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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 32-36

Correlation between maternal copper deficiency and premature rupture of membranes: A case–Control study


1 Department of Embryology, Faculty of Medicine, University of Aleppo, Aleppo, Syria
2 Analytical and Food Chemistry Department, Faculty of Pharmacy, University of Aleppo, Aleppo, Syria

Date of Submission10-Mar-2020
Date of Decision25-May-2020
Date of Acceptance08-Jul-2020
Date of Web Publication22-Sep-2020

Correspondence Address:
Muhammad Mazketly
Faculty of Medicine, University of Aleppo, Aleppo
Syria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/LIUJ.LIUJ_4_20

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  Abstract 

Background: The association between maternal serum copper levels and premature rupture of membranes (PROM) is debated. Aims: This study aims to study the relationship between maternal serum copper levels and the incidence of PROM and to determine risk factors of PROM in Aleppo University Hospital of Obstetrics and Gynecology. Settings and Design: Sixty pregnant women were subjected for this study. Materials and Methods: Pregnant women were subjected for analyzing serum copper concentrations. Maternal serum copper levels were measured by atomic absorption spectroscope. Statistical Analysis: By SPSS (version 22.0). Results: A significant correlation was found between maternal serum copper levels and the incidence of PROM. The relationship presents when copper level is considered as a categorical variable, as mothers with copper deficiency were significantly more vulnerable for PROM (Odds ratios = 0.15, confidence intervals: 0.04–0.61, P = 0.002). Furthermore, the relationship presents when copper level is considered as a numerical variable, as mothers with lower serum copper levels were at significantly higher risk to develop PROM. Difference in means between the two groups was 40.87 μg/dL with CI (14.98–66.75) μg/dL (P = 0.003). Conclusion: Within its limitations, this study suggests a significant relationship between maternal serum copper levels and PROM.

Keywords: Case control, copper, premature rupture of membranes, Syria


How to cite this article:
Nawfal H, Alhamid A, Abd Al-Jawad AH, Waez A, Hallak R, Shammou SH, Tabsho S, Mazketly M, Sa'adi MN, Sakur AA. Correlation between maternal copper deficiency and premature rupture of membranes: A case–Control study. Libyan Int Med Univ J 2020;5:32-6

How to cite this URL:
Nawfal H, Alhamid A, Abd Al-Jawad AH, Waez A, Hallak R, Shammou SH, Tabsho S, Mazketly M, Sa'adi MN, Sakur AA. Correlation between maternal copper deficiency and premature rupture of membranes: A case–Control study. Libyan Int Med Univ J [serial online] 2020 [cited 2021 May 10];5:32-6. Available from: http://journal.limu.edu.ly/text.asp?2020/5/2/32/295916


  Introduction Top


Copper is a mineral crucially needed for maintaining a hemostatic oxidative state. Copper has an essential role in catalyzing metabolic reactions[1] and in synthesis of red blood cells in adults.[2] Biochemical studies indicate that copper is present in low concentrations in viable tissues, for its function, along with Vitamin C, in the synthesis of connective tissue fibers (i.e., collagen and elastin).[3]

Syncytiotrophoblast expresses a heavy metal-binding protein, metallothionein-1. This protein binds and sequesters a host of copper and other heavy metals, including zinc, cadmium, and lead.[4]

Copper is a coenzyme for Lysyl oxidase, an enzyme that initiates collagen cross-linking, in order to increase the tensile strength of fibrillar collagens, and then, the strength of amniotic membranes.[4],[5] Copper also contributes to the formation of fetal organs such as differentiation of the central nervous system.[6]

Many studies have demonstrated a connection between maternal copper levels disturbances and the incidence of developmental abnormalities in fetal tissues. For example, increased levels of maternal copper are involved in preeclampsia[7] and neural defects.[8] On the other hand, decreased levels of maternal serum copper are associated with low birth weight[9] or intrauterine growth retardation.[10]

Premature rupture of membranes (PROM) is a rupture of amniotic membranes before the onset of labor. If PROM occurs before the 37th week of pregnancy, it is called preterm PROM. The prevalence of PROM is 2%–18% of all pregnancies.[11]

PROM increases maternal and fetal infections and causes premature delivery. Nevertheless, there are many risk factors that could induce PROM such as PROM in previous pregnancies, uterine distension (e.g., polyhydramnios and multifetal pregnancy), lower genital tract infection, maternal trauma, and cigarette smoking.[4],[12]

Decline in collagen concentrations and increased collagen catabolism, changed collagen structure, and increased oxidative stress have been suggested as the mechanisms of PROM.[5] Copper is known to serve as an anti-oxidant and a coenzyme for lysyl oxidase, which motivated researchers to investigate the relationship between copper levels and PROM, and the role of copper in the pathophysiology of PROM. The association between maternal serum copper levels and PROM is still debated.[13] In addition, the small sample size is a limitation of all related studies due to the low incidence rate of PROM.

This study aims to study the relationship between maternal serum copper levels and the incidence of PROM and to determine the risk factors of PROM in Syria. This study will be the first study to investigate the association of maternal serum copper levels with PROM and risk factors of PROM in Aleppo University Hospital of Obstetrics and Gynecology.


  Materials and Methods Top


Ethics

Before collecting the data, consent was obtained from the participants. All ethical considerations, including obtaining verbal consent, were approved by our institution.

Study design

Sixty pregnant women in Aleppo University Hospital of Obstetrics and Gynecology were subjected for analyzing serum copper concentrations, using the simple random sampling. Research data were provided as supplementary file. The samples were divided into two groups. A case group, consisting of 27 women diagnosed with PROM, and a control group, consisting of 33 apparently healthy pregnant women with no problems or complications.

We collected the blood on ethylenediaminetetraacetic acid tubes. For the case group, we collected blood within 24–40 h from gestational membrane rupture. The blood was directly centrifuged and stored in-20°C until analysis.

The case manager obstetrician filled a survey to collect the information about the demographic characteristics, medical and obstetrical history, and suspected risk factors. This survey was filled by interviewing the cases and searching the records. Maternal serum copper levels were measured by standard atomic absorption spectroscope in Bioanalysis Department in Faculty of Pharmacy. Copper serum concentration of 165–222 μg\dL in the second trimester of pregnancy and 130–240 μg\dL in the third trimester was considered normal.[4] A participant with hemoglobin concentration of <11 mg/dl was considered anemic.

Statistical analysis

We conducted the statistical analysis using the SPSS (Version 22.0; SPSS Inc.: Chicago, IL, USA). Categorical variables were presented as frequencies and percentages, whereas continuous data were summarized as mean ± standard deviation. We calculated odds ratios (OR) with confidence intervals (CI) using binary logistic regression analysis. Whichever indicated, we used Chi-square, Fisher's exact test, and Student t-test tests to calculate the P values. The P < 0.05 was considered statistically significant.


  Results Top


The study included 60 pregnant women, 27 of them were in the case group, and 33 were controls. In the case group, the mean age was 31.21 ± 7.72 years, 26 cases were in their third trimester of gestation, and one in her 2nd trimester. In the control group, the mean age was 35.8 ± 2.75 years, 31 controls were in their third trimester, and two in their 2nd trimester. No significant differences in maternal or gestational age were found between the two groups. The characteristics of both groups are presented in [Table 1].
Table 1: Mean, standard deviation and P value for the variants (mother age, gestational age and serum copper concentrations for both groups


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Seventeen (67%) cases and 8 (24%) controls had copper deficiency. The relationship between copper deficiency and incidence of PROM was significant (OR = 0.15, CI: 0.04–0.61, P = 0.002) [Table 2].
Table 2: Correlation between copper levels and premature rupture of membrane cases with P value, odd ratios, and confidence intervals


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The mean maternal serum copper level was (125.6 ± 47.4) μg/dL in the case group and (165.3 ± 51.4) μg/dL in the control group. Difference in means between the two groups was 40.87 μg/dL with CI (14.98–66.75) μg/dL. The difference in means between the two groups was statistically significant (P = 0.003).

There was no significant association between the incidence of PROM and PROM history, anemia, history of preterm labor, polyhydramnios, high chronic intra-abdominal pressure, and vaginal infection. Mechanical trauma was the only studied factor that was significantly associated with PROM (OR = 9.14, CI: 1.03–81.48, P = 0.039) [Table 3].
Table 3: Risk factors and its incidence in case and control groups with statistical values (odds ratio, confidence interval, and P value)


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  Discussion Top


Copper plays an important role in reproduction cycle and copper deficiency may result in some metabolic disorders like PROM; therefore, this study aims to determine this correlation. In this study, a significant correlation was found between maternal serum copper levels and in cadence of PROM. The relationship presents when copper level is considered as a categorical variable, as mothers with copper deficiency were significantly more vulnerable for PROM. Furthermore, the relationship presents when copper level is considered as a numerical variable, as mothers with lower serum copper levels were at significantly higher risk to develop PROM. Among the studied suspected risk factors, trauma was the only one to have a significant relationship with PROM.

This study has a major limitation which is the small sample size. This limitation presents in all related studies, as PROM has a low incidence rate,[5] and copper levels measurement is expensive, technically challenging, and these cases do not admit to our hospitals very frequently. The negative effect of the small sample size is clearly reflected by the wide CIs of the risk factors ORs. For the previous considerations, the results of our study as all related studies should be interpreted and generalized with caution.

The association between copper levels and PROM has always been debated. Artal et al.,[14] Fu et al.,[15] and Kiilholma et al.[16] found a significant association between copper levels and the incidence of PROM and the results in this research is consistent with those previous studies, while Seddighi Looyeet al.,[17] Kucukaydin et al.,[18] Bakhshandeh Nosrat et al.,[19] Rahmanian et al.,[13] Zhang et al.,[7] and Shen et al.[20] found no significant relationship between copper levels and incidence of PROM.

There are multiple factors that lead to the contradiction between studies. First, the small sample sizes which causes less precision. Second, the difference in copper measurement techniques. Third, the difference in the case and control groups. Some studies studied PROM in term pregnancies or regardless of the gestational age,[7],[13],[14],[15],[17],[19],[20] but other studies studied preterm PROM.[16],[18],[19] Furthermore, some studies used healthy term pregnancies without PROM as controls,[7],[13],[14],[15],[17],[19],[20] and some used preterm pregnancies without PROM as controls.[16],[19],[18]


  Conclusion Top


Within its limitations, this study suggests a significant relationship between maternal serum copper levels and PROM. There is still a debate about this association in the medical literature, and this debate has multiple causes related to the small sample size, to study design and to technical issues. Further studies are recommended to investigate this association with larger sample sizes, and more controlled design, and to thoroughly review and metaanalyze the available literature. This will help the next step, which is to study the effectiveness of copper supplementation to prevent pregnancy adverse events.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy. Oxid Med Cell Longev 2011;2011:841749.  Back to cited text no. 1
    
2.
Collins JF, Prohaska JR, Knutson MD. Metabolic crossroads of iron and copper. Nutr Rev 2010;68:133-47.  Back to cited text no. 2
    
3.
O'Dell BL. Roles for Iron and Copper in Connective Tissue Biosynthesis. Philos Trans R Soc Lond B Biol Sci 1981;294:91-104.  Back to cited text no. 3
    
4.
Cunningham FG, Leveno KJ, Bloom SL, Spong CY, Dashe JS, Hoffman BL. Sheffield JS. Williams Obstetrics. 24th ed. New York: McGraw-Hill Education; 2014.  Back to cited text no. 4
    
5.
Parry S, Strauss JF 3rd. Premature rupture of the fetal membranes. N Engl J Med 1998;338:663-70.  Back to cited text no. 5
    
6.
Hwang JE, de Bruyne M, Warr CG, Burke R. Copper overload and deficiency both adversely affect the central nervous system of Drosophila. Metallomics 2014;6:2223-9.  Back to cited text no. 6
    
7.
Song X, Li B, Li Z, Wang J, Zhang D. High serum copper level is associated with an increased risk of preeclampsia in Asians: A meta-analysis. Nutr Res 2017;39:14-24.  Back to cited text no. 7
    
8.
Zeyrek D, Soran M, Cakmak A, Kocyigit A, Iscan A. Serum copper and zinc levels in mothers and cord blood of their newborn infants with neural tube defects: A case-control study. Indian Pediatr 2009;46:675-80.  Back to cited text no. 8
    
9.
Abass RM, Hamdan HZ, Elhassan EM, Hamdan SZ, Ali NI, Adam I. Zinc and copper levels in low birth weight deliveries in Medani Hospital, Sudan. BMC Res Notes 2014;7:386.  Back to cited text no. 9
    
10.
Gautam B, Deb K, Banerjee M, Ali MS, Akhter S, Shahidullah SM, et al. Serum zinc and copper level in children with protein energy malnutrition. Mymensingh Med J 2008;17:S12-5.  Back to cited text no. 10
    
11.
Merenstein GB, Weisman LE. Premature rupture of the membranes: Neonatal consequences. Semin Perinatol 1996;20:375-80.  Back to cited text no. 11
    
12.
Gabbe SG, Niebyl JR, Simpson JL, Landon MB, Galan HL, Jauniaux ER, et al. Obstetrics: Normal and Problem Pregnancies. Philadelphia, PA: Elsevier Health Sciences; 2016.  Back to cited text no. 12
    
13.
Rahmanian M, Jahed FS, Yousefi B, Ghorbani R. Maternal serum copper and zinc levels and premature rupture of the foetal membranes. J Pak Med Assoc 2014;64:770-4.  Back to cited text no. 13
    
14.
Artal R, Burgeson R, Fernandez FJ, Hobel CJ. Fetal and maternal copper levels in patients at term with and without premature rupture of membranes. Obstet Gynecol 1979;53:608-10.  Back to cited text no. 14
    
15.
Fu YH. Serum copper levels and pathologic changes in the fetal membranes in cases of premature rupture of the membranes. Zhonghua Fu Chan Ke Za Zhi 1989;24:276-8, 317.  Back to cited text no. 15
    
16.
Kiilholma P, Grönroos M, Erkkola R, Pakarinen P, Näntö V. The role of calcium, copper, iron and zinc in preterm delivery and premature rupture of fetal membranes. Gynecol Obstet Invest 1984;17:194-201.  Back to cited text no. 16
    
17.
Seddighi Looye E, Moghaddam Banaem L, Afshar A. Relationships between maternal copper and iron serum levels with pregnancy outcomes and relationship between their maternal and cord levels. Hayat 2012;17:16-25.  Back to cited text no. 17
    
18.
Kucukaydin Z, Kurdoglu M, Kurdoglu Z, Demir H, Yoruk IH. Selected maternal, fetal and placental trace element and heavy metal and maternal vitamin levels in preterm deliveries with or without preterm premature rupture of membranes. J Obstet Gynaecol Res 2018;44:880-9.  Back to cited text no. 18
    
19.
Bakhshandeh Nosrat S, Ghaemi EA, Ahmadi A, Behnampour N, Marjani A, Mansourian AR. Maternal serum copper concentration in premature rupture of membrane: A case-control study. J Biol Sci 2014;14:73-6.  Back to cited text no. 19
    
20.
Shen PJ, Gong B, Xu FY, Luo Y. Four trace elements in pregnant women and their relationships with adverse pregnancy outcomes. Eur Rev Med Pharmacol Sci 2015;19:4690-7.  Back to cited text no. 20
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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