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ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 2  |  Page : 483-488

The diagnostic value of cervicovaginal and serum ferritin levels in relation to spontaneous preterm delivery


1 Obstetrics and Gynecology Department, Shebin El-Kom Teaching Hospital, Egypt
2 Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt

Date of Submission14-Mar-2018
Date of Acceptance10-Apr-2018
Date of Web Publication25-Jun-2019

Correspondence Address:
Zeinab G Baraka
El Mehlla El Kobra
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_120_18

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  Abstract 


Objective
The objective of the study was to detect the diagnostic value of cervicovaginal and serum ferritin levels in 20–24 weeks of gestation in the prediction of spontaneous preterm delivery in singleton pregnancies with no well-known risk factors of preterm delivery.
Background
Preterm delivery is one of the most important health problems in the world that may lead to severe short-term and long-term medical and developmental problems in infants.
Patients and methods
Venous blood and cervicovaginal fluid samples are drawn from 100 women with singleton pregnancies within 20–24 weeks of gestation at the Department of Obstetric and Gynecologies, El Mehalla Hospital and then they were followed up and the term of delivery were noted.
Results
Spontaneous preterm delivery in singleton pregnancies with no well-known risk factors is associated with increased levels of cervicovaginal and serum ferritin when measured within 20–24 weeks of gestation and there is a strong positive correlation between both serum and cervicovaginal ferritin levels measuring 0.83. However, the only significant predictor is serum ferritin as an increase by one unit of its value increases the preterm risk by 1.277. About 85% of preterm deliveries can be predicted by serum ferritin.
Conclusion
It has been observed that 20–24 weeks of gestation serum ferritin level is a significant predictor of preterm delivery in singleton normal pregnancies.

Keywords: cericovaginal, ferritin, preterm delivery, serum, spontaneous


How to cite this article:
Baraka ZG, Satar MM, Emara MA, El-Nasr IA. The diagnostic value of cervicovaginal and serum ferritin levels in relation to spontaneous preterm delivery. Menoufia Med J 2019;32:483-8

How to cite this URL:
Baraka ZG, Satar MM, Emara MA, El-Nasr IA. The diagnostic value of cervicovaginal and serum ferritin levels in relation to spontaneous preterm delivery. Menoufia Med J [serial online] 2019 [cited 2019 Sep 16];32:483-8. Available from: http://www.mmj.eg.net/text.asp?2019/32/2/483/260887




  Introduction Top


Preterm delivery is one of the most important healthcare problems in the world, with increasing incidence in middle-income and high-income countries that may lead to severe short-term and long-term medical and developmental problems in infants[1].

Also suspected preterm delivery is the most common cause of pregnant women hospital admission[2].

The origin of spontaneous preterm delivery is mostly unknown. However, infection and inflammation are the leading causes, mainly at early gestational ages. Intrauterine infection occurs in 12–14% of symptomatic women with preterm delivery and in 37–43% are due to premature rupture of membranes[3].

Ferritin is considered to be the main intracellular iron storage protein present in all living organisms. It is expressed in numerous cell types[4].

There is some evidence for the pathophysiology of preterm delivery that upper genital tract infections activate phospholipase, prostaglandins and other inflammatory agents[5].

During inflammation the possible role of ferritin is clear as it is mainly released by the liver, spleen, bone, placenta, and by infiltrating leukocytes reacting against infections[6].

Serum ferritin is the body iron store reflector. It is an acute-phase reactant[7].

Therefore, in patients with chronic inflammatory disease serum ferritin is increased due to the retention of iron by the reticuloendothelial cells and increased production due to inflammation[8].

The purpose of the present study was to detect the diagnostic value of cervicovaginal and serum ferritin levels in 20–24 weeks of gestation in the prediction of spontaneous preterm delivery in singleton pregnancies with no well-known risk factors of preterm delivery.


  Patients and Methods Top


The study was conducted at the Department of Obstetric and Gynecology, El Mehalla Hospital on 100 pregnant women with singleton pregnancies within 20–24 weeks of gestation.

The study protocol was approved by the Ethics Committee of the Menoufia University Hospital. The study protocol was explained to the patients.

A written concent was obtained from each case.

The inclusion criteria were single pregnancy, age between 20 and 37 years, average body weight, and gestational age between 20 and 24 weeks.

The exclusion criteria were multiple pregnancy, hypertension, smoking, poyhydramnios, placenta previa, diabetes mellitus, chonic underlying diseases, known short cervix or uterine malformation, and past history of preterm labor or surgery of the cervix.

All patients were subjected to complete history taking including iron intake (all pregnant women in the study were taking routine daily oral iron from the start of the second trimester).

Clinical assessment

General examination, abdominal examination, and abdominal US were done to each case.

Local (vaginal) examination

Sterile speculum was used before any pelvic examination to obtain a cervicovaginal sample.

Measurement of serum ferritin

A measure of 5 cm venous blood sample was drawn from each case using a disposable plastic syringe after skin sterilization with ethyl alcohol swab. A serum separator tube was used and samples were allowed to clot for 2 h at room temperature before centrifugation for 20 min at ∼1000g. The supernatant was collected for assaying. Grossly hemolyzed samples were excluded.

Measurement of cervicovaginal ferritin

A sample of mucous from external os of the posterior fornix of the vagina was taken or sucked with a pipette before any other portion of pelvic examination was performed by using sterile speculum. They were centrifuged for 20 min at 1000g to remove particulates. The supernatant was collected for assaying.

The samples were immediately placed in eppendorf tubes, then the eppendorfs were placed in an ice-box and transported to the laboratory where they were stored at −20°C and were used within 1 month.

Procedure summary

All reagents and samples were brought to room temperature (18–25°C) without additional heating and mixed thoroughly by gently swirling, before pipetting foaming was avoided.

The standard vials were centrifuged at 6000–10000 rpm for 30 s before opening.

Reagents tubes were centrifuged briefly before opening to avoid adherence to the tube wall.

A measure of 50 μl of standard or sample was added per well; 50 μl horseradish peroxidase conjugate was added to each well and then covered with a new plate sealer, and incubated for 1 h at 37°C.

The liquid from each well was aspirated and washed by adding ∼200 μl of ddH2O using a squirt bottle, multichannel pipette, manifold dispenser, or automated washer three times.

Each wash was allowed to sit for 10 s before completely aspirating. Any remaining ddH2O was removed and then the plate and tap were inverted against a clean absorbent paper.

A measure of 50 μl of substrate A and 50 μl substrate B were added to each well and incubated in the dark for 15 min at 37°C; 50 μl of stop solution was added to each well. The blue color changed to yellow immediately. The stop solution was added to wells in the same order and timing as was the substrate solution.

The optical density of each well was determined immediately using a microplate reader set to 450 nm.

Statistical analysis

The data collected were tabulated and analyzed using the statistical package for the social sciences (SPSS, IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp). Quantitative data were expressed as mean and SD and analyzed by applying Student's t-test for comparison of three groups. Qualitative data were expressed as number and percentage and analyzed.


  Results Top


This study was conducted on 100 pregnant women at 20–24 weeks of gestation, 85 of them delivered at full term (37–39 weeks). Fifteen of them delivered preterm (33–36 weeks).

In the current study, the mean serum ferritin concentration in the term group was 89.04 ± 9.7 and the range was 69–119, while in the preterm group the mean was 116.27 ± 4.9 and the range was 109–125. The P value was less than 0.001. It shows a high statistically significant difference [Table 1].
Table 1: Serum and cervicovaginal ferritin levels associated with preterm and full-term deliveries and the correlation between them

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As regards the mean cervicovaginal ferritin concentration in the term group it was 22.0 ± 5.4 and the range was 10–31, while in the preterm group the mean was 29.84 ± 2.7 and the range was 25–33.1. The P value was less than 0.001. It shows a high statistically significant difference [Table 1].

In the current study, there is a strong positive correlation between both serum and cervicovaginal ferritin levels measuring 0.83, as shown in [Table 1].

The Receiver operating characteristic (ROC) curve of serum ferritin [Figure 1] in the prediction of preterm and term deliveries, cutoff point of at least 110.5 ng/ml, sensitivity percent of 86.7%, and specificity percent of 94.1% [Table 2].
Figure 1: ROC curve for serum ferritin.

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Table 2: ROC curve of serum and cervicovaginal ferritin in the detection of preterm and term deliveries

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The ROC curve of cervicovaginal ferritin [Figure 2] in the prediction of preterm and term deliveries, cutoff point of at least 25.5 ng/ml, sensitivity of 86.7%, and specificity of 64.7% [Table 2].
Figure 2: ROC curve for cervicovaginal ferritin.

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Serum and cervicovaginal ferritin are significant predictors for preterm delivery as an increase by one unit of serum ferritin value increases the preterm delivery risk by 1.277 and an increase by one unit of cervicovaginal ferritin value increases the preterm delivery risk by 1.108. Eighty-five percent of preterm delivery can be predicted by serum and cervicovaginal ferritin, as shown in [Table 3].
Table 3: Logistic regression to detect the predictors of preterm delivery

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  Discussion Top


WHO has categorized the preterm delivery according to the gestational age at birth, with birth before 28 weeks considered to be extremely preterm; between 28 and 32 weeks very preterm; between 32 and 34 weeks moderately preterm; and between 34 and 37 weeks late preterm[9].

Ferritin concentration increases with clinical and subclinical genital tract infection, which leads to preterm delivery[10].

This opinion was supported by the finding that increased ferritin concentration was associated with neonatal sepsis in women with premature rupture of membranes at less than 32 weeks of gestation[11].

In the current study, cervicovaginal and serum ferritin levels were studied as predictors for preterm delivery on 100 women with singleton pregnancies within 20–24 weeks of gestational age at the Department of Obstetric and Gynecology El Mehalla Hospital. The gestational age at the time of delivery was reported for each case; 85 of them delivered at full term (37–39 weeks) and 15 of them delivered preterm (33–36 weeks).

In the current study, the mean serum ferritin concentration in the term group was 89.04 ± 9.7 and the range was 69–119, while in the preterm group the mean was 116.27 ± 4.9, and the range was 109–125. The P value was less than 0.001. It shows high statistically significant difference. This study is consistent with the study done by Broumand et al.[12], where 300 singleton pregnancies with a gestational age of 22–24 weeks in the Prenatal and Obstetric Care Center University Hospital in Urmia were studied as they found that the mean serum ferritin level was 58.98 ± 25.7 in term or near-term deliveries versus a mean of 99.4 ± 28.7 in early preterm deliveries, which showed a statistically significant difference (P < 0.001). Also it is consistent with the study done by Xiao et al.[13], as a study was done on 3253 women providing a second-trimester serum sample to a central laboratory of Swedish Medical Center, Seattle, Washington, USA. They reported that the relationship between elevated maternal second trimester serum ferritin concentrations and preterm delivery was strongest for spontaneous preterm deliveries (<34 weeks gestation). Women with ferritin concentrations in the highest decide (>96 ng/ml) experienced a 2.7-fold increased risk of delivering before 34 completed weeks, compared with women with concentrations of less than 26 ng/ml. It is also consistent with the study done by Paternoster et al.[14], and Paternoster et al. as they agreed to account for the association between elevated serum ferritin concentrations and spontaneous preterm delivery.

But the results of the study carried out by Goel et al.[15] in 2003is not consistent with the results of this study as they did a study on 140 women who were at risk of preterm delivery from the Department of Obstetrics and Gynecology and the Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, who reported that the mean serum ferritin at different gestations in the term and preterm group was not statistically different, but serial serum ferritin levels in patients in the term group showed a declining trend with advancing gestation as seen in normal pregnancies. However in the preterm group, a rising trend was observed. Further, serum ferritin levels of more than 30 μg/l at 26 weeks and more than 40 μg/l at 34 weeks were found to have a reasonable sensitivity and specificity for predicting preterm delivery. They made their study on high-risk women that could be the cause of disagreement.

As regards the mean cervicovaginal ferritin concentration in the term group was 22.0 ± 5.4 and the range was 10–31, while in the preterm group the mean was 29.84 ± 2.7 and the range was 25–33.1. The P value was less than 0.001. It shows a high statistically significant difference.

This study is consistent with the study done by Broumand et al.[12], as they found that the cervicovaginal ferritin in term near-term delivery group had a mean of 12.68 ± 15.85 compared with a mean of 26.02 ± 6.86 among those with VEP delivery before 32 weeks of gestational age (P = 0.02).

It is also consistent with the study done by Ramsey et al.[6], as a case–control study involving 182 women who had spontaneous preterm delivery and 182 term control patients matched for race, parity, and recruitment center, and selected from 2929 women enrolled in the Preterm Prediction Study of the National Institute of Child Health and Development Maternal-Fetal Medicine Units Network was done and they found that elevated cervical ferritin levels at 22–24 weeks of gestation in asymptomatic women are associated with subsequent spontaneous preterm birth.

The ROC curve of serum ferritin in the prediction of preterm and term deliveries, with a cutoff point of at least 110.5 ng/ml, sensitivity of 86.7%, and specificity of 94.1%.

This study is consistent with the study done by Broumand et al.[12], as they found that for a cutoff point of 63.9 ng/ml for serum ferritin to predict preterm delivery, the sensitivity was 91.1%, and the specificity was 72.5%.

It is also consistent with the study done by Movahedi et al.[16] that the serum ferritin level provides an appropriate discrimination in predicting preterm delivery, but disagree regarding that the serum ferritin values of more than 22.5 ng/ml was the optimal cut-point, yielded the best combination with a sensitivity of 78.3% and a specificity of 83.0%.

The ROC curve of cervicovaginal ferritin in the prediction of preterm and term deliveries, with a cutoff point of at least 25.5 ng/ml, sensitivity of 86.7%, and specificity of 64.7%.

This study is consistent with the study done by Broumand et al.[12] who found that for a cutoff point of 16.8 ng/ml for cervicovaginal ferritin to predict preterm delivery, the sensitivity was 86.7%, and the specificity was 80.3%.

In the current study, there is a strong positive correlation between both serum and cervicovaginal ferritin measuring 0.83.

This study is not consistent with the study done by Broumand et al.[12], as they found that the cervicovaginal ferritin levels correlated poorly with serum ferritin when assessed using Kendall's τ coefficient (Kendall's τ-a = 0.4152, P < 0.001). They had a large sample size that could be the cause of disagreement.

Serum and cervicovaginal ferritin are significant predictors for preterm delivery as an increase by one unit of serum ferritin value increases the preterm delivery risk by 1.277 and an increase by one unit of cervicovaginal ferritin value increases the preterm delivery risk by 1.108. About 85% of preterm deliveries can be predicted by serum and cervicovaginal ferritin.

This study is consistent with the study done by Singh et al.[17], where a study was performed on 40 women presenting with preterm onset of labor followed by delivery in the Department of Biochemistry, GB Pant Hospital. They found that serum ferritin has a high diagnostic value in predicting preterm labor.

This study is not consistent with the study done by Paternoster et al.[14], as they found that the preterm delivery cervical markers such as pH and Fetal fibronectin (fFN) are more predictive than the serum markers as serum ferritin, and they are useful to predict very early preterm labor (under 32 gestational weeks). Different markers could be the cause of disagreement.

This study approves elevated serum and cervicovaginal ferritin levels in midgestation as good markers for predicting preterm delivery; also the presence of a strong positive correlation between both supports this evidence, but it carries some limitations including small sample size, and does not work on high-risk pregnant women and including only singleton pregnancy.


  Conclusion Top


The 20–24-week serum and cervicovaginal ferritin levels can be used as significant predictors for preterm delivery in singleton normal pregnancies.

Future advance in developing combined biochemical-sonographic scales to provide a very high sensitivity and specificity may be promising to expect a definitive role for them in improving maternal or neonatal outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dias T, Passini R, Tedesco R, Lajos G, Rehder P, Nomura M, et al. Evaluation of prenatal corticosteroid use in spontaneous preterm labor in the Brazilian Multicenter Study on Preterm Birth (EMIP). Int J Gynecol Obstet 2017; 139:222-229.  Back to cited text no. 1
    
2.
Romero R, Erez O, Maymon E, Pacora P. Is an episode of suspected preterm labor that subsequently leads to a term delivery benign? Am J Obstet Gynecol 2017; 216:89-94.  Back to cited text no. 2
    
3.
Yuan W, Duffner A, Chen L, Hunt L, Sellers S, Bernal A. Analysis of preterm deliveries below 35 weeks' gestation in a tertiary referral hospital in the UK. A case–control survey. BMC Res Notes 2010; 3:119.  Back to cited text no. 3
    
4.
Masuda T, Chen H, Zhao G. Structure, Function, and Nutrition of Ferritin from Foodstuffs. In: Zhao G. (eds) Mineral Containing Proteins: Springer, Singapore; 2017.  Back to cited text no. 4
    
5.
Ustum C, Kocak I, Baris S, Uzel A, Saltic F. Subclinical choriomniotis as an etiologic factor in preterm delivery. Int J Gynaecol Obstet 2001;72:109-115.  Back to cited text no. 5
    
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Ramsey P, Tamura T, Goldenberg RL, Mercer BM, Iams JD, Meis PJ, et al., National Institute of Child Health and Human Development, Maternal-Fetal Medicine Units Network. The preterm prediction study: elevated cervical ferritin levels at 22 to 24 weeks of gestation are associated with spontaneous preterm delivery in asymptomatic women. Am J Obstet Gynecol 2002; 186:458-463.  Back to cited text no. 6
    
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Raj S, Rajan G. Correlation between elevated serum ferritin and HbA1c in type 2 diabetes mellitus. Int J Res Med Sci 2017; 1:12-15.  Back to cited text no. 7
    
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Madu A, Ughasoro M. Anaemia of chronic disease: an in-depth review. Med Princ Pract 2017; 26.1:1-9.  Back to cited text no. 8
    
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Mohanty RN, Shah R. SMCH – the innovative pediatric care hospital from India, Emerald Emerging Markets Case Studies, 2016. https://doi.org/10.1108/EEMCS-06-2015-0118.  Back to cited text no. 9
    
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Scholl T. High third-trimester ferritin concentration: associations with very preterm delivery, infection, and maternal nutritional status. Obstet Gynecol 1998; 92:161-166.  Back to cited text no. 10
    
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Goldenberg R, Iams J, Mercer B, Meis P, Moawad A, Copper R, et al. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998; 88:233-238.  Back to cited text no. 11
    
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Broumand F, Saeidkar S, Behrouzlak T, Khalkhali H, Sadeghi-Bazargani H. The diagnostic value of cervicovaginal and serum ferritin levels in midgestation time to predict spontaneous preterm delivery. Niger Med J 2014; 55:321.  Back to cited text no. 12
    
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Xiao R, Sorensen T, Frederick I, El-Bastawissi A, King I, Leisenring W, et al. Maternal second-trimester serum ferritin concentrations and subsequent risk of preterm delivery. Paediatr Perinat Epidemiol 2002; 16:297-304.  Back to cited text no. 13
    
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Paternoster D, Stella A, Gerace P, Manganelli F, Plebani M, Snijders D, et al. Biochemical markers for the prediction of spontaneous pre-term birth. Int J Gynecol Obstet 2002; 79:123-129.  Back to cited text no. 14
    
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Goel A, Jain V, Gupta I, Varma N. Serial serum ferritin estimation in pregnant women at risk of preterm labor. Acta Obstet Gynecol Scand 2003; 82:129-132.  Back to cited text no. 15
    
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Movahedi M, Saiedi M, Gharipour M, Aghadavoudi O. Diagnostic performance and discriminative value of the serum ferritin level for predicting preterm labor. J Res Med Sci 2012; 17:164-166.  Back to cited text no. 16
    
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Singh B, Goswami B, Gupta N, Bajaj A, Mallika V. Potential biochemical markers for preterm labor: a pilot study in north India. Indian J Clin Biochem 2011; 26:41-45.  Back to cited text no. 17
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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