Preterm Birth: Current Trends in Management

Introduction

Preterm birth is the foremost problem in modern obstetrics and is an important perinatal health problem across the globe. Developing countries, especially India, incur the highest burden in terms of absolute numbers. It is a major determinant of neonatal mortality and morbidity and has long-term adverse consequences for health.

The cause for preterm birth is in many situations elusive and unknown; many factors appear to be associated with the development of preterm birth, making the reduction of preterm birth a challenging proposition.

Infants born preterm are at greater risk for short and long term complications, including cerebral palsy, sensory deficits, learning disabilities and respiratory illnesses, compared with children born at term. The morbidity associated with preterm birth often extends to later life, resulting in enormous physical, psychological and economic costs.¹  

Definition

In humans, preterm birth refers to the birth of a baby occurring at less than 37 completed weeks or 259 days of gestation (relative to the last menstrual period).²   Premature birth, commonly used as a synonym for preterm birth, refers to the birth of a baby before its organs mature enough to allow normal postnatal survival, and growth and development as a child.³   They may have health problems because their organs did not had enough time to develop and may need special medical care in a neonatal intensive care unit (NICU) until their organ systems can work on their own (Figure 1).⁴   Preterm or premature labor is different from preterm or premature birth (Box 1).

Prevalence

Preterm birth rates have been reported to range from 5% to 7% of live births in some developed countries, but are estimated to be substantially higher in developing countries (Table 1). These figures appear to be on the rise.^1,5  

Classification

The three main conditions to explain preterm birth are (Figure 2):⁶

Medically indicated (iatrogenic) preterm birth (25%; 18.7-35.2%)

Preterm premature rupture of membranes (PPROM) (25%; 7.1-51.2%)

Spontaneous (idiopathic) preterm birth (50%; 23.2-64.1%).

A classification of preterm birth according to gestational age at birth (Figure 3) is important for neonatal prognosis and is stratified with increasing neonatal mortality and morbidity into:⁶

• Mild preterm (32-36 weeks)
• Very preterm (28-31 weeks)
• Extremely preterm (<28 weeks)

Etiology

Like other chronic conditions such as heart disease and cancer, preterm birth is a common complex disorder. Preterm birth has a multifactorial origin. The majority of multiple pregnancies (10% of all preterm births) are delivered preterm (50% for medical reasons). Medical indications relate more to fetomaternal conditions. PPROM relates more to infections and idiopathic preterm birth to lifestyle. Still, several incidences of preterm birth are not completely explained with a plausible cause for PPROM or spontaneous preterm labor suggesting that other causes have yet to be identified.⁶  

Familial aggregation, high recurrence rates, and racial disparities in preterm birth all point strongly to a genetic role. Cigarette smoking and bacterial vaginosis are among the behavioral/environmental factors believed to interact with specific genes to increase risk of spontaneous preterm birth.  ⁷  

Recent studies have suggested that infection was mostly responsible for extreme preterm birth, while stress and lifestyle accounted for mild preterm birth, and a mixture of both conditions contributed to very preterm birth.⁶  

Certain bacterial infections also have been associated with preterm labor, including Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, and Peptostreptococcus and Bacteroides species. These organisms are usually of low virulence, and it is unclear whether they are etiologic or associated with an acute inflammatory response of another etiology.⁸  

Causal factors

Causal factors linked to preterm birth include:^1,5  

• Medical conditions of the mother
• Medical conditions of the fetus
• Genetic influences
• Environmental exposure
• Infertility treatments
• Behavioral and socioeconomic factors
• Iatrogenic prematurity

Risk factors

Factors that may increase the risk of early labor and premature birth include:⁹  

• Previous history of having a preterm labor or premature birth
• Multiple pregnancy e.g. twins, triplets or other multiples (Figure 4)
• Early pregnancy – An interval of less than six months between pregnancies
• Conceiving through in vitro fertilization
• Pathology of uterus, cervix or placenta
• Genital tract infections, particularly of the lower tract
• Amniotic fluid infection
• Multiple miscarriages or abortions
• Certain chronic conditions, such as hypertension and diabetes
• Physical injury or trauma
• Being underweight or overweight before pregnancy
• Stressful life events, such as the death of a loved one or domestic violence
• Poor nutrition
• Behavior – Smoking cigarettes, drinking alcohol or using illicit drugs

Pathophysiology

The pathophysiologic events leading to preterm birth are still not completely understood although the etiology is thought to be multifactorial. It may include decidual hemorrhage (abruption), uterine overdistention, and hormonal changes possibly mediated by fetal or maternal stress; it is, however, unclear whether preterm birth results from the interaction of several pathways or the independent effect of each pathway. The final outcome of preterm birth can be reached by at least four major pathophysiologic pathways:¹⁰  

1. Inflammation and infection – They are associated with maternal and fetal cytokine response and are the most common pathway, contributing to approximately 40% of preterm labor.
2. Maternal/fetal stress and the production of placental and fetal-membrane derived corticotropin-releasing hormone (CRH) – CRH in turn enhances placental estrogen and stimulates fetal cortisol production. They contribute to approximately 25% of preterm labor.
3. Abruption or decidual hemorrhage with thrombin-induced protease expression and disturbances in uterine tone – They also contribute to approximately 25% of preterm labor.
4. Mechanical stretch due to multifetal pregnancy or polyhydramnios – They induce uterine or cervical distention and contribute to approximately 10% of preterm labor (Figure 5).

These pathways can occur independently, or more commonly, combine to lead to the shared outcome of preterm birth. How these pathways interact with the multiple factors believed to contribute to preterm birth (genetic, psychosocial, cultural, racial/ethnic, nutritional, behavioral, and environmental) is still not fully understood and denotes the complexity of the problem of preterm birth.

Consequences

The number of babies born preterm has been steadily increasing for the past two decades. The probability of infant survival for 30 completed weeks of gestation is >90 % and the limit of fetal survival has been extended to 24 weeks. The 2 % of babies born before 32 weeks, however, account for about 70 % of all infant mortality and the infants who do survive are frequently plagued with short and long-term respiratory and neurological morbidities such as bronchopulmonary dysplasia, cerebral palsy, intra-ventricular hemorrhage, patent ductus arteriosus, and poor school performance in later years.¹¹   Of all early neonatal deaths (deaths within the first 7 days of life) that are not related to congenital malformations, 28% are due to preterm birth.¹²  

Signs and symptoms

Prompt recognition of signs and symptoms of preterm labor may help prevent premature birth and can be looked even months before the due date. Different symptoms are:^9,13  

• Regular or frequent contractions or uterine tightening, often painless that occur more than eight times each hour – Pregnant lady may feel a tightening sensation in abdomen, often reminiscent of menstrual cramps
• Constant low, dull backache
• Pelvic or lower abdominal pressure or pain
• Mild abdominal cramps, with or without diarrhea
• Vaginal spotting or bleeding
• Watery vaginal discharge – this may be amniotic fluid

Diagnosis

Estrogen and progesterone establish the environment that allows parturition and probably preterm labor to occur. Thus there is physiologic and diagnostic usefulness of endocrine as well as other agents in preterm labor and delivery and their use is becoming more frequent.¹⁴   To determine women at risk of preterm birth following tests are used (Box 2):⁸  

Cervical ultrasonography

Transvaginal cervical ultrasonography is a reliable and reproducible way to assess the length of the cervix (Figure 6). Results of a prospective trial showed that the relative risk of preterm delivery increased as the cervical length decreased. Despite the usefulness of measuring cervical length as a predictor of preterm delivery, it is not recommended because of lack of effective treatments.⁸  

Fetal fibronectin testing

Numerous trials have shown an association with the presence of the fetal fibronectin protein and preterm birth and a decrease in the risk of preterm birth when the test result for this protein is negative. Although a negative test result appears to be useful in ruling out preterm delivery within two weeks, the clinical implications of a positive result have not been evaluated fully because no intervention has been shown to decrease the risk of preterm delivery. The test has limited usefulness in low-risk women. For high-risk women, the following criteria should be met:⁸  

• Intact amniotic membranes
• Minimal cervical dilatation
• Testing should be performed no earlier than 24 weeks, zero days of gestation, and no later than 34 weeks, six days of gestation
• Results must be available in time to allow for decision making, ideally within 24 hours.

Amniocentesis

This is used to determine fetal lung maturity and intra-amniotic infection.⁸  

Uterine activity monitoring

This has been suggested as a method for predicting preterm birth in high-risk women. It is recording of uterine contractions using a tocodynamometer. This method was based on the observation that some women who give
birth early have an increase in uterine activity earlier in pregnancy than women who give birth at term, and that these uterine contractions may not be recognized by the patient. Data are insufficient to support home uterine activity monitoring in preventing preterm birth, and it is not recommended. ⁸  

Salivary estriol

Observational studies have shown that maternal levels of serum estradiol and salivary estriol increase before the onset of spontaneous term and preterm labor. A test using salivary estriol levels was designed to predict preterm delivery, but maternal estriol levels peak at night and may be suppressed by betamethasone administration. The test carries a high percentage of false-positive results and can add significantly to the cost of prenatal care if used in the low-risk population. Trials with salivary estriol testing have failed to establish its usefulness for anything more than investigational purposes.⁸

Bacterial vaginosis

The presence of bacterial vaginosis (Figure 7), a common alteration of the normal vaginal flora, has been associated with preterm delivery independent of other known risk factors but it has been found in 10 to 25 percent of patients in general gynecology and obstetric patients, with 50 percent being asymptomatic. Trials of screening and treatment for bacterial vaginosis in pregnant women to reduce the incidence of preterm birth have been conducted in mixed populations with varying results. Some trials have shown an association with the presence of bacterial vaginosis and preterm delivery, but most results have failed to show if treatment for this condition can prevent preterm birth. There is insufficient data to support screening and treating women at low and high risk.⁸  

Future diagnostic tests for diagnosis of preterm labor

Whereas all of the agents discussed above have some diagnostic usefulness, none of them can be expected to predict every case of preterm delivery. The use of these tests, salivary estriol and fetal fibronectin in particular, has already had an effect on management and decision making involved in preterm labor, and the future should give more options and hopefully, better choices to manage this most difficult condition. In future, the possible diagnostic tests could be CRH and even the use of selective cytokines, probably IL-6.¹⁴  

Prevention

Analogous to other common, complex disorders, progress in prevention will require incorporating multipronged risk reduction strategies that are based on sound scientific discovery, as well as on effective translation into clinical care. Prevention needs to include newly focused and adequately funded research, incorporating new technologies and recognition that genetic, environmental, social, and behavioral factors interact in complex pathogeneses and multiple pathways leading to preterm birth.¹⁰  

The March of Dimes Scientific Advisory Committee advocated targeting six major overlapping categories for prevention of preterm birth:

1. Epidemiology
2. Genetics
3. Disparities
4. Inflammation
5. Biologic stress
6. Clinical trials

By the time a woman has missed her period, major opportunities to improve pregnancy outcome have already been lost. Like preventing heart disease, having a good pregnancy outcome requires planning. Yet half of all pregnancies overall and more than 70% of pregnancies in women under the age of 20 years are unintended. Preconception health benefits that are often missed in these women include:¹⁵  

• Daily consumption of folic acid
• Achieving optimal weight and fitness
• Ensuring immunizations are up-to-date
• Optimal management of chronic conditions (e.g., asthma, diabetes, depression)
• Treating infections (e.g., sexually transmitted diseases, urinary tract infections, periodontal disease)
• Managing stress
• Education on exposure avoidance and teratogens
• Genetic counseling and testing

Many interventions aimed at preventing prematurity have a greater impact on maternal and fetal health and may be safer when enacted prior to conception, such as weight reduction, substance abuse treatment, or changing therapies for chronic conditions.

Management¹⁶  

• Tocolytic therapy including oxytocin antagonist (atosiban), beta-mimetics (terbutaline, ritodrine); magnesium sulfate; calcium channel blockers; non-steroidal anti-inflammatory drugs (indomethacin, ketorolac)
• Antibiotics (for group B streptococcal prophylaxis only)
• Antenatal corticosteroid use (betamethasone, dexamethasone)

Note:Bed rest, hydration, and pelvic rest were considered but not routinely recommended. Repeated and maintenance tocolytic therapies were also considered, but not recommended as a general practice.

Major recommendations

The major recommendations from ACOG are as follows:¹⁶  

• The following recommendations are based on good and consistent scientific evidence (Level A):
• There are no clear “first-line” tocolytic drugs to manage preterm labor. Clinical circumstances and physician preferences should dictate treatment.
• Antibiotics do not appear to prolong gestation and should be reserved for group B streptococcal prophylaxis in patients in whom delivery is imminent.
• Neither maintenance treatment with tocolytic drugs nor repeated acute tocolysis improve perinatal outcome; neither should be undertaken as a general practice.
• Tocolytic drugs may prolong pregnancy for 2 to 7 days, which may allow for administration of steroids to improve fetal lung maturity and the consideration of maternal transport to a tertiary care facility.
• The following recommendations are based on limited or inconsistent scientific evidence (Level B):
• Cervical ultrasound examination and fetal fibronectin testing have good negative predictive value; thus, either approach or both combined may be helpful in determining which patients do not need tocolysis.
• Amniocentesis may be used in women in preterm labor to assess fetal lung maturity and intra-amniotic infection.
• Bed rest, hydration, and pelvic rest do not appear to improve the rate of preterm birth and should not be routinely recommended.

The grades of evidence (I-III) and levels of recommendations (A-C) are defined in box 3.

Progesterone and preterm birth

Possible mechanism of action of progesteron in preventing preterm labor

The best-studied immunomodulator at the maternal-fetal interface is progesterone, which clearly has a role in survival of the fetal allograft. Numerous experiments have demonstrated that progesterone blocks mitogenstimulated lymphocyte proliferation, improves allograft survival time, modulates antibody production, decreases the oxidative burst of monocytes, reduces the production of proinflammatory cytokines by macrophages in response to bacterial products and alters cytokine secretion of T-cell clones to favor IL-10 production. The mechanism by which progesterone exerts its immunomodulatory actions in reproductive tissues is unclear but may involve both direct and indirect actions on immune cells.¹¹  

One-third of preterm birth is linked to premature rupture of the fetal membranes, resulting from weakening of the membranes by apoptosis (programmed cell death). Norwitz and his Yale colleagues have shown that progesterone can prevent apoptosis in fetal membranes in an artificial environment in the laboratory. They stimulated healthy fetal membranes with pro-inflammatory mediators to prove this.  ¹⁷  

Recent studies support the hypothesis that progesterone supplementation reduces preterm birth in a select group of women (i.e., those with a prior spontaneous birth at <37 weeks of gestation). The American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin. When progesterone is used, it is important to restrict its use to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation.¹⁸  

Cetingoz E et al¹⁹   did a randomized, double blind, placebo-controlled study in 150 high-risk pregnancies to evaluate whether the prophylactic administration of vaginal progesterone would reduce the preterm birth rate in high-risk population including singleton and twin pregnancies

Risk groups included:

• Prior spontaneous preterm birth
• Twin pregnancy
• Uterine malformation

Micronized progesterone or placebo (100 mg) was administered daily by vaginal suppository between 24 and 34 weeks of gestation. They compared progesterone and placebo groups for incidence of preterm labor and preterm delivery.

Data were compared by chi-square analysis and Fisher exact test. The results were as follows (Figure 8):

• There was a statistically significant difference in the rate of preterm labor between placebo and progesterone groups (45.7 vs. 25%, respectively; p < 0.05).
• More women delivered before 37 weeks in placebo group (57.2%) than in progesterone group (40%; p < 0.05).
• Administering progesterone also reduced the preterm birth before 34 weeks of gestation. The difference between placebo and progesterone group was statistically significant (24.3 vs. 8.8%; p < 0.05).
• However, there was no significant difference in neonatal death between placebo and progesterone groups.

Thus they concluded that prophylactic vaginal progesterone reduced the rate of preterm labor and preterm delivery in high-risk pregnancies.

Use of micronized progesterone in preterm birth prevention

Rai P et al²⁰   evaluated the effect of oral micronized progesterone to prevent preterm birth in a randomized, double-blind, placebo-controlled trial of 150 women with at least one preterm birth who received 100 mg of oral micronized progesterone or placebo twice a day from recruitment (18-24 weeks) until 36 weeks or delivery. The results were as follows (Figure 9 and10):

• preterm birth occurred in 29 (39.2%) women in the treatment group (n=74) compared with 44 (59.5%) in the control group (n=74, P=0.002).
• Mean gestational age at delivery was higher in the treatment group (36.1 vs 34.0 weeks, P<0.001).
• Fewer preterm births occurred between 28 and 31 weeks plus 6 days in the treatment group (RR 0.20; 95% CI, 0.05-0.73, P<0.001).
• Neonatal age at delivery (34 vs 32 weeks, P<0.001), birth weight (2400 vs 1890 g, P<0.001), NICU stay
  (>24 h, P<0.001), and Apgar scores (P<0.001) were more favorable in the treatment group, and fewer neonatal deaths occurred (3 vs 7, P=0.190).

Thus they concluded that oral micronized progesterone reduced the risk of preterm birth between 28 and 31 weeks plus 6 days, NICU admissions, and neonatal morbidity and mortality in high risk patients.

References

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