|Year : 2016 | Volume
| Issue : 1 | Page : 3-14
Identification of biomarkers for prediction of preterm delivery
Jigna Shah, Bhavya Baxi
Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
|Date of Web Publication||5-Feb-2016|
Department of Pharmacology, Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad - 382 481, Gujarat
Source of Support: None, Conflict of Interest: None
Preterm birth is one of the most prevailing complications of pregnancy causing neonatal mortality and morbidity. Cervical length measurement has been the only criteria used till now for the prediction of preterm delivery (PTD). Research on many biomarkers in maternal serum, amniotic fluid, and cervicovaginal fluid (CVF) has been accomplished such as fetal fibronectin (FFN), α-fetoprotein, C-reactive protein (CRP), multiple members of the interleukin family (interleukin-6, interleukin 8, and interleukin 10), matrix metalloproteinases, pregnancy-associated plasma protein A, relaxin, lactate dehydrogenase (LDH), thyroid-stimulating hormone, adrenocorticotropic hormone, vascular endothelial growth factor (VEGF), ferritin, prolactin, ceruloplasmin, alkaline phosphatase (ALP), glucose, placental protein 13, corticotropin releasing hormone, tumor necrosis factor-α (TNF-α), tumor necrosis factor-β (TNF- β), estriol and human chorionic gonadotropin (hCG). Not a single biomarker has been evolved till date, which possesses sensitivity as well as reliability for the detection of spontaneous preterm birth. The variability in results across the studies may have arisen due to dissimilarities in study designs, different timings of collection of blood, and diversities in the study population. Study on a large sample size is needed for the confirmatory conclusion of use of biomarker in PTD. A single biomarker or even in combination, if found for the prediction of preterm labor (PTL), can decrease the hospital cost as well as restrict the treatment.
Keywords: Amniotic fluid, biomarker, C-reactive protein (CRP), fetal fibronectin (FFN), maternal serum, preterm birth
|How to cite this article:|
Shah J, Baxi B. Identification of biomarkers for prediction of preterm delivery. J Med Soc 2016;30:3-14
| Introduction|| |
The World Health Organization (WHO) factsheet revealed that 15 million babies are born too early every year and almost 1 million children die each year due to complications of preterm birth.  Preterm birth, i.e., birth before 37 weeks of gestation period, an important obstetric problem, is the major cause of neonatal mortality and morbidity across the globe. Nearly 70% of the neonatal deaths are due to preterm delivery (PTD).  Preterm pregnancy accounts for about 10% of the total pregnancies. There has been an increase in the number of preterm deliveries in the last 25 years.  The causes of preterm labor (PTL) include multiple pregnancies, infections, and chronic conditions such as diabetes and high blood pressure. The reports also suggest that PTL may be due to one or more of the pathophysiologic processes such as amnio-chorionic-decidual or systemic inflammation, activation of the maternal or fetal hypothalamic-pituitary-adrenal axis, decidual hemorrhage, or pathologic distension of the uterus. But a clear understanding of the molecular mechanism has not developed yet.  All the women coming with the symptoms of PTL do not go for active labor or preterm birth. More than 70% of these women continue for the full term and thus, it is essential to differentiate and find out who will progress for preterm birth. This can reduce the unnecessary hospital stays and unwanted treatments. 
Cervical length measurement has been the only criterion used till now for the prediction of PTD wherein the short cervical length (<30 mm) is indicative of preterm birth. But the sensitivity and specificity of this method are low.  Many maternal and biochemical data as well as other demographic and behavioral factors have been used and tried for the prediction of PTD but none of them have succeeded.  Thus, there is an urgent necessity to develop such a marker which can render information regarding PTD.
In response to the call for early detection of PTD, several diagnostic biomarkers are currently in development. Biomarkers are substances, which are measured in a biological sample, and provide information on the potential effects of that exposure. The search for reliable biomarkers for detecting PTD has led to the identification of a plethora of markers in the biological fluids such as cervicovaginal fluid (CVF), amniotic fluid, and blood serum.
| Search Methodology|| |
Systematic literature search was performed and a total of 71 review/research articles published from 1991 to 2015 were identified from electronic databases to investigate potential biomarkers used for the detection of PTD and the types of biological samples used for the measurement of such biomarkers. Data were extracted and the information with respect to the study design, sample size, gestational age at the time of sampling, type of biological sample, concentration of biomarkers in these cases was collected. As depicted in [Table 1], more than 45 research studies have been published from the late 1990s until today, suggesting more than 40 biomarkers as potential contenders to detect PTD. But for the prediction of PTD in asymptomatic women, no biomarker has consistently performed well.
|Table 1: Literature search for research studies on biomarkers for the prediction of preterm delivery|
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This review article will furnish an up-to-date list of the potential biomarkers for detection of PTD. Also, it will focus on some emerging issues and challenges that seem to be major obstructions on the way to bringing reliable PTD biomarkers into actual clinical use. Also, it will increase the awareness on the part of both researchers and clinicians, with the hope that good solutions may be generated more quickly by group efforts in this field. More than 25 biomarker research studies have investigated the constituents of the maternal serum although eight studies did investigate amniotic fluid samples. Also, around 16 studies have reported CVF for biomarker research and new avenues are explored for salivary biomarkers for the determination of PTD.
CVF is a fluid originating from vagina, along with the fluids flowing in the vagina from the cervix, endometrium, and oviduct. CVF contains mainly water with other factors such as carbohydrates, cholesterol, lipid, mucin, proteins, amino acids, and inorganic ions. , whereas amniotic fluid is a complex mixture, which provides the essential nutrients to the developing fetus. It forms a layer around the fetus, which allows the fetal movement and growth as well as prevents the fetus from any thermal or mechanical shock. It contains maximum amount of water (98%), along with other electrolytes, lipids, hormones, carbohydrates, proteins, and peptides. 
Blood is a mixture of erythrocytes, leukocytes, and platelets suspended in an aqueous medium called plasma. Erythrocytes are the main component of blood cells comprising 45% of the total blood volume and the major protein in these cells is hemoglobin (Hb). The other 55% of blood consists of plasma, which is a water- and protein-rich formulation that has a balanced salt concentration acting as a buffer to maintain stable pH levels and other cellular components. Nutrients absorbed into the blood stream from digested food, dissolved gases, and other blood proteins and lipids are also found in blood plasma. 
Apart from CVF, amniotic fluids, and serum plasma, the salivary biomarkers are also there, which are used for the detection of PTD. Salivary estriol is of the biomarker used to detect PTL. Estriol is an estrogen, which is present in an ample amount in the serum of pregnant women. Estriol, estradiol, and estrone, all three play an important role in the preparation of uterine tissue, which signals the parturition. It is observed that a rise in estriol is there preceding the labor.  A study on 466 singleton pregnant women by Soghra et al. in Iran revealed that there was a significant relation between salivary estriol level and PTL. They also suggested that single-time estriol measurement can reveal the women at low risk of PTL; thus, interventions to delay the PTL can be minimized.  Another study by Heine et al. on 956 pregnant women also observed that increased salivary estriol levels are suggestive of preterm birth.  Another salivary biomarker, progesterone is significant in maintaining pregnancy, and in animal models the progesterone withdrawal leading to labor is well-known.  A study by Priya et al. in Delhi, India on 90 asymptomatic pregnant women suggested that low progesterone concentration can be used for detecting early PTD.  Another study conducted by Hussein et al. on 338 pregnant women suggested that salivary estriol and progesterone can both be useful for the detection of PTL. 
| C-Reactive Protein|| |
C-reactive protein (CRP) is an important inflammatory biomarker, which is studied extensively. We analyzed several studies conducted across the globe and found that inconsistent results were obtained from different studies. In a study conducted in Korea, 72 women at mid-trimester were included, 36 women having PTL and 36 having full-term delivery. The women having complications, which can cause PTL were excluded. Amniotic fluid was collected through amniocentesis in women between 16 weeks and 19 weeks of gestation period and the sample was stored until delivery. This study showed that the levels of CRP were almost similar and no significant difference was obtained in both the groups.  Another study was conducted in Turkey on 94 pregnant women to predict the biomarkers associated with spontaneous preterm birth. In this study, patients with multiple pregnancies, higher risk of PTL, and other maternal complications were excluded. Amniocentesis was performed in women at 16-22 weeks of gestation and after that serum blood samples were also collected. This study too showed that there was no significant association between amniotic fluid CRP and spontaneous preterm birth. The study also revealed that there was no significant correlation between serum CRP level and PTD. The study anticipated that the variation in results might have been due to the use of low-sensitivity CRP kit.  A study conducted by Törnblom et al. investigated the role of various cytokines and inflammatory markers in peripheral circulation - White blood cell (WBC) count and CRP. They found significantly higher levels of WBC and CRP when compared the laboring groups (preterm and term) to the groups not in labor (preterm not in labor and term not in labor) (P < 0.001 and P = 0.02, respectively) irrespective of the gestational age.  These findings are suggestive of the possibility of WBC and CRP as markers of active labor without any infection although further studies with a larger number of patients are warranted to confirm this.
In contrast to these reports, studies have also suggested a positive correlation between maternal serum CRP and PTD. A study conducted by Lohsoonthorn et al. on 1796 women in the USA suggested that elevated maternal serum CRP levels in early pregnancy are positively associated with PTD risk. They noted no association between elevated CRP and risk of preterm premature rupture of membranes and little evidence of an association between maternal serum CRP concentrations and risk of delivery between 34 weeks and 36 weeks of gestation (i.e., moderate PTD). However, elevated CRP concentrations were associated with an increased risk of delivery prior to the completion of 34 weeks gestation (i.e., very PTD). 
A retrospective cohort study involving 1,124 women was conducted by Hastie et al. in Scotland to determine association of PTD and raised maternal CRP in later life. They also tried to study the association of the same with respect to indicated or spontaneous PTD. They concluded that the women who undergo the indicated PTD are at an increased risk of raised CRP in later life. 
Dhok et al. in 2011 indicated that increased serum high-sensitivity CRP (hsCRP) levels in early second trimester primigravidae were significantly associated with adverse pregnancy outcomes such as PTD and pregnancy-induced hypertension (PIH).  The predictive significance of CRP in spontaneous PTD was explored by Halder et al. and showed that high levels of CRP in early pregnancy in the absence of any medical/surgical or obstetric complication was associated with nearly a twofold increased risk of PTD. It was also shown that neonatal outcomes such as preterm, low birth weight, septicemia, birth asphyxia, and others are more likely in such patients. 
Ghezzi et al. looked into whether the amniotic fluid CRP level at the time of genetic amniocentesis is a marker for spontaneous PTD before 34 weeks and 37 weeks of gestation. They reported that there was no correlation between amniotic fluid CRP and maternal blood CRP concentrations. It was markedly observed that there was no relationship between maternal blood CRP concentration and PTD before either 34 weeks or 37 weeks. But the amniotic fluid CRP concentration of >110 ng/mL had a sensitivity of 80.8% and a specificity of 69.5% in the prediction of spontaneous PTD at <34 weeks. These data are really indicative of an association of CRP and PTD. 
Hvilsom et al. conducted a prospective nested case-control study including 84 singleton, preterm deliveries (cases) and 400 singleton, term deliveries (controls) at Denmark. They studied the association between the CRP levels in the maternal serum early in the second trimester with that in PTD. Different statistically significant odds ratios between 1.7 and 2.0 were calculated, depending on the CRP level's cutoff value, and ranging 5.6 mg/L (75th percentile) to 16.4 mg/L (95th percentile). The highest level was achieved at the 85th percentile (7.6 mg/L); odds ratio 2.0 [95% confidence interval (CI), 1.2-3.5]. They also reported high CRP levels at the beginning of a pregnancy was associated with a nearly twofold increased risk of PTD.  Basima and Seenaa conducted a case-control study including 150 pregnant women at Iraq for analysis of the serum level of visfatin and CRP. They reported a significant increment of CRP in preterm in labor cases when compared with term in labor women. 
All these reports indicated that CRP is a nonspecific biomarker for early PTD prediction. The level of CRP varies during infection and other pathogenic abnormalities. The elevated CRP level in early pregnancy is associated with PTD and vise-versa. High CRP levels in later life are also suggestive of cardiovascular events.
| Fetal Fibronectin|| |
Fetal fibronectin (FFN), a glycoprotein produced by the fetal membrane, is one of the biomarkers for the detection of PTL. Its presence within the CVF is said to be an indicator of the presence of PTD.  The release of FFN is thought to be due to mechanically mediated damage or inflammatory-mediated damage to membrane or placenta before birth.  Generally FFN is not present during 24-37 weeks gestation period. Its presence in the CVF is a signal of spontaneous preterm birth within 7 days. In 2002, Honest et al. published a systematic review on the predictive capacity of fibronectin for PTD. They identified 40 studies which were conducted on total 26,876 women in total and concluded that cervicovaginal FFN was the most accurate test in predicting spontaneous preterm birth within 7-10 days of testing. In practice, it is used as a negative marker.  Absence of FFN suggests that the patient is at a low risk of PTD and thus, the patient can be discharged, minimizing unnecessary hospital stay and unwanted treatment.  Zygmunt et al. investigated the plasma fibronectin as an indicator for pregnancies with a high risk of PTD. They detected high values, particularly in patients with PTL delivering before 32 weeks of gestation. However, leukocyte concentration, bacteriological smear, and cervical dilatation did not correlate with fibronectin concentrations in patients with PTD or controls. They inferred that the higher plasma concentrations of fibronectin in women with PTL may be a biochemical marker and a predictor of PTD. 
Another study conducted by Goldenberg et al. included 2,929 women for determining the levels of vaginal and cervical FFN during 24-30 weeks and its association with spontaneous PTD. It was observed that positive vaginal and cervical FFN test were directly proportional to spontaneous preterm birth. 
Three more studies have been conducted in different parts of the world and these researchers have observed that FFN can be used as a reliable biomarker for predicting PTD. ,,,, and detection of the same would decrease the number of admissions for PTL, the length of stay in hospitals, and unnecessary tocolytic agent treatment. 
A study was conducted for the quantification of FFN in the cervicovaginal secretions of Canadian women presenting with symptoms of PTL between 24 weeks and 34 weeks of gestation. The positive predictive value of the test was observed to be 37.5% for delivery within 7 days of testing and 63% for delivery before 34 weeks of gestation. They also found that FFN, when measured in symptomatic patients between 24 completed weeks of gestation and 34 completed weeks of gestation provides a high negative predictive value for continuing pregnancy beyond 7 days after testing and for prolonging gestation beyond 34 weeks. 
In another study in China, 213 cases were analyzed and 47 women (22.1%) had positive FFN. The average cervical length of women with positive FFN (2.3 ± 0.9 cm) was significantly shorter than that of women with negative FFN (3.1 ± 0.8 cm; P = 0.02). There were 25 (11.7%) and 38 (18.8%) cases with PTD at <34 + 0 weeks and <37 + 0 weeks, respectively. By individual analyses, the highest PTD rate was 51.2% in women with positive FFN at <37 + 0 weeks. The values of diagnostic efficiency by FFN were >80% at <34 + 0 weeks and <37 + 0 weeks. In the combined analysis, the highest PTD rate was 57.1% in women with cervical length ≤2.5 cm and positive FFN at <37 + 0 weeks. 
Research until now indicates that FFN is a reliable biomarker and is suggestive of PTD within 7 days. The FFN levels, along with the cervical length measurement, are used as a sensitive method of the detection for PTD. Still further studies on large sample sizes are recommended to confirm FFN as a predictor spontaneous preterm birth.
| Interleukins|| |
Cytokines are protein and polypeptide products secreted by cells that regulate intracellular cell functions. They have diverse actions including growth factor effects, chemotaxis, and angiogenesis. Their actions are mediated by specific membrane receptors, which in turn activate intracellular pathways. These mediators regulate the immune response against infection and thus, help maintain pregnancy; however, the inflammatory response to infection can have a detrimental effect on the pregnancy and the fetus.  Interleukins (ILs) are inflammatory cytokines that have been studied extensively for their association with PTL since decades. Various members of the IL family such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, and IL-18 have been studied by many researchers and found to be involved in PTD.
IL-6 is produced by monocytes and macrophages and is one of the first cytokines to be released in response to an infectious stimulus. It is the major mediator of the acute phase response; it activates B-cells to differentiate into antibody secreting plasma cells and mediates the differentiation of mature T-cells to cytotoxic T-cells. The main source of IL-6 in the amniotic fluid is the amnion.  Out of whole IL family, IL-6, a proinflammatory cytokine, is studied by many researchers. It is a controversial marker as different studies showed different results of its association with PTD.  A few studies showed a distinctive difference of IL-6 levels with preterm and full term delivery, concluding that amniotic fluid IL-6 concentration in women having PTD was more than women delivering at full term.  A prospective study in Italy including 225 asymptomatic Caucasian women showed a correlation between CVF IL-6 and PTD but no association was found between serum IL-6 and spontaneous preterm birth.  Another prospective study by Brik et al. in Spain conducted on 100 women between 24 weeks and 34 weeks of gestational age revealed the capability of cervical IL-6 to predict PTD as good as the cervical length.  Also, in a study performed at Madrid, Spain maternal serum IL-6 levels were monitored in 103 women during PTL and delivery. They observed the utility of IL-6 as a biomarker for the prediction of spontaneous preterm birth.  Also, a study by Coleman et al. on 104 women analyzed and reported that measurement of IL-6 in CVF has the ability to predict the spontaneous preterm birth.  On the other hand, no correlation of maternal serum IL-6 , or amniotic fluid IL-6  or human cervical tissue  with preterm birth was observed.
IL-8 is an 8 kDa nonglycosylated protein secreted by macrophages and monocytes following stimulation by IL-1 and tumor necrosis factor-α (TNF-α). The main action of IL-8 is recruitment of neutrophils to sites of inflammation. Elevated amniotic fluid IL-8 concentration is a marker of inflammation in the amniotic fluid and is often associated with amniotic fluid infection.  Becher et al. conducted a study to evaluate the concentrations of MMP-2, TIMP-1, MMP-8, and MMP-9 in the CMP in relation to the gestational age, IL-8 as an indicator of inflammation. They found that concentration of IL-8 was threefold to fivefold higher in CMP of PTL in comparison to term labor (TL).  Another prospective cohort study was conducted in Sweden on 142 women with singleton pregnancy and without any major medical problems and maternal serum was tested for 27 proteins using xMAP technology. The study depicted that IL-1, IL-2, and IL-8 did not possess any association with PTD.  In another study in Sweden, 50 women were included for the study wherein 17 women in spontaneous PTL and 8 not in labor at preterm (PTnotL) were in the test group and 14 women in TL and 11 not in labor at term (TnotL) served as controls. The levels of IL-8 were monitored in the human cervical tissue. The study did not reveal any significant difference in any contents of tissue homogenate or blood samples between any groups of PTD and term delivery.  A study by Coleman et al. also stated that cervicovaginal IL-8 does not relate to PTD. 
These reports led us to conclude that although IL-8 is an inflammatory marker, the elevated levels do not correlate with PTD at all.
IL-10 is an immune-inhibitory cytokine secreted by T-lymphocytes and monocytes following lipopolysaccharide-induced cell activation. In the choriodecidual unit, IL-10 inhibits the production of IL-1β, IL-6, and TNF-α, and the production of prostaglandin E 2 .  During study by Tsiartas et al., it was observed that during spontaneous preterm birth, there was an increase in serum IL-10 level.  Puchner et al. in Greece conducted a case-control study to compare mid-trimester concentrations of amniotic fluid IL-1β, IL-10, and IL-18 in women delivering at term or preterm. Out of 362 women included in the study, 38 presented with PTL. Thirty-eight women with TL, matched for chronological and gestational age served as controls. They observed no significant association of IL-10 with PTD.  Another study by Lisangan et al. compared the level of IL-10 in aterm labor and PTL. This research was a cross-sectional study including 48 women, 12 of whom were in the aterm group and 35 were in the preterm group. The mean level of IL-10 in this study was 30.36 ± 10.65 pg/mL. They observed a significant difference of IL-10 level between the PTD group and aterm delivery group.  In one study, amniotic fluid and IL-10 level were measured in 96 women who underwent genetic amniocentesis between 15 weeks and 23 weeks of gestation. Fifteen patients delivered at or before 36 weeks and 81 patients delivered after 36 weeks. There was an inverse correlation obtained between amniotic fluid, IL-10 concentration, and gestational age at delivery. IL-10 level in second-trimester amniotic fluid obtained at the time of genetic amniocentesis appeared to be higher in patients who subsequently developed PTD. 
All of the above studies propose that the role of IL-10 in prediction of PTD is not a reliable one.
| Matrix Metalloproteinases|| |
Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix. MMPs are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions.  MMP-8 is a neutrophil collagenase released due to inflammation from the polymorphonuclear cells. Various inflammatory mediators were investigated by Kim et al. The study revealed that MMP-8, along with IL-6, could serve as a potential biomarker for the prediction of PTD. But still further research is desirable.  A research performed in Denmark studied the levels of MMP-2, MMP-8, and MMP-9 in cervical mucus plug (CMP) in 15 women with PTL and compared that with 15 women with TL. They found that concentration of MMP-8 was double in PTL CMP. The concentration of MMP-9 was threefold to fivefold higher in CMP of PTL in comparison to TL. No major difference was found in MMP-2 concentration in both the groups. This study had not only studied the association of these biomarkers with PTL but also their relation to gestational age and as an indicator of inflammation.  These data indicate that although MMP-8 has shown promising results as a biomarker for PTD, further studies with large sample sizes are indicated to confirm the same.
| Pregnancy-Associated Plasma Protein A|| |
Pregnancy-associated plasma protein A (PAPP-A) is a metalloprotease, which is routinely measured in the maternal serum as a part of the first-trimester screening. PAPP-A expression has been shown to be regulated by inflammatory cytokines such as TNF-a and IL-1b.  Thus, PAPP-A is shown to be implicated as an acute reactant in inflammatory processes, one of which may be PTL.  A study was conducted in 477 pregnant women whose pregnancy progressed beyond 20 weeks to monitor the PAPP-A levels. The decrease in PAPP-A levels was noted in women with PTD compared to term delivery. The limitation of the study was its low sample size.  Similar results were obtained in Taiwan to confirm the association between PAPP-A and PTD. The study included 2,621 women with singleton pregnancies.  Granovsky et al. in 2007 conducted a prospective cohort study on 26 women and reported that PAPP-A levels ≤30,000 mUl (−1) at admission were associated with increased risk for preterm birth of ≤7 days.  Another researcher in London, England attempted to develop a model for the prediction of PTD and they found a small decrease in serum PAPP-A at 11-13 weeks in pregnancies that subsequently deliver spontaneously before 34 weeks.  A research study conducted in Turkey showed that late PAPP-A levels decreased in PTL. The levels of PAPP-A of <29.8 mIU/mL was associated with increased risk for preterm birth.  The above studies suggest that PAPP-A is associated with PTL and its measurement can further help for detecting PTD.
| Relaxin|| |
Relaxin is a polypeptide hormone produced in the female by corpus luteum of the pregnancy and decidua.  Various studies were performed by Vogel to investigate the correlation of serum relaxin with PTD. In one study on 2,846 women with singleton pregnancies, it was observed that serum relaxin levels increased during spontaneous preterm birth.  Another study involving 1,545 women evaluated the possible correlation between serum relaxin levels in the 18th gestational week and PTD. It was noted that serum relaxin levels were higher in women having preterm birth and thus, can be used as an independent predictor of spontaneous preterm birth.  In another research, 61 pregnant women were included wherein the relationship between serum concentrations of relaxin and soluble CD163 with cervical length and PTD in women with previous spontaneous PTD was measured. It was observed that serum relaxin level is not clinically useful predictor of spontaneous preterm birth.  Still, these data are not sufficient enough to consider serum relaxin as a potential biomarker for detecting PTD.
| Lactate Dehydrogenase|| |
Lactate dehydrogenase (LDH) levels in amniotic fluid as well as serum were found to be similar in PTL and full-term labor in a study performed by Erdnic et al. The results may vary due to the measurement of different LDH isotopes during different studies.  In a study conducted in Turkey, 55 women were included for the detection of LDH in amniotic fluid as a marker for PTD. They observed that amniotic fluid LDH levels were significantly higher in patients with PTD.  In another study by Garry et al., amniotic fluid LDH levels were monitored. They studied 131 women in PTL and found that LDH levels were greater in women with PTD. They also concluded that LDH was readily available, inexpensive, and rapid that could be measured at any laboratory for detecting PTD.  A study by Borna et al. compared CRP, ferritin, and LDH concentrations in mid-trimester amniotic fluid of patients with preterm and term deliveries and found out their predictive values for PTD. The study was conducted on 90 pregnant women who underwent genetic amniocentesis between the 15 th week and the 20 th week of gestation. The study showed women with PTD at <37 weeks (n = 17) had a higher median of amniotic fluid LDH concentration than those women who delivered at term (n = 73). 
The above studies indicate that LDH can be a reliable marker for the prediction of PTD. Still, further studies with large sample sizes can be performed to confirm the same.
| Thyroid-Stimulating Hormone|| |
Thyroid hormones are vital for the development of the brain both during fetal life and early postnatal life. Impaired maternal thyroid hormone availability may induce irreversible brain damage with consequent neurological abnormalities.  According to a pilot study conducted in India in the search of potential biomarker for PTD, 40 women who presented with PTL between 28 weeks and 34 weeks of gestation and 40 women with full-term delivery were studied. They had excluded women with any comorbidity or previous maternal complication. Serum concentration of thyroid-stimulating hormone (TSH) was monitored but no significant difference was noted during the study.  Another study was conducted by Green et al. to examine the association of thyroid hormones and very PTD on 124 women with PTD and 124 women with full-term delivery. This study also observed no association between TSH levels and PTD.  The data until now are suggestive of the absence of a significant role of TSH in predicting PTD.
| Adrenocorticotropic Hormone|| |
Pituitary adrenocorticotropin [adrenocorticotropic hormone (ACTH)] is the major regulator of adrenocortical zona fasciculata and reticularis function and is a significant growth factor for normal adrenocortical cells. The actions of ACTH are mediated by its specific membrane receptor.  During a study conducted by Singh et al., they found that there was a rise in the ACTH level in PTD as compared to the control group. This rise during the gestation period may be due to multiple factors such as placental synthesis and release of biologically active corticotropin-releasing hormone (CRH) and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors such as vasopressin and CRH.  In a study by Makrigiannakis et al., 79 pregnant women were observed for plasma ACTH level. They found that ACTH level was significantly higher in women who delivered preterm compared to full term. 
The above studies show ACTH to be a useful biomarker for PTD prediction although further studies are warranted for the same.
| Alpha-Fetoprotein and Human Chorionic Gonadotropin|| |
Alpha-fetoprotein (AFP) is a glycoprotein produced by the fetal liver and gastrointestinal tract. Small amounts of AFP cross the placenta and can be measured in the maternal serum.  A study was conducted by Waller et al. on 500 women to determine whether high levels of serum AFP predict increased risk of adverse pregnancy outcomes, including preterm birth. They observed a strong gradient of increasing risk of preterm birth with increasing levels of serum AFP. Among women with high levels of serum AFP, 24.3% had preterm births. They concluded that high levels of serum AFP are strongly associated with preterm birth, preeclampsia, and placental abnormalities.  Davis et al. performed a study to determine whether low birth weight associated with unexplained elevations of mid-trimester maternal serum AFP levels is due to prematurity or fetal growth retardation. They included 5,555 women, predominantly white, who were screened for neural tube defects (group 1) and 843 women, predominantly black, with risk factors for low birth weight (group 2). It was observed that in both the groups, increasing levels of maternal serum AFP were significantly associated with PTD but not with fetal growth retardation.  Thus, it can be concluded that with further studies, AFP can become a significant biomarker for PTD prediction.
Beta-human chorionic gonadotropin (β-hCG) was also studied for its relation with PTD. Various studies showed an increased concentration of the marker during spontaneous preterm birth.  In a study by Ramos et al., they monitored β-hCG in CVF as a marker for PTD in 86 women. They concluded that β-hCG can be a useful predictor of preterm birth in symptomatic women.  Another study was performed, which included 77 women who attended the prematurity prevention clinic that also revealed that levels of β-hCG in CVFs were higher in those who delivered before 34 weeks of gestation as compared to those who delivered at term.  Another study was performed on 102 women with a diagnosis of threatened PTL by Gurbuz et al. Increased concentration of hCG in CVF was found in women with PTD. They also concluded that the test has advantage of low cost and wide availability.  It can, therefore, be proposed that extensive study regarding β-hCG as a biomarker for PTD prediction can be encouraged.
| Vascular Endothelial Growth Factor|| |
Vascular endothelial growth factor (VEGF), belonging to heparin-binding growth factor, is a critical mediator of inflammation that can be linked to PTL.  The VEGF levels in the maternal serum decreases during PTD, which is an important biomarker for the detection of preeclampsia, along with other markers such as placental growth factor (PLGF), soluble fms-like tyrosine kinase (sFlt), and endoglin that are responsible for normal placental vascular development.  A study by Kim et al. investigated the level of VEGF and inflammatory markers in midtrimester amniotic fluid for having predictive value for spontaneous preterm birth in singleton pregnancy. The mean values for the preterm and full-term groups for VEGF were 30.76 pg/mL and 22.36 pg/mL, respectively, which represented a significant difference between the groups with a sensitivity of 91.7% and a specificity of 75.0%. These figures suggested that VEGF signaling at the maternal fetal interface is a critical mediator of inflammation that can be linked to PTL.  Galazios et al. probed to determine whether the increased levels of VEGF are implicated in the pathogenesis of preeclampsia and in PTD. They compared umbilical cord serum VEGF levels from women with uncomplicated term pregnancies (control group, n = 24), with pregnancies complicated by preeclampsia (n = 21) or with PTD (n = 29). No significant increase in VEGF concentrations in the PTD group was noted as compared with the control group.  Hong et al. dwelled on an experiment on second-trimester amniotic fluid samples of women who delivered at <37 weeks of gestation (n = 36) and in 36 matched controls who delivered at ≥37 weeks of gestation. Amniotic fluid VEGF levels in the preterm group (32.24 ± 4.87 pg/mL) were significantly higher than those in the control group. These results showed that amniotic fluid VEGF levels in the second trimester were more predictive of PTD.  Also, Yilmaz et al. investigated the effectiveness of cervicovaginal VEGF in predicting PTD. Cervicovaginal VEGF was measured in 30 women who presented symptoms or signs of threatened PTL and the control group of 30 healthy pregnant patients. They observed no correlation between cervicovaginal VEGF values and PTD. 
It can be concluded that the correlation of VEGF with PTD is unpredictable and therefore, VEGF cannot be a reliable marker for predicting PTD.
| Ferritin and Prolactin|| |
It was observed during a study conducted by Singh et al. that serum ferritin, which is an iron storage protein, showed an increase in its level during PTL although there is a prevalence of anemia during pregnancy.  Erdinc et al. also revealed the same results of only serum ferritin level being associated with PTD and not the amniotic fluid ferritin level. But if the results vary, they may vary due to iron supplementation, infection, and inflammation.  In another study at Chicago, Illinois, USA 182 women were included having spontaneous PTD and 182 women having term delivery. This study too stated that cervical ferritin level was higher in women with PTD.  Thus, ferritin has shown a promising correlation with the PTD till now.
The level of serum prolactin was also predicted by Singh et al. but no significant difference was observed.  Mazor et al. also observed no difference between amniotic fluid or maternal plasma concentrations of prolactin in women with PTL compared to full-term delivery.  Unlike this, a study by O'Brein et al. on 80 women noted that the cervicovaginal prolactin level was higher in women with preterm birth and thus, can be used as a biomarker for its detection.  The association of prolactin with PTD has not been fully understood yet.
| Ceruloplasmin and Alkaline Phosphatase|| |
Ceruloplasmin is a copper-carrying protein and a member of inflammation-sensitive protein family related to systemic inflammation. It was also studied in the maternal serum as well as CVF by Erdinc et al. but no association with PTD was observed. 
Alkaline phosphatase (ALP), present within trophoblast cells of the human placenta, are polymorphic and heat-stable enzymes. It is a glycoprotein that resides in the apical and basal cells of the syncytiotrophoblast plasma membrane and at the surface of cytotrophoblast chorionic villi.  In 2010, Singh et al. reported an increase in serum ALP during PTD.  In opposition to that, Erdinc et al. noted no correlation between serum ALP and PTD.  A prospective study by Grgić et al . tried to examine the reliability of human placental alkaline phosphatase (hPLAP) in 200 pregnant mothers' serum as a marker of premature labor. It was concluded that hPLAP can be used as a reliable marker of idiopathic premature labor.  In 2014, Tripathi et al. conducted a prospective nested cohort study to predict the PTL in low-risk pregnancies. It was conducted over a period of 3 years including 1,884 women out of which 137 women who delivered before 35 weeks were treated as cases and an equal number of matched controls were chosen. Significant correlation between preterm birth and serum ALP levels at 24-28 weeks was observed but its values were affected in conditions such as hemolysis, liver disorders, and so forth.  Meyer et al. had studied 270 pregnant women and concluded that women with elevated placental ALP levels are at an increased risk for PTD.  Also, a nested case-control study involving 127 women was performed by Moawad et al. in which other 127 women who had a term birth served as matched controls. They observed a significant elevation in ALP in pregnancies that ended in spontaneous preterm birth.  Hence, it can be concluded that ALP is an important but not a reliable marker. Further study can enhance its use for detecting PTD.
| Glucose|| |
Erdinc et al. also measured amniotic fluid glucose level, which showed a decrease in glucose concentration in PTD compared to full-term delivery, whereas no difference was found between serum glucose levels in the control group or test group.  A study conducted in Turkey on 216 pregnant women between the 15 th week and 18 th week of gestation found that amniotic fluid glucose level were lower in women with spontaneous PTD compared to those who delivered at term.  Contrary to this, Romero et al. supervised 120 patients with PTL for glucose levels of amniotic fluid but no significant results were obtained regarding the association of glucose with PTD.  Thus, glucose as a biomarker for detecting PTD is uncertain and not efficient.
| Placental Protein 13|| |
Placental protein 13 (PP-13) is produced by the syncytiotrophoblast, present at the maternal-fetal interface. A study conducted in the USA on 471 pregnant women observed a decrease in PP-13 levels in women with PTD compared to term delivery. The study suggested that PP-13 was associated with PTL and that its measurement could further help for detecting PTD.  Another study by Wolterboer et al. on 88 pregnant women also noted that the level of PP-13 was reduced in women delivering preterm.  On the other hand, a study by Cowans et al. on 1,940 pregnant women revealed no correlation between serum PP-13 level and PTD.  All these studies indicate the unclear use of PP-13 as a marker.
| Corticotropin-Releasing Hormone|| |
CRH is a hypothalamic neuropeptide that plays a central role in regulating the activity of the hypothalamic-pituitary-adrenal (HPA) axis and physiologic response to stress.  Coleman et al. observed 94 women with PTL between 24 weeks and 34 weeks of gestation and monitored the pregnancy outcomes. They measured CRH in maternal serum but did not obtain any significant results and concluded that CRH was not related to PTD.  Another study performed on 170 pregnant women revealed that no difference was observed in plasma CRH levels between those delivering preterm and those delivering at term.  Counter to this, Hill et al. inferred that CRH beyond 28 weeks gestation is the most accurate biomarker in predicting preterm birth within 48 hours.  Thus, the use of CRH as a biomarker for predicting PTD is imprecise because of the varying study results.
| Other Biomarkers|| |
Other biomarkers such as TNF-α, tumor necrosis factor-β (TNF- β), and estriol in maternal serum and CVF have been studied and tested for their association with PTL but no confirmatory results have been obtained till date. It was also proposed that homocysteine, a sulfur-containing amino acid, may also be a marker for and even a contributor of preterm birth. However, the data obtained were not satisfactory and thus, a further study is needed on this.  Another novel biomarker, which is studied in the maternal serum is serpin B7. A study was performed wherein serum samples were collected from 35 cases and 35 controls at 19-24 weeks of gestation and 16 cases and 16 controls at 28-32 weeks of gestation. They obtained a higher concentration of serpin B7 levels in PTD compared to the controls. 
In an independent cohort study conducted on 129 women in Australia to identify a biomarker to predict spontaneous PTL within 7 days, Liong et al. identified differential proteins by proteomic analysis and concluded that prediction of PTD within 7 days using a dual biomarker model [albumin/vitamin D-binding protein (VDBP)] yielded a sensitivity of 77.8%, specificity and PPV of 100%, and NPV of 98.0% (n = 109). 
The variability in results across the studies may have arisen due to dissimilarities in study designs, different timings of collection of blood, and diversities in the study population. For example, a few investigators may have collected any of the samples during the first antenatal visit while a few may have collected it during the later stages of pregnancy. The variation across the studies might also be contributed to the presence of subclinical infections across the diverse population. 
Research on many biomarkers in the maternal serum, amniotic fluid, and CVF are accomplished but not a single biomarker has evolved till date, which possesses sensitivity as well as reliability for the detection of spontaneous preterm birth. Study on a large sample size is needed for the confirmatory conclusion of use of biomarker in PTD. A single biomarker or even in combination, if found for the prediction of PTL, can decrease the hospital cost as well as restrict the treatment. The tocolytics or corticosteroids, which are generally used to prevent preterm birth, are found to cause severe side effects in both the mother and child, and its use can be minimized by predicting PTD. PTD is a major and complex health care problem leading to neonatal mortality and thus, it needs to be focused on in more detail.
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