Obstetrics & Gynecology: Preterm Labor Mala Arora, Jennifer R Niebyl, Asha Rijhsinghani
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Etiopathogenesis of Preterm Labor

Ashadeep Chandrareddy MD
Cloud Nine Hospitals, Bengaluru 560 011, Karnataka, India

ABSTRACT

Preterm labor has varied etiology, which is intimately linked to maternal physical and psychological health. Teenage pregnancy, poor maternal nutritional status, short interpregnancy interval, excessive physical labor, smoking, and use of alcohol and recreational drugs contribute to preterm labor. A strong association is identified with intrauterine infection and inflammation. In patients with uterine overdistension, decidual hemorrhage, uteroplacental insufficiency, uterine malformations, maternal medical disorders, and congenital fetal anomalies, preterm birth is more common. Multiple etiological factors may initiate cervical changes, uterine contractions, and/or premature rupture of membranes (PROM) that will culminate in preterm birth. Biomarkers, which are being evaluated to predict preterm labor are maternal serum ferritin, lactate dehydrogenase, and proinflammatory cytokines like interleukin (IL)-6. However, they have a limited sensitivity and specificity at present.
 
INTRODUCTION
Preterm labor and delivery have a considerable health impact, as they are one of the leading causes of perinatal morbidity and mortality and several chronic diseases in the long-term.1 The incidence of preterm delivery has been estimated to be 14.5% in India.2,3 A variety of maternal and fetal factors are known to increase the risk of preterm labor, including maternal demographic and socioeconomic characteristics, behavioral factors, and obstetric history. Literature to date suggests a complex, multifactorial etiopathogenesis for preterm labor as a result of interplay of maternal inflammatory, vascular, or neuroendocrine dysfunctions and stress, preconceptional health, genetic, epigenetic, and gene-environment interactions, systemic or maternal genital tract infections, uteroplacental ischemia or vascular lesions, and uterine overdistension.1,4
Email: ashadeepc@yahoo.com
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Additionally, the fetus also recognizes a hostile intrauterine environment and triggers preterm labor by premature initiation of a fetoplacental parturition pathway. The pathogenic pathways of preterm labor are presumed to be secondary to high circulating levels of inflammatory cytokines and differ in their initiating factors, triggers, and mediators; but eventually, they share many common features that result in preterm labor.5 The traditional empiric approach towards preterm labor/delivery assumes a single pathologic process for which treatment has also been presumed to be uniform. This has encountered limited success in management and prevention of preterm labor. There is no effective primary prevention of preterm labor/delivery at present. Sensitivity and specificity of laboratory markers are low. A better understanding of the etiopathogenesis of preterm labor will allow better outcomes and stratification of fetuses for therapies in preterm labor.
Villar et al.6 described “preterm birth syndrome” and proposed a classification on the basis of clinical phenotypes that were defined by characteristics of the mother, fetus, placenta, signs of labor, and pathway to delivery. There are several causes and pathways leading to preterm labor and preterm delivery, and this article is a review of the various etiological factors and pathogenesis of preterm labor.
 
ETIOLOGY AND RISK FACTORS
A specific pathogenic pathway for preterm labor/delivery is infection and inflammation.7 Other potential pathogenic pathways, particularly impaired hormonal milieu and uteroplacental ischemia have been extensively studied. Potential molecular and biological mechanisms, including abnormal expression of various genes connected with the process of preterm labor/delivery are also being studied.
In most cases, preterm labor is unpredictable. Etiological factors include:
  • Decidual hemorrhage (abruption)
  • Uterine overdistension (multiple gestation or polyhydramnios)
  • Cervical insufficiency (congenital, trauma, cone biopsy)
  • Uterine distortion (Müllerian duct abnormalities, fibroid uterus)
  • Infection [bacterial vaginosis (BV), trichomoniasis]
  • Systemic inflammation/fever (urinary tract infection)
  • Hormonal and metabolic alterations, particularly those of gestagens and corticotropin-releasing hormone (CRH) (mediated by maternal or fetal stress)
  • Allergy, impaired maternal tolerance of fetus (fetus as an allograft)
  • Uteroplacental insufficiency (hypertension, insulin-dependent diabetes)
  • Drug abuse, smoking, alcohol consumption8,9
  • Fetal anomalies
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  • Genetic and hereditary predisposition
  • Maternal demographic characteristics, such as low socioeconomic status, extremes of maternal age, parity, low prepregnancy weight, periodontal disease, obstetric history characteristics like previous history of preterm delivery, previous history of second trimester abortion, short interpregnancy interval (<1 year), and high-risk behavior (smoking, substance abuse, etc.) have all been implicated. Socioeconomic deprivation, stressful life situations (domestic violence, work, and home environment) have all been associated with increased risk of preterm labor.10,11
Many such primary predictors of preterm labor including individual factors, socioeconomic factors, working conditions, and obstetric and gynecological history have been used to determine risk scores. However, the predictive value of these scores is poor.
 
Infection
Preexisting intrauterine inflammation in early gestation is an important risk factor for preterm labor, and it is the subclinical form, which is the main causative factor. Subclinical infection of the choriodecidual space and amniotic fluid is the most evaluated etiological factor underlying spontaneous preterm labor.12 A significant number of women with preterm delivery have evidence of bacterial infection in the amniotic fluid and/or histological chorioamnionitis.13 Also, preterm labor is linked to maternal symptomatic systemic infections, such as those of the urinary or respiratory systems.
Biochemical, microbiological, and clinical studies have established the association between genital tract infection and preterm labor. Clinical and subclinical intrauterine infection is responsible not only for preterm labor but also for many neonatal sequelae, including periventricular leukomalacia, cerebral palsy (CP), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC).14
Normal vaginal flora predominantly consists of acidophilic facultative lactobacilli with more anaerobes than aerobes. Lactic acid produced by lactobacilli keeps the vaginal pH acidic and inhibits the growth of pathogens. When the pH is low, lactobacilli produce hydrogen peroxide that is toxic to bacteria. When alkalinity is increased, lactobacilli produce a lower amount of hydrogen peroxide, thus, permitting the overgrowth of other organisms. Understanding of the vaginal flora, mucosal immunity, and the biology of BV is necessary to design studies analyzing the utility of antibiotics in the prevention of preterm labor.15,16
Several case control and cohort studies have established the impact of BV on adverse pregnancy outcomes and its role as a risk factor for preterm birth. Periodontal disease and BV share microbiological similarities, and both conditions 4are associated with preterm labor. In addition, periodontal disease and BV have been linked through gene polymorphism.17,18
Organisms commonly cultured from the amniotic cavity following preterm delivery include Ureaplasma urealyticum, Mycoplasma hominis, bacteroides, Gardnerella vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and group B hemolytic streptococci. Use of molecular microbiology techniques to diagnose intrauterine infection may reveal the role of fastidious microorganisms that have not yet been determined.19–21
Microorganisms gain access to amniotic cavity and fetus by:
  • Ascending from the vagina and cervix
  • Blood (e.g., due to periodontal infection) via placenta
  • Migration from the abdomen via the fallopian tubes
  • Invasive procedures like amniocentesis and chorionic villous sampling.
Ascending infection from vagina and cervix is the most common pathway of intrauterine infection. This is followed by colonization of fetal membranes and decidua. Preterm labor is triggered by microorganisms due to initiation of the maternal (host) response to these organisms via cytokines, proteolytic enzymes, and prostaglandins (PGs). This also triggers the fetal inflammatory response syndrome (FIRS) in response to microbial products and is associated with fetal multiorgan involvement and a higher rate of perinatal morbidity.22
Antibiotic administration to patients with asymptomatic bacteriuria is associated with a significant reduction in the rate of preterm labor/delivery. However, such benefit has not been demonstrated for patients with Streptococcus agalactia, Ureaplasma urealyticum, or Trichomonas vaginalis. Antibiotic administration to patients with premature rupture of membranes (PROM) is associated with prolongation of pregnancy and a reduction in the rate of clinical chorioamnionitis and neonatal sepsis. This benefit has not been demonstrated in patients with preterm labor with intact membranes.23,24
 
Previous Preterm Labor
A history of spontaneous preterm delivery is one of the strongest predictors for a preterm labor in subsequent pregnancies. Given a baseline risk of preterm labor/delivery of about 10%, the risk of recurrent preterm delivery after 1, 2, and 3 consecutive preterm delivery may be increased to approximately 15%, 30%, and 45%, respectively. Spontaneous preterm delivery, preeclampsia, and fetal growth restriction in a first pregnancy predispose to complications in subsequent pregnancy, especially, if severe.
Infection (e.g., syphilis), antiphospholipid syndrome (APS), abnormal placentation, immunological causes, thrombophilias, cervical insufficiency, 5upper genital tract anomalies, diabetes, substance abuse, and genetic disorders are all known causes of midtrimester pregnancy loss. A history of one or more second-trimester miscarriages or a previous history of preterm labor/delivery also increases the risk of subsequent preterm labor/delivery, suggesting that midtrimester pregnancy loss and preterm delivery between 24 and 28 weeks are essentially, clinical manifestations of the same disease process. The pathogenesis and risk factors are the same, but the timing of onset of uterine activity and cervical dilation may be delayed in preterm delivery. Women with a prior history of late miscarriage are at increased risk of preterm labor and vice versa. The risk of preterm labor in women with prior midtrimester pregnancy loss approximates the same recurrence risk documented for women with a previous history of preterm delivery, suggesting that midtrimester miscarriage characterizes the lower end of the spectrum of preterm labor.
The increased risk for preterm labor/delivery with an interpregnancy interval of less than 6 months is estimated to be 30–60%. The magnitude of a short interpregnancy interval is greatest when the index pregnancy was a preterm delivery rather than a term delivery. Short interpregnancy interval is primarily a marker for high risk of preterm labor rather than independent cause of preterm labor.
 
Uterine Malformations
Congenital uterine anomalies and fibroids are the common uterine causes of preterm labor/delivery. Cervical insufficiency can lead to painless cervical dilation and preterm labor/delivery. Congenital causes of cervical insufficiency include the rare cervical hypoplasia and the now historical, diethylstilbestrol (DES) exposure of the mother. Acquired cervical insufficiency is usually due to previous cervical surgery including cervical conization, large loop excision of the transformation zone (LLETZ), multiple endocervical dilations, and obstetric injury at delivery. A history of multiple first trimester elective terminations or one or more second-trimester elective abortions leads to increased risk of preterm labor. Incidence of preterm delivery and cervical insufficiency may be increased significantly after preconceptional cervical trauma with risk of subsequent preterm labor, proportional to the extent of damage. Another potential risk is intrauterine infection, which may be associated with cervical insufficiency, a factor to be considered with regard to placement of cervical cerclage.
 
Uterine Overdistension
Congenital uterine disorders, polyhydramnios, and multiple pregnancies are associated with the risk of preterm labor/delivery. Fetal anomalies, such 6as gastrointestinal atresias are the most common cause of polyhydramnios leading to preterm labor. Excessive uterine expansion overrides the relaxation effect of progesterone and nitric oxide (NO), leading to increase of myometrial contractility, PG release, and expression of gap junction proteins, particularly Connexin-43 (Cx43). Excessive amniochorionic expansion results in mechanic damage of the membranes, potentially resulting in PROM that leads to preterm labor.
 
Multiple Pregnancies
Multiple pregnancies are an important cause of preterm labor/delivery. Median gestation at delivery for twins is approximately 35 weeks and for triplets 33 weeks. Presently, assisted reproduction techniques are responsible for 1/3rd of twin pregnancies and more than 2/3rd of triplets leading to an increasing incidence of preterm labor/delivery.25
 
Maternal Medical Conditions
A number of maternal conditions are associated with preterm labor including, PROM. These are low prepregnancy weight, obesity, family history of spontaneous preterm delivery, short interpregnancy interval, infertility treatments, and the resulting risk of multiple gestations.
Chronic maternal illness, can alter the placental delivery of oxygen and nutrients to the developing fetus, possibly resulting in fetal growth restriction and predispose to spontaneous preterm labor.
Serious infective illnesses, such as pyelonephritis, appendicitis, and pneumonia are associated with preterm labor. This association is thought to be due either to direct blood-borne spread of infections to the uterine cavity or, indirectly, due to chemical triggers, such as endotoxins or cytokines. Many other medical complications, such as cholestasis of pregnancy and surgical procedures during pregnancy are associated with preterm labor, although the mechanisms remain obscure.
 
Subfertility Treatments
The use of infertility treatments has risen dramatically in the past 20 years. An unintended consequence of these technologies is multiple gestations and the increased risk of preterm labor. Efforts to reduce multiple pregnancies by limiting the number of embryos transferred and timely fetal reduction in triplets and higher order births need to be widely practised. Evidence indicates that a portion 7of the reported association between infertility treatments and preterm labor may be attributable to the underlying biological reasons for infertility.
 
Behavioral and Psychosocial Contributors
Socioeconomic factors associated with preterm labor include social class, working conditions, daily life activities, family status, and psychosocial stress factors. A favorable lifestyle, better health consciousness, physical activity, and a nutritious diet are all associated with a reduced risk of preterm labor. Studies have generally found no increased risk of preterm labor in association with being employed as such, but suggest that long work-hours, physically demanding work, and stressful conditions may be associated with an increased risk.26,27
Substance abuse and socioeconomic risk factors are known to increase risk of preterm labor. It is a challenge to measure many of these behaviors with accuracy, because of their innate complexity, inability to recall, or the associated stigma (e.g., alcohol and illicit drug use). Behaviors are confounded with low socioeconomic conditions and unfavorable health behaviors. Women with poor diet often exhibit other potentially harmful behaviors. Vaginal microbial colonization known to be associated with increased risk of preterm labor may simply be an indicator of socioeconomic, sexual, or behavioral risk factors.
Smoking is strongly related to placental abruption, reduced birth weight, and infant mortality; however, the relationship of cigarette smoking to preterm birth is not entirely consistent.
Evidence is limited and inconsistent by the quality of the self-report and the absence of biological markers in case of alcohol use by mothers. Different effects may be observed at different dose levels. The issue of whether a relationship exists between alcohol use and preterm birth remains unresolved.
Cocaine users have approximately twofold increased risk of preterm labor compared with that for non-users. Although vasoconstriction is the underlying mechanism and the association is found with reasonable consistency, there are no trials to prove that the association is causal.
 
Maternal Weight/Body Mass Index
The Preterm Prediction Study suggests that a low prepregnancy body mass index (BMI) is strongly associated with an increased risk of preterm labor. A recent meta-analysis found that morbidly obese women (BMI >35) had an increased risk of preterm birth. A low level of weight gain during pregnancy is associated with an increased risk of preterm labor. What is less certain is whether this association reflects a cause-effect relationship, or they are manifestations of some shared etiology.28,298
 
Nutrition
Randomized studies in both developed and developing countries have noted an absence of benefit from dietary supplementation in preventing preterm labor/delivery.
  • Iron deficiency anemia, which has been found to be correlated with an increased risk of preterm labor in a number of studies, is unlikely to be an actual cause of preterm labor. Besides, serum ferritin levels also reflect a response to inflammation and infections, not necessarily an influence of iron intake. Despite the reasons to question whether anemia is part of a causal pathway that leads to preterm birth, there is some consistency in the evidence from randomized trials that iron supplementation may reduce the rates of preterm birth
  • Increased folate levels reduce the risk of preterm labor; however, studies show mixed findings
  • Observational studies show that low vitamin C levels are associated with an increased risk of PROM, leading to preterm labor
  • Increased levels of calcium have also been possibly associated with a reduced risk of preterm labor/delivery
  • Although randomized trials suggest a possible benefit of zinc and fish oil consumption on pregnancy duration, the information is not consistent.
 
PATHOGENESIS
 
Infection and Inflammation
 
Fetal Inflammatory Response Syndrome
The cascade of preterm labor/delivery is triggered by the interaction of infection, inflammation, and genetic predisposition. Infection results in a fetal and/or maternal inflammatory response—chorioamnionitis, funisitis, and particularly the FIRS, which are all part of intra-amniotic inflammation.30 FIRS is an independent risk factor for severe perinatal morbidity due to neonatal sepsis, severe IVH, periventricular leukomalacia, NEC, BPD, myocardial dysfunction, and CP. FIRS has definite laboratory, histological, and clinical criteria. Current criteria of FIRS include elevated cytokine levels [particularly interleukin (IL)-6], elevated levels of immature neutrophilic granulocytes, elevated C-reactive protein in umbilical blood sampled after the delivery, histological (funisitis, chorionamnionitis, umbilical arteritis, and umbilical perivasculitis), and clinical correlates. Uterine contractions and cervical changes are clinical manifestations of inflammation resulting in preterm labor and PROM. All these clinical signs might be associated with FIRS.31,329
 
Microbial Invasion of Amniotic Cavity
Microbial invasion of amniotic cavity is associated with qualitative (funneling) and quantitative (shortening) changes of the cervix and leading to cervical insufficiency. The frequency of microbial invasion of the amniotic cavity among women presenting with cervical insufficiency is up to 51%.33,34
The sonographic finding of dense aggregates of particulate matter in the amniotic fluid close to the internal cervical os, known as amniotic fluid ‘sludge’, is known to be associated with impending preterm delivery, microbial invasion of the amniotic cavity, and histologic chorioamnionitis. The combination of ‘sludge’ and a short cervix has been shown to confer a higher risk for spontaneous preterm delivery at less than 28 weeks and less than 32 weeks than a short cervix alone.35
In preterm labor with intact membranes, elevated amniotic fluid macrophage migration inhibitory factor is associated with intra-amniotic inflammation and histologic chorioamnionitis.36 An increased expression of migration inhibitory factor protein and mRNA in chorioamniotic membranes is seen in patients with histologic chorioamnionitis. Microbial invasion of the amniotic cavity, histologic chorioamnionitis, and term labor are associated with elevated amniotic fluid heat shock protein (HSP70) concentrations. Additionally, HSP70 plays a role in the host defense mechanism by activating the immune response and mechanisms of preterm labor and term labor may involve HSP70.37 Angiopoietins which are necessary for angiogenesis have also been linked to inflammation. Angiopoietin-2, a protein involved in the process of vascular remodeling and angiogenesis, and a physiologic constituent of the amniotic fluid is higher in patients with intra-amniotic infection.38
Infection-induced maternal immune activation leads to preterm labor through upregulation of genes coding for contraction-associated proteins, which are essential for the development of the uterine contractility. Maternal immune activation also leads to FIRS mediated by cytokines and is implicated in the development periventricular leukomalacia and CP. Intrauterine infection is associated with maternal immune activation leading to preterm birth through upregulation of contraction-associated proteins.39
 
Progesterone and Uterine Activity
Progesterone is the most significant hormone for continuation of pregnancy and inhibits uterine contractility. The actions of progesterone are mediated by progesterone receptors (PR-A and PR-B), which function as ligand-activated modulators of gene expression.40
Regulation of uterine activity during pregnancy is via progesterone, relaxin, prostacycline, NO, and CRH. These agents regulate intracellular cyclic adenosine 10monophosphate (cAMP), which inhibits the release of calcium ions and the enzyme myosin kinase. Actin and myosin in myocytes are connected with gap and tight junctions. Interaction between actin and myosin is responsible for the coordination and synchronization of uterine contractions.
There are two kinds of membrane receptors in the uterine myocytes.
  • Type 1 receptor – α-adrenergic/muscarinic/cholinergic. These are formed under the effect of estrogens. These are the receptors that oxytocin and PG act on
  • Type 2 receptor – β-adrenergic receptors. These are formed under the effect of progesterone.
The calcium influx into the cells is stimulated by type-1 receptor agonists. The return of calcium is stimulated by type-2 receptor agonists, β-mimetics, and magnesium. Relaxation of the contractile system depends on the amount of these receptors and concentrations of their agonists and antagonists. This forms the basis for management of preterm labor with tocolytics in clinical practice, including calcium-channel blockers, β-mimetics, magnesium sulfate, cyclooxygenase inhibitors, oxytocin receptor antagonists, and NO donors.
During labor, there is myometrial stimulation by oxytocin, PGs, and CRH. PGs are produced by enzyme PG synthase from arachidonic acid in amnion, chorion, decidual, and myometrial cells. Activity of PG synthase is controlled by CRH, probably of placental origin.41 PG dehydrogenase is the key catabolic enzyme that controls levels of biologically active PGs. PG dehydrogenase activity is stimulated and inhibited with endogenous corticoids and progesterone, respectively. Maternal and fetal stress can activate the hypothalamic-pituitary-adrenal axis and alter levels of adrenal hormones, cortisol, PGH2, and PGE2. Increased circulating adrenocorticotropin hormone (ACTH) levels during pregnancy may be due to placental synthesis and release of biologically active CRH and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors, such as vasopressin and CRH. All these pathways are involved in preterm labor.42,43
 
Inflammation
The maternal/host immune response is initiated by pattern recognition receptors (PRR), particularly the Toll-like receptors (TLRs), which have an ability to identify molecular structures in microorganisms and to bind to oxidative stress products. The binding of ligand on the PRRs results in the activation of nuclear factor kappa-B (NF- k B), which in turn stimulates gene transcription for cytokines, matrix metalloproteinases, and growth factors. IL-10 is an anti-inflammatory cytokine and is important for maintenance of pregnancy and IL-6 and IL-8 are proinflammatory. Elevated levels of IL-6, IL-8, and matrix metalloproteinases-8 11in amniotic fluid are thought to be markers for preterm labor. Acute chorio-amnionitis of infectious origin and chronic chorioamnionitis of immunological origin are two major placental lesions of preterm labor associated with elevated amniotic fluid IL-6 and C-X-C-motif-chemokine 10 (CXCL10) concentrations, respectively.44,45
Proteins osteoglycin and progesterone receptor component 2 have been shown to be upregulated during term and preterm labor, while galectin-1, annexin-3, annexin-5, and protein disulfide isomerase are to be upregulated only during preterm labor and represent potential novel predictive markers for preterm labor. Transforming growth factor (TGF)- β1 represents one of the cytokines of the initiation phase of inflammation and has been studied in correlation with the condition of fetus as an allograft.45
High mobility group box-1 (HMGB-1) protein activates inflammation and tissue repair. The binding of HMGB-1 to the receptor for advanced glycation end-products (RAGE) induces cytokines production, modulated by the soluble forms of RAGE (sRAGE). After the interaction of advanced glycation end products with the transmembrane receptor RAGE, the signal cascade including p21 ras and mitogen activated protein (MAP)-kinase is initiated and followed by the activation of the NF- k B. This is followed by the stimulation of proinflammatory cytokines. An increase in the amniotic fluid HMGB-1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis. High sRAGE concentrations might play a protective role in preterm labor by regulating the development of inflammation.46
 
Genetic, Genomic, and Epigenetic Factors
The leading risk factor for preterm labor is a previous preterm birth, and this supports the idea that genetic factors affect the risk of preterm labor. Growing evidence reveal genetic contribution to pathogenesis of preterm labor and may reflect interaction of environmental and genetic factors.47,48
Epigenetics and proteomics have the potential to provide a greater understanding of the pathways to preterm labor.
Currently available literature provides some evidence of familial and intergenerational influences on preterm labor:
  • COL5A2, COL5A1 and PON1 genes, which affect cell communication and extracellular matrix are thought to be associated with preterm labor49,50
  • Claudin genes encode proteins important in tight junction formation and function. Claudin gene expression is reduced in cervical epithelial cells during both preterm labor/delivery and term delivery. Claudin gene upregulation increases after administration of progestogens, suggesting that progestogens have a potential role in management of preterm labor
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  • Tumor necrosis factor (TNF)- αis a proinflammatory cytokine present in the amniotic fluid of women with intrauterine infection and preterm labor. Women with TNF- αgene mutation and BV are at higher risk of preterm labor/delivery than those with BV without the mutation
  • Alterations in the genes involved in controlling fetal inflammation (IL-6 receptor 1) and maternal genes encoding for proteins involved in extracellular matrix metabolism have also been implicated
  • Progesterone appears to relax the myometrium by downregulation of the expression of two critical genes, Cx43, which encodes a major gap junction protein that helps synchronize contractile activity and the oxytocin-receptor gene (OXTR), which determines the responsiveness of myometrial cells to oxytocin, a potent stimulator of contraction. These genes are also thought to influence preterm labor.
Functional genomics may be a promising diagnostic tool. However, identification of genes intrinsic to labor is potentially challenging. Proteomic delineation of the amniotic fluid offers a more precise avenue for recognition of inflammation by several biomarkers, including defensins-2 and −1, calgranulin-C, and calgranulin-A, which are highly predictive of intrauterine inflammation. Thus, proteomic studies potentially facilitate identification of patients who may benefit from interventions in utero.51,52
 
Uteroplacental Ischemia
Thrombogenic tendency affects placental microcirculation and results in endothelial dysfunction. This results in PRR activation and preterm labor. Thrombogenic states are as follows:
  • Inherited thrombophilias
    • Factor V Leiden mutation
    • Prothrombin gene mutation
    • Methylenetetrahydrofolate reductase (MTHFR) mutation
  • Acquired thrombophilias
    • APS
    • Hyperhomocysteinemia.
Besides preterm labor, these disorders play a role in venous thromboembolism, intrauterine fetal death, IUGR, placental abruption, severe preeclampsia, and multiple spontaneous abortions.53,54
Recent studies suggest that MTHFR mutation might be associated with preterm labor/delivery. Preterm labor has been associated with an increase in membrane hemosiderin deposits, which are thought to reflect decidual hemorrhages. The association between placental abruption and uterine activity and/or PROM is well known.13
 
Immunologic
 
Fetus as an Allograft
Presence of abnormal immunological mechanisms in the etiopathogenesis of preterm labor is known. There is evidence to suggest that preterm labor and/or multiple miscarriages occur due to fetus behaving like an allograft. Mechanism of maternal tolerance of the fetus is a balance between downregulation and upregulation of the major histocompatibility complex antigens. While the genes for class I human leukocyte antigen (HLA)-A and -B are downregulated during pregnancy by trophoblasts, and the genes for class HLA-G antigens, protecting the fetus against maternal immune response, are upregulated during pregnancy. Inadequate recognition of fetal antigens might result in discontinuation of pregnancy and preterm labor. Animal studies show reduced expression of galectin-1 (an immune-regulation protein) in multiple pregnancy losses. Also, a number of autoimmune diseases, particularly when uncontrolled, are associated with a higher risk of preterm labor. The most common ones include systemic lupus erythematosus (SLE) and immune thyroid disorders.53,54
 
Allergy
Uterus is a rich source of mastocytes; however, degranulation of mastocytes results in uterine activity via PG release. Eosinophillic granulocytes are increased in amniotic fluid obtained from women with preterm labor and suggest an abnormal immune/allergic response as one of the mechanisms of preterm labor; however, the antigen triggering this reaction has not been found yet, and the potential role of antihistamines in prevention of this category of preterm labor is yet to be explored.55,56
 
POTENTIAL BIOMARKERS
  • Serum ferritin, an iron storage protein and acute phase reactant, is significantly raised in preterm labor and PROM. Ferritin is produced by the macrophages in the choriodecidual interface following bacterial colonization. Asymptomatic or subclinical infection can also lead to increased ferritin and may facilitate prediction of preterm labor/delivery. Ferritin/iron ratio is also presumed to be a biomarker for preterm labor/delivery57,58
  • Serum alkaline phosphatase activity is increased in pregnancy due to presence of placental isoenzyme. Studies have shown significant correlation between increased alkaline phosphatase levels with threefold increased risk for preterm labor/delivery
  • Prolactin has also been evaluated as a potential biomarker with not much success
  • Proinflammatory cytokines like IL-6 have been studied in cervical secretions as a biomarker for preterm labor59
    14
  • Midtrimester lactate dehydrogenase is thought to be quite effective in the prediction of preterm delivery60
  • Studies report association of thyroid hormonal status and autoimmune thyroid disease in euthyroid women with risk for preterm labor/delivery; however, data is inconclusive
  • The synergistic stimulation of the fetoplacental unit and the pituitary adrenal axis of both fetus and mother are important in initiation of labor. Serum ACTH levels have been studied as a predictive marker of preterm labor.
A panel of various biologic markers might be useful in predicting risk of preterm delivery.
 
CONCLUSION
There are various etiological factors culminating in preterm labor. A genetic predisposition coupled with factors in the genital tract play an important role. Inflammation appears to be the final common pathway that culminates in preterm labor. The triggering factors for the inflammatory response may be infective, immunological, or hormonal. Once the cascade of liberation of inflammatory cytokines and matrix metalloproteinases is set in motion, all therapeutic interventions will have only limited success. Current research is geared towards finding new markers to ensure early identification of risk of preterm labor/delivery. Many biochemical markers are being studied, but none has reached up to clinical expectations. Proteomics holds promise for the future.

Editor's Comment

Multiple etiologies lead to the cascade of preterm labor. Intrauterine inflammation is an important cause, which could result from an infectious process. Maternal or fetal stress can precipitate preterm labor by increasing the secretion of corticotropin-releasing hormone. Maternal age, health, nutrition, behavioral patterns, and psychological stress also contribute to preterm labor. A number of potential biomarkers are being evaluated, but none is of clinical significance at this time.
Mala Arora
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