.

Selenium deficiency was observed in 14.8% and 8.6% of pregnant women with pre-eclampsia and healthy pregnant women, respectively. This finding indicated that the majority of the study population (study and control groups) had normal selenium concentrations. This finding is similar to that of a similar report in Obi-Apkpor area of Rivers State where no pregnant women were deficient in selenium.³³ Selenium is a major component of two important antioxidant proteins, glutathione peroxidase and thioredoxin reductase. These enzymes have selenocysteine in their active sites and it is selenium-dependent for their activity.³⁴ Selenium is also useful in the formation of thyroid hormones and maintenance of normal thyroid function. The normal reference range of selenium in the adult population is 63 to 160 µg/L (0.8–2.0 µmol/L).²⁹ Serum selenium concentrations fall with the progression of pregnancy.³⁵ Selenium values of 65 µg/L in the first trimester and 50 µg/L in the third trimester have been recorded.^29,36 There is a world-wide variation in serum concentrations depending on the intake and method of assessment. Selenium is reduced in pregnant women compared with non-pregnant women, and this reduction decreases further with increasing gestation.^37–39 This reduction is even more pronounced in patients with pre-eclampsia and eclampsia.⁴⁰

Soil selenium concentrations are related to the serum selenium concentration in individuals.⁴¹ Therefore, high soil selenium concentrations in Nigeria, and in Enugu³⁷ in particular, may have affected the serum concentrations in pregnant women with pre-eclampsia and normal pregnant women in this study area. The women in this study population were mainly urban dwellers who depended on imported food items rich in selenium, which may have contributed to reducing the incidence of selenium deficiency among them.^42,43 Recently, there appeared to be increased demand and intake of various supplements rich in selenium by pregnant women in Enugu and globally⁴⁴ owing to the increased knowledge of the role of selenium in reducing the incidence of pre-eclampsia and other cardiovascular diseases in the population.⁹ Some countries have attempted supplementing the amount of selenium that their citizens receive from the food that they consume. Finland and New Zealand have used selenium soil supplementation using soil selenium-rich fertilizer to reduce the incidence of pre-eclampsia in their environment by 61% and 71%, respectively.⁴⁵

Copper deficiency was observed in this study, with rates of 44.4% and 29.6% in pregnant women with pre-eclampsia and healthy pregnant women, respectively. These findings are similar to those in a related study⁴⁶ in Abakaliki, Nigeria, which is in the same region as the participants recruited in this study. Copper is an essential trace element that serves as a co-factor for a number of enzymes involved in angiogenesis, metabolic reactions, and oxygen transport. Copper displays antioxidant functions when found as a component of the following enzymes: catalases, superoxide dismutase known as an oxidant defense enzyme, and cytochrome c oxidase.⁴⁷ Importantly, copper is a redox-action transition metal, which can participate in single electron reactions and catalyze the formation of free radicals that can contribute to oxidative stress, which is characteristic of pre-eclampsia. Therefore, copper can act as a pro-oxidant, but when in association with the copper/zinc superoxide dismutase enzyme, it functions as an antioxidant. Serum copper concentrations increase as gestational age increases.^37,48–50 Our findings on copper in this study may be associated with the diet of the participants. Foods rich in carbohydrates and low in animal proteins are predominant in the study area,⁵¹ and have been associated with copper deficiency.⁵² Other likely causes of copper deficiency include malnutrition, poor absorption, and intestinal diseases.⁵³ However, the copper deficiency found in this study is different from that of 2.7%, which was found in another study.⁵⁴ conducted in a rural population of pregnant women in India where the study excluded women below 28 weeks of gestational age.

Zinc is an essential trace element with a wide range of functions. Zinc is a constituent of more than 200 metalloenzymes involved in protein and carbohydrate metabolism and nucleic acid synthesis, and it is essential for successful embryogenesis. Zinc is a major component of the copper/zinc superoxide dismutase enzyme, where it functions as an antioxidant. The normal reference range of zinc in adults is 80 to 120 µg/dL (12–18 µmol/L).²⁹ Plasma zinc concentrations decrease with progression in pregnancy (first trimester: 71 ± 12.9 µg/L; third trimester: 58.5 ± 11.5 µg/L).²⁹ The requirement of zinc in the third trimester in pregnant women is twice as high as that in non-pregnant women. Some studies in Africa have reported low plasma zinc concentrations in pregnant women^46,55 and even further deficiency in women with pre-eclampsia.^21,23,24 Although there was no significant difference in zinc deficiency between the two groups, the odds of developing zinc deficiency appeared higher in women with pre-eclampsia in our study. The high level of zinc deficiency in this study is similar to that reported in Rivers State, Nigeria where the level of zinc deficiency was 97.3%.³³ However, zinc deficiency in this study is higher than that recorded by Ugwuja et al⁴⁶ in Abakiliki, Nigeria where 45.8% of pregnant women were zinc deficient. Other studies in Ibadan, Nigeria (22.5%),⁵⁶ Malawi (36%),⁵⁷ India (49%),⁵⁸ and Pakistan (73.5%)⁵⁹ recorded low zinc deficiencies in their study populations. The feeding and food supplementation patterns in the study areas may have been responsible for the differences between studies.

Magnesium is an intracellular ion that is useful in cellular metabolism, such as muscle contraction, secretions, and neuronal activity, and is even involved in cell death events. Magnesium works in conjunction with calcium to maintain normal cell function. Magnesium may function as a co-factor to some endogenous antioxidant enzymes. This trace element has been implicated in seizure disorders, which complicate pre-eclampsia. Magnesium has been used successfully in treating eclamptic seizures,⁶⁰ and its effect on vascular smooth muscle in vitro suggest that it is deficient in women with pre-eclampsia.⁶¹ Despite the presence of magnesium in commonly available foods, such as green vegetables, seeds and grains, the deficiency of this micronutrient is experienced in low- and middle-income countries where the intake of this element is low.⁶² A systematic review with a limited number of studies showed that a higher total energy, reduced magnesium intake, and low calcium intake during pregnancy was associated with hypertensive disorders of pregnancy.⁶³ Magnesium administered through different sources has resulted in varied outcomes. The administration of magnesium reduced the incidence of pregnancy-related hypertensive diseases in some studies.^64,65 In other studies, there was no significant difference in the occurrence of pregnancy-related hypertensive conditions after intake of different formulations of magnesium.^66,67

On a positive note, magnesium sulfate is routinely used in the treatment of seizures in women with eclampsia. This fact further suggests that magnesium deficiency plays a role in the pathogenesis of pre-eclampsia.⁶⁰ Magnesium and other nutrient deficiencies have been suggested as a possible cause of hypertensive diseases in pregnancy and other poor outcomes of pregnancy.⁶⁸ Therefore, unsurprisingly, all women with pre-eclampsia in this study were deficient in magnesium. A similar finding was reported in a study in Benin, Nigeria.⁶⁹ We expected a significantly lower magnesium deficiency in the control arm of this study, which we did not find. However, magnesium deficiency has been found in low-income countries owing to a poor intake. Our finding suggests that magnesium deficiency alone is not a trigger factor for pre-eclampsia. A drop below a critical value of serum magnesium may be necessary for the development of pre-eclampsia as suggested by the marked difference in the mean values of this element between our two groups. Therefore, further studies are required to identify this possible critical serum level.

Manganese is a free element in nature that is often found in combination with iron. Manganese is sourced from the intake of commonly available foods, such as shellfish, grains, legumes (soyabeans, peanuts), spices (black pepper), black tea, spinach, and pineapple. Manganese is an important co-factor in a number of enzymes, such as oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, lectins, and integrins. A major antioxidant function occurs in the enzyme manganese superoxide dismutase, which protects the placenta from oxidative stress by detoxifying superoxide anions.⁷⁰ The normal reference value for serum manganese in adults is 0.5 to 1.3 µg/L (9–24 nmol/L).⁴⁹ Manganese is one of the least studied trace element, but some available data have suggested that low manganese concentrations are found in women with fetal growth restriction.⁷¹ Low concentrations of manganese may lead to the accumulation of superoxides, which could lead to endometrial dysfunction and possibly trigger pre-eclampsia and its complications. A deficiency of manganese is rare because it is found in commonly available foods. Deficiency in manganese commonly results when manganese- and iron-rich foods are eaten together, resulting in reduced absorption of manganese because manganese and iron compete for the same proteins for their absorption in the intestines. A marked depletion of manganese plays a role in the pathogenesis of pre-eclampsia.²⁴ This study showed no deficiency of manganese in the controls. This finding is consistent with a survey by Osadolor and Omogiade in Nigeria,⁷² where only 4% of the healthy pregnant women were manganese deficient. Similarly, raised serum manganese concentrations were also observed in a study in Germany.⁷³ Lui et al studied 1274 women in Boston, USA, and supported our findings where they reported that a 1 standard deviation increment in serum manganese concentrations was associated with a 32% lower risk of developing preeclampsia among the studied cohorts.⁷⁴ This finding suggested that women deficient in serum manganese concentrations may be predisposed to the development of pre-eclampsia. However, a deficiency of manganese does not nullify the contributions from other antioxidant micronutrients, which are components of enzymes that regulate oxidative stress in the placenta and maternal circulation. Manganese remains one of the least studied among the trace elements, and the number of studies on its supplementation in pregnancy is low globally.

A deficiency of micronutrients plays a major role in the development of pre-eclampsia. The extent to which a lack of these elements affects the severity of pre-eclampsia was not clear in this study, probably because a significant difference between mild and severe pre-eclampsia is difficult to identify. Although serum micronutrient deficiencies were observed in the participants, the degree of severity of the deficiency of the elements was not directly related to the severity of the pre-eclampsia. Other factors, such as the time of onset of the disease, the presence or absence of comorbidities, and the degree of response of the arteries to vasoconstrictive and vasodilatory factors released in pre-eclampsia equally play a role in determining the severity of pre-eclampsia.⁷⁵ The clinical implication of the findings is that deficiencies of the trace elements studied were common in the study area, and this may have contributed to complications of pregnancies (e.g., pre-eclampsia/eclampsia) in the women. Therefore, assessing the levels of trace elements pre-pregnancy and during the antenatal period will help in determining those that may require immediate supplementation before and during pregnancy. Additionally, coordinating with other ministries other than health, such as agriculture, water, and pharmaceutical sectors, will help in formulating policies that will assist in the fortification of foods and enrichment of drugs, water, and even fertilizers that are used for crop cultivation. This process will ensure that the food eaten, water drank, and drugs taken by pregnant women have high contents of the above-mentioned trace elements.

This study has some strengths and limitations. Despite the low prevalence of pre-eclampsia, the sample size used was large enough compared with other previous studies.^23,24 A strength of this study also relied on the fact that an atomic absorption spectrophotometer was used in the determination of serum trace elements levels, ensuring that accurate serum values of the micronutrients were obtained. A limitation of this study is that it was not a multicenter study. We suggest that multicenter studies should be performed to help improve the validity of the findings on this topic.

Conclusion

Micronutrient deficiency is common among pregnant women with pre-eclampsia and healthy pregnant women in Enugu. Additionally, the occurrence of micronutrient deficiency is not different between these groups of women, except for manganese, which is significantly lower in women with pre-eclampsia. Pregnant women in this environment should have their food supplemented with these micronutrient antioxidants. Further studies on the possible role of manganese deficiency in the etio-pathogenesis of pre-eclampsia should be performed.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231209159 - Supplemental material for Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu, Nigeria: a cross-sectional analytical study

Supplemental material, sj-pdf-1-imr-10.1177_03000605231209159 for Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu, Nigeria: a cross-sectional analytical study by Joseph Tochukwu Enebe, Cyril Chukwudi Dim and Akudo Chidimma Omeke in Journal of International Medical Research

Supplemental Material

sj-xls-2-imr-10.1177_03000605231209159 - Supplemental material for Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu, Nigeria: a cross-sectional analytical study

Supplemental material, sj-xls-2-imr-10.1177_03000605231209159 for Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu, Nigeria: a cross-sectional analytical study by Joseph Tochukwu Enebe, Cyril Chukwudi Dim and Akudo Chidimma Omeke in Journal of International Medical Research

Footnotes

Author contributions

JTE conceptualized and designed the study,collected and analyzed the data,and was involved in preparing the final draft of the manuscript. CCD made a major contribution to the conceptualization and design of the study,and collected and analyzed the data. ACO was involved in the conception and design of the study,and the collection and analysis of the data,and contributed to writing of the final draft of the manuscript. All authors read and approved the final manuscript.

Data availability statement

The dataset used and/or analyzed during the current study is attached in the Supplementary file.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public,commercial,or not-for-profit sectors.

ORCID iD

Joseph Tochukwu Enebe

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Supplementary Material

Please find the following supplemental material available below.

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Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu,Nigeria: a cross-sectional analytical study

Abstract

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Study design

Study setting

Study area

Study participants

Exclusion criteria

Sample size calculation

Sample selection

Drug/diet evaluation of the subjects

Socio-demographic characteristics and anthropometric measurements

Ethical approval and informed consent

Data and sample collection

Biochemical analysis of the samples

Outcome measures

Statistical analysis

Results

Basic characteristics of the participants

Trace element deficiency states among the participants

Trace element deficiency by the presence of severe symptoms of pre-eclampsia

Discussion

Conclusion

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231209159 - Supplemental material for Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu, Nigeria: a cross-sectional analytical study

Supplemental Material

sj-xls-2-imr-10.1177_03000605231209159 - Supplemental material for Maternal antioxidant micronutrient deficiencies among pre-eclamptic women in Enugu, Nigeria: a cross-sectional analytical study

Footnotes

Author contributions

Data availability statement

Declaration of conflicting interest

Funding

ORCID iD

References

Supplementary Material