Preterm Labor

INTRODUCTION

Preterm labor is the presence of contractions of sufficient strength and frequency to effect progressive effacement and dilation of the cervix between 20 and 37 weeks gestation. Preterm birth occurs in 6-8% of pregnancies; preterm labor with intact membranes accounts for 30-40% of preterm births. Preterm birth accounts for 70% of neonatal morbidity, mortality, and health care dollars spent on the neonate. Unfortunately, despite this impact and the massive use of material, manpower, and money, incidence of preterm birth has remained stable for more than 25 years. To be successful in reducing the incidence of preterm birth, a much better understanding of the causes and mechanisms of preterm birth is needed.

Goals of management

RISK OF PRETERM LABOR

Preterm labor has been associated with many factors, including infection (bacterial vaginosis [BV], sexually transmitted diseases [STDs], urinary tract infections, chorioamnionitis), uterine distention (multiple gestation, polyhydramnios), uterine distortion (müllerian duct abnormalities, fibroid uterus), compromised structural support of the cervix (incompetent cervix, previous cone biopsy or loop electrosurgical excision procedure [LEEP]), abruptio placentae, and uteroplacental insufficiency (eg, hypertension, insulin-dependent diabetes, drug abuse, smoking, alcohol).

Preterm labor and birth are associated with stressful life situations (eg, domestic violence, close family death, insecurity over food, home, or partner) either indirectly by associated risk behaviors or directly by mechanisms not completely understood. Many of these risk factors present together, such as chlamydia endocervicitis and third trimester bleeding.

Recently, the role of the fetus in the initiation of labor has been recognized. In a simplistic sense, the fetus recognizes a hostile intrauterine environment and precipitates labor. Future tocolytic therapy may be directed at modifying fetal response.

Preconceptual evaluation

The risk for preterm birth in nulliparous patients is hard to determine. In multiparous women, past behavior is the best predictor of future behavior. Women who are seeking birth control have a 30% chance of being pregnant in the next 2 years. The presence of the following risk factors should be addressed prior to pregnancy.

Cervical trauma

Trauma is a major cause for midtrimester loss and preterm birth. The most common etiologies for cervical injury are elective abortion, surgeries to treat cervical dysplasia, and injury occurring at delivery. A single uncomplicated elective abortion at less than 10 weeks does not appear to increase the risk of midtrimester loss or preterm birth. If the cervix has been forced to greater than 10 mm at the time of the abortion, then the risk increases. Gentle cervical dilatation, at the time of abortion, with laminaria or ripening agents such as misoprostol are significantly less likely to traumatize the cervix than is a term delivery. Patients with a history of multiple first trimester elective terminations or one or more second trimester elective abortions are considered at higher risk.

Cervical dysplasia needs to be treated appropriately whenever diagnosed. However, incidence of preterm birth and cervical incompetence are increased 200-300% after preconceptual surgical treatment (eg, cold knife cone, cryoconization, laser cone, Loop Electrosurgical Excision Procedure) of cervical intra-epithelial neoplasia. The risk appears to be proportional to the amount of tissue removed. The ease of performing LEEP for relatively minor abnormalities has led to more cervical injury than was observed with the relatively few cases of classic cone biopsy.

Obstetric trauma is an often underestimated risk for midtrimester loss or preterm birth. While women may relate a history of cervical lacerations, often they are unaware of the injury. Obstetricians may misread the records of the previous delivery by not scrutinizing the reports to such detail. The obstetrician must rely on visual inspection of the cervix, serial examination, or ultrasonic measurements. Scars that extend into greater than 50% of the visual cervix suggest a patient at high risk for midtrimester loss.

Unfortunately, many women with midtrimester loss have no easily explainable etiology. Multiple factors working in concert probably explain a large proportion. A history of any second trimester loss places the patient at risk for recurrence.

Obtain a detailed description of surgical procedures on the cervix. The description includes the indication, location, depth, and volume of the specimen. Educate the patient concerning the potential pregnancy complications. In pregnant women, the evaluation of cervical integrity relies on visual examination of the cervix at the first prenatal visit and the measurement of cervical length in high-risk women. Cervical length should be measured by ultrasound in the second trimester (15-17 weeks).

Genital tract infection

The young gynecology patient who has been diagnosed with gonorrhea, chlamydia, or trichomoniasis has an approximate 25% risk of reinfection in the following 12 months. All of these organisms are associated with preterm birth if present during pregnancy. BV has been associated with a 50% increase in preterm birth. BV tends to be a recurrent infection, and 25% of successfully treated patients have recurrent BV by 12 weeks after therapy. A Gram stain score greater than 6 or the presence of 3 of 4 diagnostic signs (homogenous grey/white discharge, greater than 20% clue cells on saline wet smear, positive whiff test, and a vaginal pH greater than 4.5) diagnoses BV.

Obtain an assessment of high-risk behaviors at each visit. Test for gonorrhea culture (GC), chlamydia, trichomonas, syphilis, and BV at initial visit and at 34-36 weeks. Patients who report high-risk behavior may need testing more frequently. Treat positive tests per Centers for Disease Control (CDC) guidelines with test-of-cure sampling and treatment if necessary. Hepatitis B vaccine (during pregnancy) is recommended for anyone with a history of STD or high-risk behavior. This includes human papilloma virus infection (CIN). Additionally, the vaccine is recommended for women who report relationships with men that are not mutually monogamous, history of recent drug abuse, recent separation or divorce, or patients younger than 20 years who are pregnant.

Preterm labor/birth history

High-risk pregnancy history includes losses suggestive of incompetent cervix or deliveries less than 37 weeks or 2500 g. Of all the predictors of preterm birth, past obstetric history remains one of the strongest predictors of recurrent preterm birth. Given a baseline risk of 8%, the risk of recurrent preterm birth after 1, 2, and 3 consecutive preterm births is 15%, 30%, and 45%, respectively. Preconceptual counseling affects incidence of preterm birth by encouraging patients to make informed decisions concerning future pregnancy. Often, the best time to counsel the patient is at her 4-6 week postpartum check after a preterm delivery.

Midtrimester loss

At the initial visit, review history of each midtrimester loss in order to distinguish incompetent cervix from other causes (eg, abruption, infection, intrauterine death, ruptured membranes). Review pathology or autopsy reports.

Parental karyotypes should not be obtained unless more than 1 midtrimester loss or a midtrimester loss where the fetus was structurally or genetically abnormal occurred.

Specific laboratory tests, rapid plasma reagent (RPR) test, gonorrhea/chlamydia (GC/CT) screen, vaginal pH/wet smear/whiff test, anticardiolipin antibody, lupus anticoagulant antibody, partial thromboplastin time (PTT), and a 1-hour glucose challenge test should evaluate each of the above etiologies. Order TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, herpes simplex), immunoglobulin G (IgG), and immunoglobulin M (IgM) screening upon indication, not as a routine screen for this population.

A random drug screen is not standard of care unless other supporting high-risk behavior exists. A preconceptual hysterosalpingogram is recommended with the history of 2 or more midtrimester losses. Some obstetricians have used the test of being able to pass, with ease, a number 8 Hegar dilator into the nonpregnant cervix as a sign of cervical incompetence. Perform a transvaginal ultrasound for cervical length at 13-17 weeks. Abnormal findings include a length less than 2.5 cm or funneling greater than 5 mm.

MANAGEMENT OF ACTIVE PRETERM LABOR: BASELINE INFORMATION

The ability of tocolytics to prevent preterm birth or reduce neonatal mortality/morbidity has not been proven. The best outcome is a delay of delivery for 48 hours for the maximum benefit of glucocorticoids on the fetal lungs. Most tocolytics are able to attain this goal when membranes are intact. However in some studies the effectiveness of tocolytics barely has out performed bedrest and hydration, both of which have fewer side effects than tocolytics. Preterm labor often is difficult to diagnose, and considerable potential exists for overtreatment of uterine irritability. Tocolytic agents, while generally safe in appropriate dosages and with monitoring, are potentially lethal medications and only should be used after considered judgment. One must always keep in mind that the intrauterine environment may be more hostile to the fetus than the risks of the extrauterine environment.

The decision to use tocolytics must recognize the potential benefit for the fetus. Neonatal morbidity and mortality is very sensitive to gestational age (GA). Prior to 23 weeks, the neonate has essentially no chance of survival, and less chance of survival without significant medical complications. The risk of neonatal mortality and morbidity is so low after 34 completed weeks that tocolytics are not recommended in gestations greater than 34 weeks. Between 24 and 33 weeks, the neonate has much more potential for benefit. Table 1 describes survival, major short-term morbidity, and intact long-term survival by gestational age.

Table 1: Neonatal Morbidity and Mortality by Gestational Age

Progressive advantages seem to exist at the specific gestational ages of 25, 28, 32, 34, and 37 weeks. An obstetrician will be more aggressive to stop labor at less than 32 weeks than after 32 weeks.

Diagnosis

Contractions of sufficient strength and frequency to affect progressive effacement and dilation of the cervix: If the diagnosis is suspected, obtain a vaginal fetal fibronectin sample before the pelvic cervical examination. If after the pelvic examination preterm labor obviously is present, the specimen can be discarded. If a question of the etiology for the contractions exists, the specimen is sent.

Criteria that allow the consideration of tocolytic therapy include contractions greater than 6 per hour plus documented cervical change (preferably by the same observer). Cervical change is defined as a cervix that is either less than 2.5 cm in length by ultrasound measurement, greater than 80% effaced by digital examination, or cervical dilation greater than 1 cm. If contractions are present without cervical change, management options include continued observation for cervical change for a total of 23 hours or therapeutic sleep (morphine sulphate 15 mg SQ). If fetal fibronectin is negative, the patient may be sent home with appropriate follow-up.

Assessment and management prior to tocolytic therapy

Review dating criteria: Dates are determined by the first day of the last menstrual period (LMP) and confirmed by one or more of the following: a positive pregnancy test (home or clinic) prior to the expected date of the second missed period; consistent uterine size at less than 12 weeks; electronically amplified fetal heart tones noted at 9-12 weeks; or a consistent ultrasound estimated gestational age (EGA) (first trimester within 1 week, second trimester within 2 weeks, and third trimester within 3 weeks). When LMP is not clear, the gestational age is determined by the results of the first ultrasound (preferably performed at <24 wk). Preferably, the first ultrasound EGA would be confirmed by a consistent ultrasound performed at a 3- to 4-week interval. Tocolytics are recommended for preterm labor between 22 and 34 weeks in an appropriately selected population.

Document fetal well-being: The presence of fetal anomalies requires more discrimination when initiating tocolytics. A maternal-fetal medicine specialist should first give consent to the use of tocolytics in the presence of fetal anomalies. Tocolytics are not indicated in patients with either symptomatic or asymptomatic intrauterine infection. Use tocolytics cautiously and under the recommendation of a maternal-fetal medicine specialist when evidence of a hostile intrauterine environment is evident, such as fetal growth restriction, oligohydramnios, nonreactive nonstress test, positive contraction stress test, absent or reversed diastolic flow on doppler examination of umbilical blood flow, repetitive variable decelerations, or vaginal bleeding. Nonstress test; amniotic fluid index; estimated fetal weight; fetal anatomy scan to rule out lethal abnormalities; placental position or abnormality (abruption, grade); and cervical length at less than 31 weeks are recommended prior to the initiation of tocolytics.

Evaluate for the presence of genital tract infection

Tocolytics are contraindicated in the presence of symptomatic upper genital tract infection. The definition of intra-amniotic infection (chorioamnionitis) includes a temperature greater than 38.0蚓 (100.0?F), plus 2 of the 5 following signs: WBC greater than 15,000, maternal tachycardia greater than 100 beats per minute (BPM), fetal tachycardia greater than 160 BPM, tender uterus, and foul-smelling discharge. In situations where the diagnosis is not clear, an amniocentesis for fluid culture (aerobic/anaerobic bacteria), Gram stain (bacteria is present if Gram stain is positive or if WBC count is >50 cells/mm³), glucose (positive if <15 mg%), or leukocyte esterase may be indicated. Amniocentesis may result in a false positive fetal fibronectin test. Tocolytics are not indicated in the presence of any positive test on amniotic fluid.

All patients with preterm labor need documentation of the presence or absence of lower genital tract infection. The following tests are recommended prior to the initiation of antibiotics and/or tocolytics: sterile speculum examination for ruptured membranes; endocervical sampling for GC and chlamydia; vaginal fluid pH; wet smear for BV and trichomonas; potassium hydroxide (KOH) smear for yeast and whiff test; Gram stain of the upper lateral vaginal wall for BV score; GBS culture from the lower one third of vagina and anus (same swab) selective GBS media (Todd-Hewitt or Lim broth) is recommended for optimal isolation rates; and urine analysis and culture on a specimen obtained by catheter. Positive results are treated with appropriate antibiotics.

Assess for medical contraindications to tocolysis

Use tocolysis with considerable caution in patients with cardiac disease that require medication, history of congestive heart failure, history of cardiac surgery, significant pulmonary disease, renal failure, or maternal infection (pneumonia, appendicitis, pyelonephritis). Obtain a maternal-fetal medicine consult prior to the initiation of tocolytics in these cases.

Contraindications to the specific tocolytics are indomethacin (aspirin-induced asthma, coagulopathy, significant liver disease); magnesium sulphate (use of calcium channel blockers, gentamicin, myasthenia gravis, neuromuscular disorders); and beta mimetics such as ritodrine and terbutaline (cardiac arrhythmia, valvular disease, ischemic heart disease). Beta mimetic tocolytics are relatively contraindicated in diabetes. No tocolytic agent should be used in the presence of known allergy to that agent.

Fetal therapy

Prophylactic glucorticoids: Prophylactic steroids are the standard of care when the threat of delivery of a fetus at 24-34 weeks gestation in the absence of clinical infection is present. Delivery must be delayed a minimum of 12 hours in order to observe the benefits of antenatal steroids. The benefits are proven to last 7 days. Betamethasone 12.5 mg every 24 hours for 2 doses or dexamethasone 6 mg every 6 hours for 4 doses is recommended. Special circumstances include the following:

• In the presence of insulin-dependent, insulin independent (adult-onset), or gestational diabetes, the provider must be prepared for aggressive control of blood sugars (including intravenous insulin drip) to maintain a blood sugar between 70-110 mg%.

  　

• In the event of abnormal biophysical parameters (nonreactive nonstress test or positive contraction stress test, biophysical profile >8 of 10, absent or reversed diastolic flow on doppler evaluation of the umbilical blood flow, or oligohydramnios), the use of prophylactic steroids requires a considered decision. Prophylactic steroids should not delay the delivery of an acutely distressed fetus.

  　

• Patients with advanced labor or with contractions plus cervical dilation greater than 6 cm will not benefit from prophylactic steroids.

The benefit of repeated weekly courses of prophylactic steroids has not been proven, and there is retrospective data that fetal growth is slowed after 3 courses of steroids. Recommended treatment is to repeat a course of steroids only in recurrent threatened preterm birth and longer than 1 week after previous dose of steroids. Other authors specifically feel retreatment has no support in the literature.

Group B streptococci prophylaxis

All patients in preterm labor are considered at high risk for neonatal GBS sepsis and should receive prophylactic antibiotics against GBS regardless of culture status.

Agents include penicillin G (5 million units IV, then 2.5 million units IV q4h), ampicillin (2 g IV q6h), or clindamycin for patients who are allergic to penicillin (600 mg IV q6h).

MANAGEMENT OF ACUTE PRETERM LABOR : TOCOLYTIC AGENTS

The most common agents used in academic centers are magnesium sulphate and indomethacin. In the past, beta-mimetic agents, such as subcutaneous terbutaline or ritodrine, were used commonly. These agents are equally efficacious in delaying delivery at least 48 hours. While clinicians have much more experience with magnesium sulphate, it is associated with more maternal toxicity than indomethacin. On the other hand, indomethacin may have more fetal and neonatal toxicity. Calcium channel blockers, such as nifedipine, have also been used for treatment of preterm labor, but are not considered standard of care.

Retrospective studies, where neonates were exposed to magnesium and indomethacin either sequentially or concurrently, have suggested a higher incidence of intraventricular hemorrhage and necrotizing enterocolitis. These studies likely selected a population to be at higher risk for the serious outcomes in the dually treated group as opposed to the population that was treated only with magnesium sulfate.

In addition, a transient closure of the fetal ductus arteriosus and decreased urinary output in the mother and fetus appear to occur. When the duration of therapy is less than 72 hours, adverse sequelae from either finding do not appear to occur.

Indomethacin may be a better first-line tocolytic in early preterm labor (<32 wk) or preterm labor associated with polyhydramnios. More inflammatory response in the membranes and decidua is observed at gestational ages less than 30 weeks than at 30-36 weeks. Indomethacin reduces prostaglandin synthesis from decidual macrophages. The renal effects of indomethacin may be beneficial to reduce polyhydramnios.

Beta mimetics (eg, ritodrine, terbutaline) have been used for many years with good success at delaying delivery for 48 hours. Unfortunately, the maternal cardiac and metabolic risks of beta-mimetic therapy are greater than either magnesium sulphate or indomethacin. Currently, beta mimetics are considered a second-line tocolytic.

Management with specific agents

Magnesium sulphate

Baseline labs include CBS and serum creatinine. Baseline observations include urine output greater than 30 cc/hour, vital signs, mentation, cranial nerve examination, deep tendon reflexes, and auscultation of lung fields. Dose is 4-6 g IV over 20 minutes followed with a maintenance dose of 1-4 g/hour.

Follow-up: Monitor mentation, visual symptoms, deep tendon reflexes (DTRs), cardiac rhythm, and auscultation of lung fields every 4 hours for toxicity. Monitor urine output to maintain at greater than 50 cc/hour. This requires a Foley catheter. Limit IV intake to less than 125 cc/hour. Oral intake is at the discretion of the provider. Total intake is limited to greater than 2000 mL/day. Intake and output are recorded. Serum magnesium levels may be obtained 1 hour after the loading dose and then every 6 hours. The dose of IV magnesium sulfate is titrated to maintain a serum level between 4-8 mg/dL.

Length of magnesium sulfate therapy: The primary therapeutic goal is to prevent preterm delivery within 48 hours from the initiation of steroid prophylaxis. Little evidence exists that the majority of patients benefit from extended magnesium sulfate therapy. Discontinue magnesium sulphate therapy after 48 hours in most patients. When the gestational age is less than 27 weeks, a gain of 3-4 days may reduce neonatal morbidity and mortality as to justify continuous therapy. Obtain a maternal-fetal medicine consult if magnesium sulfate is continued longer than 72 hours. No evidence exists that oral beta mimetics, subcutaneous terbutaline pump, or oral magnesium compounds are effective in delaying preterm birth. Follow-up oral tocolysis is not recommended.

Acute magnesium sulphate toxicity: If a mild overdose and good urine output occur, the magnesium sulphate is discontinued, and the serum magnesium and DTRs are followed back to the normal range. If the symptoms are life threatening, administer 1 g of calcium gluconate slow IV push.

Indomethacin

MANAGEMENT OF ACUTE PRETERM LABOR: FOLLOW-UP

If the patient has had true preterm labor, this episode becomes a powerful risk factor for recurrent preterm birth, in addition to other risk factors she may have had prior to the current episode. The prior risk factor may have been modified; for example, infection may have been identified and treated or behavioral risk factors have been modified. Little evidence exists that oral beta-mimetic, sub-cutaneous beta-mimetics, or oral magnesium gluconate reduce the incidence of recurrent preterm birth.

Biweekly contact, face-to-face or by telephone, with the same knowledgeable nurse or physician is as effective as home uterine activity monitoring (HAUM) or pharmacological therapy. Direct contact with the patient is supplemented by education and phone access to a knowledgeable consistent provider 24 hours a day 7 days a week. There are some unique situations in which HAUM is still felt to be beneficial, including patients who are paraplegic and unable to appreciate any muscular contractions.

The goal of follow-up therapy is to maximally reduce recurrence risk and speed the access to subspecialty care if preterm labor should recur.

Inpatient

If the labor has been arrested, a gradual return to limited activity is planned. If the patient tolerates mild ambulation, discharge can be considered. The decision to discharge the patient is determined by cervical dilation less than 4 cm, fetal presentation (cephalic), number of fetuses (singleton), gestational age (>27 wk), access to the hospital (within 20 min), social support at home (transportation at all times, telephone), the ability to maintain limited activity and pelvic rest, and good patient compliance (early prenatal care, none or few missed prenatal visits). If the patient was referred to a subspecialty care facility, the local obstetrician and pediatrician should be comfortable with home management. If labor should recur, they may have to care for a rapidly delivering premature infant.

The patient should receive documented education regarding the signs and symptoms of preterm labor. The critical signs include contractions greater than 4 per hour, rhythmic back or thigh pain, increasing pelvic pressure, unusual discharge, vaginal spotting/bleeding, or rupture of membranes, tenesmus, and urgency.

Outpatient

The provider should have weekly contact with the patient, and the patient needs a specific individual to contact at any time to answer questions. The contact may be phone calls and office visits. If genital tract infection may have played a role in the preterm labor, repeat a screen 2-4 weeks after discharge.