Preeclampsia is a complex multisystem disorder of pregnancy with an unclear etiology and is associated with substantial maternal and fetal morbidity and mortality. After hemorrhage and embolism, it ranks as the third leading cause of maternal death worldwide [1]. The World Health Organization (WHO) estimates that between 50,000 and 75,000 women die annually from preeclampsia-related complications. It is also considered the most frequent cause of iatrogenic prematurity. Clinically, preeclampsia is diagnosed when hypertension ≥140/90 mmHg is recorded on two separate occasions at least 4 hours apart, in association with proteinuria of ≥300 mg in a 24-hour urine sample, first recognized after the 20th week of gestation. The condition complicates approximately 2–3% of pregnancies, although incidence rates vary depending on population characteristics and diagnostic criteria. Nutrition plays a pivotal role in pregnancy, encompassing both macronutrients (carbohydrates, proteins and fats) and micronutrients (vitamins and minerals) [2-4]. Micronutrients, particularly trace elements such as zinc (Zn) and copper (Cu), are vital for numerous physiological processes that maintain fetal health and protect against cellular damage. Several studies suggest that altered serum concentrations of trace elements may contribute to the pathogenesis of preeclampsia, although findings remain inconsistent [5-8]. The bioavailability of these elements during pregnancy is influenced by diet and physiological changes in digestion, absorption and utilization. Inadequate intake before and during gestation increases the risk of adverse maternal and fetal outcomes. Deficiencies or imbalances of trace elements like zinc and copper have been implicated in multiple reproductive complications, including infertility, miscarriage, congenital anomalies, preeclampsia, placental abruption, premature rupture of membranes, stillbirth and low birth weight [9,10]. Preeclamptic women often exhibit lower serum Zn and Cu levels compared with normotensive pregnant women. Both trace elements possess antioxidant properties and their deficiency or impaired metabolism may exacerbate oxidative stress, complicating pregnancy and impairing fetal growth ⁽¹¹⁻¹⁵⁾. Consequently, supplementation to meet daily requirements is recommended for pregnant women. Zinc is widely distributed in nature and, at the cellular level, is primarily located in the cytosolic compartment. It forms an essential component of several enzymes, including carbonic anhydrase, alkaline phosphatase and Superoxide Dismutase (SOD), the latter protecting cells from free radical–induced oxidative damage. The daily zinc requirement is approximately 12 mg in non-pregnant women, increasing to 15–20 mg during pregnancy to support fetal development. Reduced zinc concentrations during pregnancy have been linked to congenital malformations, intrauterine growth restriction, preterm labor, preeclampsia and postpartum hemorrhage [16-18]. Copper, another essential trace mineral, plays a critical role in normal cellular function and enzymatic activity. It is a cofactor in numerous enzymes, such as cytochrome oxidase, tyrosinase, dopamine hydroxylase, catalase, monoamine oxidase, ascorbic acid oxidase and SOD, contributing significantly to the antioxidant defense system [19-24]. The estimated daily requirement of copper is 1.7 mg in non-pregnant women and approximately 3 mg in pregnancy. Although no formal recommended dietary allowance exists, an intake of 2–3 mg per day is generally considered adequate [25-27]. Reduction in copper levels during gestation can impair antioxidant defenses, leading to increased oxidative stress. Some studies have demonstrated decreased plasma copper concentrations during the first trimester in association with pathological conditions such as spontaneous abortion, threatened miscarriage, missed abortion and blighted ovum [28,29]. However, no significant alterations have been reported during the second trimester in conditions such as threatened preterm labor and pyelonephritis. In contrast, higher plasma copper levels have been observed in the third trimester in pregnancies complicated by intrauterine growth restriction [30-32]. Overall, the literature presents conflicting evidence regarding the relationship between trace element status and preeclampsia. Therefore, well-designed studies investigating maternal serum Zn and Cu concentrations in preeclamptic versus normotensive pregnancies, while also considering maternal demographic characteristics, are crucial to clarify their role in the pathogenesis and outcomes of this disorder. 

Patients and Methods 

A case-control study was conducted in the obstetrics ward, labor room and outpatient obstetrical clinic of Azadi Teaching Hospital, Kirkuk, Iraq, over an eight-month period from February 1 to October 1, 2020. The study protocol was reviewed and approved by the Scientific Council of Obstetrics and Gynecology, Iraqi Board for Medical Specializations. A total of 100 pregnant women were recruited and divided equally into two groups: 50 women diagnosed with preeclampsia (case group, Group A) and 50 normotensive women with uncomplicated pregnancies (control group, Group B). All participants were matched for maternal age and gestational age. Eligible patients were admitted for follow-up and evaluation, including blood pressure monitoring, urinalysis for albumin and renal and liver function testing, with gestational ages ranging from 24 to 38 weeks.

Diagnostic Criteria

Preeclampsia was defined as persistent hypertension (≥140/90 mmHg) developing after 20 weeks of gestation or during the postpartum period, accompanied by proteinuria (≥300 mg/24 h) or new-onset maternal organ dysfunction, including thrombocytopenia, renal or hepatic impairment, pulmonary edema, or neurological symptoms such as visual disturbances or seizures.

Inclusion Criteria

Maternal age 16-40 years; singleton viable pregnancy; gestational age 24–38 weeks; adequate antenatal care; no history of zinc or copper supplementation; informed consent to participate.

Exclusion Criteria

History of chronic medical disorders; multiple pregnancies; nonviable fetus; antepartum hemorrhage; pregnancy-induced hypertension; zinc or copper supplementation; gestational age >38 weeks; or refusal to participate.

Biochemical Tests

Full blood count, serum urea, creatinine, uric acid, SGPT, SGOT and alkaline phosphatase were performed. Ultrasound examination was carried out to confirm gestational age, viability and to exclude multiple pregnancies. BMI was calculated (kg/m²). Serum zinc and copper levels were measured by spectrophotometry, in which venous blood samples were collected into clot activator tubes. After clotting, zinc and copper reacted with the chromogen in the reagent to produce a colored compound proportional to the concentration of each element.

Ethical Considerations

Verbal informed consent was obtained from all participants and anonymity was preserved. Approvals were granted by the Iraqi Board for Medical Specializations and the Department of Obstetrics and Gynecology at Azadi Teaching Hospital.

Statistical Analysis

Data were analyzed using SPSS version 25. Continuous variables were expressed as mean ± standard deviation and compared using the independent two-tailed t-test. Categorical variables were expressed as frequencies and percentages. Pearson’s correlation coefficient (r) was used to evaluate associations between continuous variables. A p-value of <0.05 was considered statistically significant.

A total of 100 pregnant women were the subjects of this study. Fifty pregnant women were diagnosed with PE (Case group) and the other 50 pregnant women were healthy participants (Control group). The distribution of study groups by certain clinical characteristics is shown in (Figure 1) and (Table 1).

Table 1: Comparison between Study Groups by Age, BMI and GA

BMI: Body Mass Index, GA: Gestational Age

Figure 1: Distribution of Study Groups by Age

Women’s age was ranging from 16 to 40 years with a mean of 37.98 and standard deviation (SD) of ±3.16 years. The highest proportion of study patients in case and control groups was aged ≥35 years (58 and 54% respectively).

The comparison between study groups by maternal blood pressure parameters is shown in (Table 2). 

Table 2: Comparison between Study Groups by Maternal Blood Pressure 

SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure

A statistically significant difference was found in the means of SBP and DBP between case and control groups. Women with preeclampsia had a significantly higher means of SBP and DBP compared to that in women with normal pregnancy (154.9 versus 115.4, p = 0.001 and 96.9 versus 70.6, p = 0.001, respectively).

The comparison between study groups by laboratory investigations are shown in Table (3). 

Table 3: Comparison between Study Groups by Serum Zinc and Copper Levels

There was no statistically significant difference between the study groups in terms of Blood urea (p = 0.055), Serum Creatinine (p = 0.924), Serum Uric acid (p = 0.542), Serum GPT (p = 0.439), Serum GOT (0.299), Serum Alkaline phosphatase (0.432), Platelet count (0.130) (Figure 2).

Figure 2: Distribution of Study Groups by Levels of Serum Zinc and Copper

The level of serum zinc was significantly, inversely correlated  with  SBP (r = -0.780, p = 0.001) and DBP (r = -0.783, p = 0.001); while no significant correlation was found between serum zinc level and each of age (p = 0.946) and BMI (p = 0.092), as shown in Tables 4 and 5.

Table 4: Correlation between Serum Zinc and Age, BMI, SBP and DBP

BIM: Body Mass Index, SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure

Table 5: Correlation between Serum Copper and Age, BMI, SBP and DBP

BMI: Body Mass Index, SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure

In the current study, the mean serum zinc level was significantly lower in the preeclamptic group compared with the control group (44.05 Vs. 94.72 µg/dL, p<0.0001). This result is in agreement with several studies, including Mohamed et al. [8], Sarwar et al. [28], Rafeeinia et al. [15], Mbah et al. [29] and Kanagal et al. [30], all of which demonstrated a significant association between reduced maternal zinc levels and preeclampsia compared with normotensive pregnant women. In contrast, findings reported by Eltayeb et al. [31] and Mohamed et al. [32] showed elevated serum zinc levels in preeclamptic women, highlighting the inconsistency in the literature. Several mechanisms may explain zinc deficiency in preeclampsia. Zinc is passively transferred from the mother to the fetus through the placenta, leading to decreased maternal serum levels during normal pregnancy, with a further reduction observed in preeclampsia [33-39]. Zinc depletion in preeclamptic women may also result from hemodilution due to fluid retention, increased endogenous steroid production and reduced concentrations of zinc-binding proteins [16,23]. Moreover, elevated cortisol levels, which are further increased in preeclampsia, have been shown to reduce circulating zinc, thereby exacerbating maternal hypozincemia [39,40]. Other contributing factors may include low maternal dietary intake and diseases causing malabsorption [4,12]. Regarding copper, this study revealed that the mean serum copper level was also significantly lower in preeclamptic women compared with healthy controls (83.20 Vs. 87.42 µg/dL, p = 0.018). Similar findings were reported by Baral et al. [2] and Canfield et al. [35], who noted that preeclampsia is associated with placental insufficiency, decreased serum copper and reduced activity of copper-dependent enzymes synthesized in the placenta. However, Wilson et al. [36] found significantly higher copper concentrations in obese preeclamptic women compared with those of normal weight, suggesting that maternal body mass and metabolic status may influence trace element levels.

The pathogenesis of altered copper levels in preeclampsia remains controversial. On one hand, low serum copper may be explained by excessive lipid peroxidation and oxidative stress, both of which play central roles in preeclampsia. Copper deficiency impairs the antioxidant activity of the Cu–Zn Superoxide Dismutase (SOD) system, thereby increasing oxidative damage and vascular dysfunction [16,32]. On the other hand, elevated copper levels observed in some studies may be attributed to increased ceruloplasmin synthesis during pregnancy, which is further upregulated in preeclampsia as a response to oxidative stress [7,39]. Since 96% of plasma copper is bound to ceruloplasmin, assays measuring total copper may not accurately reflect bioavailable copper. Ethnic differences in study populations and methodological variations (free Vs. bound copper detection) may also contribute to discrepancies among studies [13,34].

This study confirmed that both zinc and copper levels were significantly reduced in women with preeclampsia compared to normotensive controls in the second and third trimesters. Moreover, reduced zinc and copper were significantly associated with elevated systolic and diastolic blood pressures, suggesting their possible role in the pathophysiology of preeclampsia.

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