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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 52  |  Issue : 4  |  Page : 498-500
Predictive value of mid-trimester amniotic fluid high-sensitive C-reactive protein, ferritin, and lactate dehydrogenase for fetal growth restriction

1 Department of Gynecology and Obstetrics, Tehran University/ Medical of Science, Iran
2 Department of Pathology, Tehran University/ Medical of Science, Iran
3 Department of Gynecology and Obstetrics, Kerman University/ Medical of Science, Iran

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Date of Web Publication1-Oct-2009


Background: Fetal growth restriction (FGR) is surprisingly common with placental dysfunction occurring in about 3% of pregnancies and despite advances in obstetric care, FGR remains a major problem in developed countries. Aim: The purpose of this study is to find out the predictive value of amniotic fluid high sensitive C-reactive protein (hs-CRP), ferritin, and lactate dehydrogenase (LDH) for FGR. Materials and Methods: This prospective strategy of this study has been conducted on pregnant women who underwent genetic amniocentesis between 15th and 20th weeks of gestation. All patients were followed up on until delivery. Patients with abnormal karyotype and iatrogenic preterm delivery for fetal and maternal indications were excluded. The samples were immediately sent to laboratory for cytogenetic and biochemical examination. Non-parametric tests and receiver-operator characteristic curve analysis were used for statistical purpose. Results: A significant correlation between incremental amniotic fluid alpha fetoprotein (αFPr) and LDH levels and FGR at gestational weeks 15th-20th was found out. We also found an optimum cut-off value >140 IU/L for the amniotic fluid LDH concentration with a sensitivity of 87.5% and a specificity of 82.4% for the prediction of FGR. Conclusion: Once the LDH value is confirmed, it could serve as a prediction factor for FGR at the time of genetic amniocentesis at gestational weeks 15-20.

Keywords: Amniotic fluid, ferritin, fetal growth restriction, fetal growth restriction high sensitive C-reactive protein, lactate dehydrogenase

How to cite this article:
Borna S, Abdollahi A, Mirzaei F. Predictive value of mid-trimester amniotic fluid high-sensitive C-reactive protein, ferritin, and lactate dehydrogenase for fetal growth restriction. Indian J Pathol Microbiol 2009;52:498-500

How to cite this URL:
Borna S, Abdollahi A, Mirzaei F. Predictive value of mid-trimester amniotic fluid high-sensitive C-reactive protein, ferritin, and lactate dehydrogenase for fetal growth restriction. Indian J Pathol Microbiol [serial online] 2009 [cited 2023 Sep 30];52:498-500. Available from:

   Introduction Top

Fetal growth restriction (FGR) is defined as a fetal growth rate that prevents an infant from obtaining the complete genetic growth potential. [1] It is surprisingly common with placental dysfunction occurring in about 3% of pregnancies.

Several reports have suggested that reduced endovascular trophoblast invasion and impaired vascular remodeling of spiral arteries contribute to the pathogenesis of FGR. [2],[3] Consequently, reduced uteroplacental perfusion caused by shallow implantation could cause placental hypoxia. A hypoxic ischemic placenta may release several substances including cytokines and reactive oxygen species, which could initiate vascular and endothelial dysfunction. [4]

High-sensitive C-reactive protein (hs-CRP), being a sensitive marker of tissue damage and inflammation, can be a potential marker. Plasma hs-CRP levels rise in cases of acute infection, malignancy, and inflammatory diseases. [5] High ferritin levels have been associated with many conditions including acute and chronic infections and ferritin itself is an acute-phase reactant. Several investigators associated altered serum ferritin and CRP concentrations with various pregnancy complications such as low birth weight. [6],[7] Lactate dehydrogenase (LDH) catalyses the reversible oxidation of lactate to pyruvate at final steps of glycolytic pathway and is a marker of acute inflammation in body fluids. [8]

Therefore, prediction of FGR has been a major clinical and research issue for the past 20 years. [9] The purpose of this study was to find out the predictive value of amniotic fluid hs-CRP, ferritin, and LDH for FGR.

   Materials and Methods Top

Study design and setting

This prospective study involving 110 pregnancies was conducted for a period of 9 months in 2007. Written consent for tests described herein was obtained from all women. The ethics committee of our hospital approved the study. Pregnancies with singleton that underwent amniocentesis at weeks 15-20 for standard genetic indications were enrolled in the study. Pregnancies with an evidence of fetal structural or chromosomal anomalies and conditions known to be associated with IUGR (i.e., chronic hypertension, overt diabetes with vascular diseases, thrombophilia, lupus, and a history of low-birth-weight infants) were excluded from the study.

Gestational age was defined as completed weeks since last menstrual period (LMP) confirmed within two weeks by ultrasound before gestational week of 20. If a woman was unsure of her LMP, or if there was a discrepancy of more than 2 weeks between ultrasound and LMP, ultrasound age was used to calculate gestational age at delivery.

FGR(FGR) defined as birth weight below the 10th percentile for gestational age and appropriate weight for gestational age (AGA) as birth weight between 10th and 90th percentile. Preeclampsia was defined as a rise in systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg and proteinuriaproteinuria ≥300 mg/I for 24 hrsrs urine sample.

All of the pregnancies were followed up until delivery. At the end of the study, patients were divided into 2 groups who delivered growth-restricted baby (FGR group) and appropriate birth weight for gestational age babies (AGA group).


Amniocentesis was performed using 21-gauge needle under ultrasonographic guide and a free-hand technique. The first 0.5 ml of amniotic fluid was collected into a 5-ml syringe and discharged to avoid maternal contamination. Subsequently, 15-20 ml of amniotic fluid was collected using a 20-ml syringe and used for karyotype determination and hs-CRP, ferritin, and LDH concentrations measurements. The amniotic fluid specimens were centrifuged for 10 min to obtain the cellular components for karyotype determination. The supernatant was processed for hs-CRP, ferritin, and LDH concentration determination. Amniotic fluid supernatant was tested for hs-hsCRP, LDH, and ferritin in an automated analyzer (Alcyon 300, Abbott, USA) by turbidimetric method (high sensitive CRP and LDH, Biosystems Reagents and Instruments, Spain; ferritin, Biokit, Germany). The sensitivity of the assay for ferritin was up to 0.05 ng/ml. The detection limit of kit for hs-CRP was 0.06 mg/l and it was 4.7 U/L for LDH.

Statistical analysis

Data were reported as means ΁ standard deviation (SD) or median with 1th and 3th quartiles (whenever the data did not appear to have normal distribution) for quantitative variables and categorized variables were summarized. Mann-Whitney U test was used for non-normal distributed variable and categorical variable were compared using Chi-square or Fisher's exact test between two groups. For statistical analysis, the statistical software SPSS (version 13.0 for windows, SPSS Inc., Chicageo, lL) was used. All P values were for two-tailed tests and P<0.05 considered significant.

   Results Top

During the study, 110 patients underwent amniocentesis. A chromosomal abnormality was observed in fourfour cases. Three out of the 110 patients were categorized in termination of pregnancy for fetal or maternal indications (intrauterine fetal death, overt diabetes) and 10 patients could not be reached. The study was completed with 93 subjects, eighteight out of them (8.6%) were FGR. Meanwhile, 11 women developed preeclampsia (11.8%). There were also no significant differences between groups with respect to maternal age, gestational age at amniocentesis, parity, and indication for amniocentesis and location of placenta, maternal serum hCG (human chorionic gonodotropin), uE3 (unconjugated estriol), and multiple of median (MOM) values [Table 1].

Elevated maternal serum AFP (alpha-fetoprotein) was significantly associated with birth weight less than the 10 th percentile (P =0.032). Preeclampsia was more common in mothers of FGR infants than in mothers of AGA infants (37.5% and 9.4%, respectively). Amniotic fluid hs-CRP, ferritin,ferritin, and LDH concentrations of the patients are shown in [Table 2].

Median of amniotic fluid LDH concentration was higher in FGR group than AGA group (median = 99.00; range: 63.00-120.00 IU/l vs. median =150.50; range: 140.75-201.00 IU/l; P=0.03).

Receiver-operator characteristic curve analysis was performed to evaluate the screening efficiency of amniotic fluid LDL, hs-CRP and ferritin in predicting FGR [Table 3]. Amniotic fluid LDH was found to be effective in predicting FGR. Mid-trimester amniotic fluid LDH concentration >140 IU/l was found out to be an optimal cut-off value for prediction of FGR with a sensitivity of 87.5% and a specificity of 82%. Positive predictive value of FGR was 22.7 in these women.

   Discussion Top

FGR constitutes an important issue in obstetrics, notably in developing countries. It may traumatize the infant, the mother,mother and other family members. Hence, identification of its causes and finding remedies for this scourge would definitely leave positive impacts on the family and the whole of the society. In this study, we tried to find a valuable factor in amniotic fluid to help us predict FGR. Our study found a significant correlation between incremental αFPr and LDH levels in the amniotic fluid and of FGR at gestational weeks 15 th -20 th , the higher the αFPr and LDH levels in the amniotic fluid, the more likely will be FGR. It is also noteworthy that previous studies such as WenstromWenstrom study found a direct relationship between αFPr level and incidence of FGR which was consistent with our results, but the involvement of LDH is a landmark here. [10] We found the optimum cut-off value >140 IU/L for the amniotic fluid LDH concentration with a sensitivity of 87.5% and a specificity of 82.4% in the prediction of FGR.

LDH is a widely distributed cytoplasmic enzyme. It produces the final catalysis of anaerobic glycolysis with reversible transformation of pyruvate into lactate. Five iso-enzymes have been identified as a function of their distribution in different tissues and their electrophoretic separation. LDH is a tetrameric protein composed of four monomers and exists in two forms: muscle (M) and heart monomer (H). LDH5 is composed of four types of M chains and is mainly found in skeletal muscle. In contrast, LDH1, composed of four type-H chains, is mainly present in the heart. LDH1 and LDH2 are predominantly found is tissues with an aerobic metabolism, conversely, LDH4 and LDH5 are dominant in tissues with an anaerobic glycolysis. In pathology, iso-enzymes of LDH1 and LDH2 increase following acute heart muscle injury and serum LDH5 is also high in acute liver injury. [11]

In our study,study, no significant correlation was found between mother's age, parity, and mother's serum level of HCG, ferritin level of amniotic fluid, and gestational age at the time of amniocentesis for FGR. A study by Hou et al.[12] suggested that serum ferritin levels might serve as markers to identify women at risk of having asymmetric-FGR infants. Whether that measurement ultimately will be useful clinically for predicting or serving as an adjunct to the diagnosis of asymmetric-FGR fetuses is worth further investigation. [12] The study does not comment on the amniotic fluids ferritin and its possible prediction role in the incidence of FGR. A study by Tjoa et al. [13] showed that in a low-risk population, CRP levels are already elevated between weeks 10 and 14 in pregnant women who develop preeclampsia or deliver a growth-restricted baby. [13] The study did not comment on the amniotic fluid's CRP level and the incidence of FGR. A study by Verspyck et al. [11] revealed that LDH iso-enzyme profiles were similar between human fetuses and adults with a predominant percentage of aerobic iso-enzyme activity. The results suggest that fetal LDH in plasma is a useful biologic marker for severe chronic distress and could be used as a prognostic factor in small-for-gestational age fetus but this study did not comment on the amniotic fluids LDH and its possible predictive role in FGR. [11] Our study faced restrictions like small sample size. Therefore, future studies are recommended to take larger samples and/or examine LDH iso-enzymes separately.

   Conclusion Top

Once the lactate dehydrogenase lactate dehydrogenasevalue is confirmed, it could serve as a prediction factor for fetal growth restriction fetal growth restriction at the time of genetic aminocentesis at gestational weeks 15-20.

   References Top

1.Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Preeclampsia and fetal growth. Obstet Gynecol 2009;96:950-5.  Back to cited text no. 1      
2.Kupfermine MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth rretardation, abruption placentae and second trimester loss. Acta Obstet Gynecol Scand 2000;79:963-7.  Back to cited text no. 2      
3.Lim KH, Zhou Y, Janatpour M, McMaster M, Bass K, Chun SH, et al. Human cytotrophoblast differential invasion is abnormal in preeclampsia. Am J Pathol 1997;151:1809-18.  Back to cited text no. 3      
4.Redman CW, Sacks GP, Sargent IL. Preeclampsia, an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 1999;180:499-506.  Back to cited text no. 4      
5.Du Clos TW. The interacton of C-reactive protein and serum amyloid P component with nuclear antigens. Mol Biol Rep 1996;23:253-60.  Back to cited text no. 5      
6.Kuvibidila S, Yu L, Warrior RP, Ode D, Mbele V. Usefulness of serum Ferritin levels in the assessment of iron status in nopregnant Zairean women of childbearing age. J Trop Med Hyg 1994;97:171-9.  Back to cited text no. 6      
7.Tamura T, Goldenberg RL, Johnston KE, Cliver SP, Hickey CA. Serum Ferritin: A predictor of early spontaneous preterm delivery. Obstet Gynecol 1996;87:360-5.  Back to cited text no. 7      
8.Madazli R, Atis A, Uzun H, Aksu F. Mid-trimester amniotic fluid angiogenin, lactate dehydrogenase and fibroreaction in the prediction of preterm delivery. Eur J Obstet Gynecol repord Biol 2003;106:160-4.  Back to cited text no. 8      
9.Sibai B, Dckker G, Kupfermine M. Preeclampsia. Lancet 2005;362:785-99.  Back to cited text no. 9      
10.Wenstrom KD, Owen J, Davis RO, Brumfield CG. Prognostic significance of unexplained elevated amniotic fluid alpha- fetoprotein. Obstet Gynecol 1996;87:213-6.  Back to cited text no. 10      
11.Verspyck E, Gaillard G, Parnet F, Marret S, Marpeau L. Fetal lactic Dehydrogenase variation in normal pregnancy and in cases of severe Intra-uterine Growth Restriction. Prenat Diagn 1999;19:229-33.  Back to cited text no. 11      
12.Hou J, Cliver S, Tramura T, Johnston K, Goldenberg R. Maternal serum Ferritin and fetal Growth. Obstet Gynecol 2000;95:447-52.  Back to cited text no. 12      
13.Tjoa M, van Vugt JM, Go A, Blankenstein M, Oudejans C, van Wijk IJ. Elevated c-reactive protein levels during first trimester of pregnancy are indicative of preeclampsia and intrauterine growth restriction. J Reprod Immunol 2003;59:29-37.  Back to cited text no. 13      

Correspondence Address:
Alireza Abdollahi
Department of Pathology, Tehran University/ Medical of Science
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.56136

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  [Table 1], [Table 2], [Table 3]

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