Preterm labor and delivery is associated with significant perinatal morbidity and mortality, and its prevention is one of the most urgent tasks in perinatal medicine. Preterm labor is defined as the presence of uterine contractions of sufficient frequency and intensity to cause progressive effacement and dilatation of the cervix prior to term (<37 weeks). Preterm labor precedes almost half of all preterm births. Though the rate of preterm birth all over the world does not vary greatly (5–12%), it accounts for 70% of neonatal morbidity and mortality. Preterm birth and its consequences are a burden for both individuals and society, and vast expenditure in the past few decades has been directed towards research for prevention of preterm labor.Early identification of risk factors, timely diagnosis of preterm labor, prophylactic pharmacologic therapy to prolong gestation and reduce incidence of respiratory distress syndrome (RDS) and intra-amniotic infection, tocolytic therapy when indicated, and systematic maternal and fetal surveillance with patient education will improve neonatal outcome. The focus of this article is the etiological risk factors, prediction and prevention of preterm labor.</sec><sec id="sec002"><title>Risk factors and etiology

Journal of Neonatology

0971-2179

National Neonatology Forum

jn-21-2-002

REVIEW ARTICLE

Prematurity - Can we prevent it?

Raut

Vanita S

^1,*Chauhan

Anahita R

¹Department of Obstetrics & Gynaecology, LH Hiranandani Hospital, Mumbai, Powai.²Department of Obstetrics & Gynaecology, Seth GS Medical College & KEM Hospital, Mumbai.

*E-mail: raut@vsnl.com

4–62007

2128286

Preterm labor and delivery is associated with significant perinatal morbidity and mortality, and its prevention is one of the most urgent tasks in perinatal medicine. Preterm labor is defined as the presence of uterine contractions of sufficient frequency and intensity to cause progressive effacement and dilatation of the cervix prior to term (<37 weeks). Preterm labor precedes almost half of all preterm births. Though the rate of preterm birth all over the world does not vary greatly (5–12%), it accounts for 70% of neonatal morbidity and mortality. Preterm birth and its consequences are a burden for both individuals and society, and vast expenditure in the past few decades has been directed towards research for prevention of preterm labor.Early identification of risk factors, timely diagnosis of preterm labor, prophylactic pharmacologic therapy to prolong gestation and reduce incidence of respiratory distress syndrome (RDS) and intra-amniotic infection, tocolytic therapy when indicated, and systematic maternal and fetal surveillance with patient education will improve neonatal outcome. The focus of this article is the etiological risk factors, prediction and prevention of preterm labor.</sec><sec id="sec002"><title>Risk factors and etiology

The exact mechanism of preterm labor is still unknown but is believed to include decidual hemorrhage (abruption, mechanical factors such as uterine overdistension from multiple gestation), cervical incompetence, uterine distortion, cervical inflammation, maternal inflammation/fever, hormonal changes and uteroplacental insufficiency. The fetus is also believed to play a role in the initiation of labor; it recognizes a hostile intrauterine environment and precipitates labor by premature activation of a fetal-placental parturition pathway.

Risk factors for preterm birth include demographic characteristics, behavioral factors, and aspects of obstetric history such as previous preterm birth. The most important risk factor for preterm birth is a previous preterm delivery. Demographic factors include low socioeconomic status, non-white race, maternal age <18 years or >40 years, multiple gestation, preterm premature rupture of membranes (PPROM) and maternal history of one or more spontaneous midtrimester abortions. Maternal behaviors like smoking, alcohol and drug use, domestic stress and violence, and lack of antenatal care are also contributory.

Uterine causes include myomata (particularly submucosal or subplacental), uterine septum and uterine anomalies like bicornuate or unicornuate uterus. A major risk factor is cervical incompetence. The most common etiologies for cervical injury are elective abortion, surgeries to treat cervical dysplasia or prolapse, and injury occurring at delivery. Though a single uncomplicated elective first trimester abortion does not increase the risk of preterm birth, patients with a history of multiple first trimester elective terminations or one or more second trimester elective abortions may be at increased risk for preterm delivery.

Inflammation has been implicated in preterm and term parturition, as well as fetal injury. Of all of the suspected causes of preterm labor and delivery, infection and/or inflammation is the only pathological process for which both a firm causal link with preterm birth has been established and a molecular pathophysiology defined¹. 30 to 50% of cases of preterm labor are due to infectious causes and include chorioamnionitis, bacterial vaginosis (BV), asymptomatic bacteriuria, acute pyelonephritis and periodontitis. Chorioamnionitis itself is the cause of 20 to 30% of all cases of preterm labor. The commonest organisms found in amniotic fluid and placenta are Ureaplasma urealyticum, group B streptococcus, Gardnerella vaginalis, Escherichia coli, Mycoplasma hominis and Chlamydia trachomatis. Evidence is accumulating that periodontitis caused by oral bacteria, especially P. gingivalis may cause preterm birth by causing low-grade bacteremia, which lodges in the decidua, chorion and amnion or by releasing endotoxins into the maternal circulation. Several clinical trials of treatment of periodontitis are continuing, but until their results are known there is currently little evidence that treatment of periodontitis during pregnancy reduces the incidence of preterm birth².

Medical or obstetric indications like severe preeclampsia, eclampsia, severe IUGR, intrauterine fetal death and fetal congenital anomalies may account for iatrogenic preterm labor. Investigations targeted to specific etiological causes may be helpful.

Prediction of preterm labor

Prediction of preterm labor has dominated research efforts for the last decade. The successful prediction of preterm labor potentially allows interventions to prevent preterm births and improve perinatal outcome. Prediction of preterm labor should ideally involve a screening test with high sensitivity and high negative predictive value. If the test is positive, there should be effective interventions available to arrest it.

Obtaining an accurate history is important in identifying high risk women. Risk scoring strategies have been devised to assess a woman's potential for preterm birth based on her socioeconomic status, clinical history, lifestyle, and past obstetric and current perinatal complications. However, these strategies have proved to be of limited value. Numerous screening methods have been evaluated for preterm labor; they mainly fall into four main groups:

monitoring of uterine activity

assessment of cervical length

measurement of cervico vaginal markers

presence of bacterial vaginosis in early pregnancy

Monitoring of uterine activity

This can be simply done by educating the patient. However this is purely subjective, time consuming, has poor sensitivity and can increase patient anxiety. Another method is home uterine activity monitoring (HUAM) with tocometer. It is expensive, time consuming, results vary according to the position and tension on the belt and there is no good correlation with improved pregnancy outcome. Hence HUAM is not clinically useful for predicting preterm labor.

Assessment of cervical length

There is consistent evidence that digital cervical examination is a weak predictor of preterm labor. Sonographic evaluation of the cervix is a better option. USG evaluation of normal pregnancy shows that cervical effacement begins at around the 32^nd week. In pregnancies destined to deliver preterm, the process may begin much earlier, between 16^th and 24^th week. Effacement starts at the internal os and funneling and shortening of the cervix which occurs prior to dilatation of the external os can be accurately assessed only by USG. A transvaginal cervical assessment by sonography is more standardized as compared with alternative techniques of transabdominal or translabial/transperineal approaches.

A study by Cook showed that there is a strong association between a short cervix (cervical length <21mm at 20 weeks or earlier) and preterm birth³. The rationale for screening the low risk population is that a significant portion of preterm deliveries occurs in pregnancies with no historical risk factors.

A multicentric study by Iams showed a significant association between the risk of preterm labor and a short cervix in the general asymptomatic population; other studies show little evidence to suggest that screening a low risk population is useful as an effective intervention to improve pregnancy outcome has not yet been demonstrated⁴. Sonographic cervical assessment can also be used in patients with symptoms of preterm labor as early diagnosis of preterm labor potentially allows early intervention and risk reduction.

As the incidence of preterm delivery is significantly higher in multiple pregnancies, cervical screening by USG is definitely helpful in these patients. Skentou showed a significant inverse relationship between cervical length and the risk of preterm birth⁵.

Measurement of cervico-vaginal markers

Markers like fetal fibronectin, interleukin 6 (IL-6) and tumor necrosis factor (TNF) have been studied for the prediction of preterm labor. Of these only the evaluation of fetal fibronectin has shown promising results.

Fetal fibronectin is a glycoprotein found in the amniotic fluid, placental tissue and deciduas basalis. It is normally found in cervico-vaginal secretions prior to 16 to 18 weeks of gestation, before the fusion of the fetal membranes and decidua is complete. It is also found toward the end of pregnancy, prior to the onset of labor, but is not normally present in the cervico-vaginal secretions between 22 and 37 weeks. As a result of infection, the chorio decidual interface may get disrupted, leading to the occurrence of fetal fibronectin in cervico-vaginal secretions; hence when seen in the later part of the second and early third trimesters, fetal fibronectin can be predictive of preterm labor. Currently, ELISA containing the monoclonal antibody FDC 6 has been developed and can be used as a bedside test^6,7.

A metanalysis found that fetal fibronectin was useful in the prediction of delivery prior to 34 weeks, with an overall sensitivity of 53% and specificity of 89%. Sensitivity for the prediction of delivery was better for the short term 71% (within 7 days) as compared to the long term (within 21 days) 59%. Hence fetal fibronectin is a reasonably effective marker in predicting preterm delivery in the short term, particularly in women with symptoms of preterm labor⁸.

Screening for bacterial vaginosis (BV) in early pregnancy

The relative risk of preterm labor is doubled if the mother has BV. Despite this reasonably convincing evidence of a link between early infection with BV and preterm delivery, screening and subsequent treatment of BV remains controversial. A Cochrane Collaborative Review showed that antibiotic therapy successfully treated BV but failed to reduce the risk of preterm birth before 37 weeks. In those women who had a previous preterm birth, treatment of BV did not decrease the risk of a subsequent preterm birth but did decrease the risk of PPROM^9,10.

Hence, there is strong evidence that preterm birth can be predicted using vaginal sonography, fetal fibronectin in cervicovaginal secretions and IL-6 in amniotic fluid. There is consistent evidence that digital cervical examination is a weak predictor, and clinical utility of HUAM is questionable. There is scanty evidence about the predictive ability of maternal history and perceptions of symptoms of preterm labor¹¹.

Though successful interventions may not be possible when preterm labor is predicted, the neonatal outcome can be improved by antenatal steroid administration and in utero transfer. An additional use of these predictive tests is the value of negative results. In patients with negative results, unnecessary admission and interventions like cervical cerclage as well as repeated doses of steroids can be avoided.

Strategies for prevention of preterm labor

Assessment of risk is based on history and examination. In high risk cases more frequent antenatal assessment in the latter half of pregnancy, vaginal and cervical microbiological swabs electively at 20 to 24 weeks, USG assessment of cervical length and patient education regarding signs and symptoms of preterm labor is advisable and feasible in our setting. Various strategies tried for prevention of preterm labour include bed rest, hydration therapy, protein, nutrition, calcium and fish oil supplements, tocolysis, cerclage and progesterone. Only the clinically significant ones are included here, as large randomized controlled trials have shown that most of the interventions are of no or limited use.

Bed rest and hospitalization

Though practiced routinely, according to a Cochrane review there is no evidence, either supporting or refuting the use of bed rest at home or in the hospital to prevent preterm birth in women facing an increased risk of preterm birth. According to another Cochrane review, currently there is not enough evidence to support a policy of routine hospitalization for bed rest in multiple pregnancies. No reduction in the risk of preterm birth or perinatal death is evident, although there is a suggestion that fetal growth is improved¹².

Tocolytics

Surveys of obstetricians indicate a high usage of tocolysis for preterm labor, but evidence that this treatment confers benefit is still lacking. For the relatively small proportion of women in otherwise uncomplicated preterm labor prior to 34 weeks’ gestation, there appears to be a place for short-term tocolysis to gain time so that corticosteroids can be administered to enhance fetal lung maturation and, if necessary, to transfer the woman to a facility with a neonatal intensive care unit. Tocolytics are not indicated in patients with either suspected or confirmed intrauterine infection or when evidence of a hostile intrauterine environment exists. Maintenance tocolysis is not recommended for routine practice.

The perfect tocolytic that is uniformly effective with complete fetomaternal safety does not exist. Tocolytic agents differ in cost, specificity, safety, efficacy and whether they are licensed for use. The main three agents that are used worldwide are beta-agonists (ritodrine, terbutaline), calcium channel blockers (nifedipine) and vasopressin/oxytocin receptor antagonists like atosiban. There is no evidence of effectiveness for magnesium sulphate as a tocolytic. Beta agonists are now correctly being abandoned in favor of either nifedipine or atosiban, which have superior tocolytic properties and better neonatal outcomes. Evidence indicates that atosiban is as effective as nifedipine and more effective than beta-agonists, and significantly safer than both^13,14.

Atosiban was developed specifically to treat preterm labor, but is not universally available and is expensive. A recent Cochrane review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes; however it has fewer maternal side effects. The finding of an increase in infant deaths in one placebo controlled trial was disturbing. Another recent Cochrane review suggests that calcium channel blockers (mainly nifedipine) are associated with better neonatal outcome and fewer maternal side-effects than betamimetics. However, a randomised comparison of nifedipine with placebo is not available^15,16. Current research is addressing the COX-2 inhibitor, rofecoxib, which has theoretical advantages with respect to fetal safety.

Antibiotics

Bacteria are normally present in the birth canal and are useful in maintaining the health of the vagina. BV is an imbalance of the normal vaginal flora with an overgrowth of anaerobic bacteria and a lack of the normal lacto bacillary flora. BV during pregnancy has been associated with poor perinatal outcome and in particular preterm birth.

Once labor has begun it is almost certainly too late for antibiotics to have any effect in delaying birth and it is more logical to treat biologically relevant microorganisms early in pregnancy in order to prevent activation of the cytokine cascade.

Morales and associates were able to demonstrate a significant reduction in the incidence of preterm labor, preterm delivery and low birth weight and PPROM using oral metronidazole compared to placebo¹⁷. This beneficial effect was not seen with locally administered antibiotics.

A Cochrane review of trials found that antibiotic prophylaxis given during the second or third trimester of pregnancy reduces the risk of pre labor rupture of membranes when given routinely to pregnant women. Beneficial effects on birth weight and the risk of postpartum endometritis were seen for high risk women¹⁸. Antibiotic treatment instituted prior to 20 weeks of gestation reduces the risk of preterm birth. Another Cochrane review provided little evidence that screening and treating all pregnant women with asymptomatic BV will prevent preterm birth and its consequences¹⁹.

Hence it is not advisable to screen all pregnant women for BV. Only the high risk group should be screened for asymptomatic vaginal infection. Antibiotic treatment should be given only to symptomatic patients and to those who are positive on screening to prevent preterm labor.

Probiotics

Probiotics are defined as live micro-organisms which confer a health benefit on the host by displacing and killing pathogens and modulating the immune response by interfering with the inflammatory cascade that leads to preterm labor. During pregnancy, local treatment restoring normal vaginal flora and acidity without systemic effects appears attractive. However there are currently insufficient data from trials to assess overall impact on preterm birth²⁰.

Corticosteroids

The use of “prophylactic” maternal corticosteroids to enhance fetal lung maturity in women at risk for preterm delivery is currently restricted to threatened preterm labor and established PPROM during the immediate episode, if it occurs between 24 and 34 weeks in the absence of clinical infection. An attempt should be made to delay delivery for a minimum of 12 hours to obtain the maximum benefits of antenatal steroids. The recommended dosage of betamethasone is two doses of 12mg intramuscularly 24 hours apart or dexamethasone 4 doses of 6mg at 12 hourly intervals. In the presence of insulin-dependent or gestational diabetes, the obstetrician should be prepared for control of blood sugars.

Two doses of corticosteroid have a proven beneficial effect on neonatal pulmonary function, with a possible reduction in intraventricular hemorrhage and necrotizing enterocolitis. However controversy exists regarding single versus multiple doses of corticosteroids for pregnancies at risk of preterm delivery between 24 and 34 weeks. Wafisch and colleagues reviewed 280 articles on the subject and commented that an increasing body of evidence raises the concern of adverse consequences from the use of repeated courses of steroids. Retrospective human studies have suggested caution with regard to the former practice of repeated maternal corticosteroid administration in high risk women because of possible fetal intrauterine growth restriction and neonatal neuro-developmental impairment. Hence it is recommended that only a single course of antenatal corticosteroids be given to all women at risk for preterm birth at 24 to 34 weeks gestation²¹.

Progesterone

Progesterone is a hormone that inhibits the uterus from contracting and is involved in maintaining pregnancy. A Cochrane review of trials using progesterone either as intramuscular injections or as vaginal pessaries for preventing preterm birth, has shown beneficial effects, including prolonging the gestation age, but there is insufficient evidence about the harms. Intramuscular progesterone is definitely associated with a reduction in the risk of preterm birth less than 37 weeks’ gestation, and infant birth weight less than 2500 grams. However, other important maternal and infant outcomes have been poorly reported to date. It is unclear if the prolongation of gestation translates into improved maternal and longer-term infant health outcomes. Information regarding the potential harms of progesterone therapy to prevent preterm birth is limited. Further information is required about the use of vaginal progesterone in the prevention of preterm birth²².

Cerclage

Randomized clinical trials of cerclage for sonographically suspected cervical incompetence (shortened cervical length and/or funneling) have been inconclusive with respect to prevention of preterm delivery. However, a history of two or more midtrimester losses with loss of cervical integrity, often results in recommendation for cerclage placement between 13 and 17 weeks’ gestation²³.

Many of the above interventions, though they do not directly prevent preterm birth, may improve outcome by causing increased fetal weight gain or increased lung maturity at a given gestational age, hence are still used in clinical practice.

Future

Preterm birth may be the result of interactions between specific genes and maternal - fetal environment. Strong familial clustering, documented increased risk in patients with a personal or family history of preterm birth and racial disparity in the incidence of preterm birth all support a genetic component. New technologies such as microarray, single nucleotide polymorphism analysis, and proteomics are being studied and will lead to the eventual identification and characterization of the genetic etiology of preterm birth²⁴.

Conclusions

Efforts worldwide are directed to predicting preterm labor so as to prevent and reduce the incidence of preterm labor and its consequences and burden on society. The obstetrician should use good clinical judgment, selected tests and investigations and in light of current evidence, should not over- use or misuse tocolytics, coricosteroids and cerclage.

Summary of Interventions and their efficacy in preventing preterm birth

Intervention	Efficacy

Prenatal care (routine or enhanced)	No
Risk scoring systems	No
Programs for stopping tobacco, drug and alcohol abuse	No
Psychological support	No
Nutrition counseling & calorie and protein supplementation	No
Vitamin or mineral supplementation	Uncertain
Patient education about preterm labor signs	No
Frequent contact with a health care provider	No
Home uterine activity monitoring	No
Tocolytic therapy	Yes (48 hrs)
Bed rest	No
Hydration	No
Progestin supplementation (for history of preterm labor)	Yes
Cervical cerclage (for incompetent cervix)	Yes
Screening for and treatment of UTI and BV	Yes
Antibiotics for preterm labor or PPROM	Yes

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