GOAL OF MANAGEMENT :
Goals of management include (1) early assessment of risk for preterm birth, (2) diagnosis of preterm labor, (3) identifying the etiology of preterm labor, (4) documenting fetal well-being, (5) providing prophylactic fetal therapy, (6) making a thoughtful choice to initiate tocolytic therapy, and (7) establishing a plan of surveillance and patient/provider education for at-risk patients and after the initial therapy.
MANAGEMENT OF ACTIVE PRETERM LABOR :
Tocolytics have not been proven efficacious to help prevent preterm birth or reduce neonatal mortality or morbidity. The best outcome is a delay of delivery for 48 hours to allow the maximum benefit of glucocorticoids to take effect on the fetal lungs. Most tocolytics are able to effect this goal when membranes are intact. However, in some studies, the effectiveness of tocolytics is only slightly better than bedrest and hydration, both of which have fewer adverse effects compared to tocolytics. Preterm labor is often 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 should only be used after thoughtful consideration. Always keep in mind that the intrauterine environment may be more hostile to the fetus than the extrauterine environment.
The decision to use tocolytics must take into account the potential benefit for the fetus. Neonatal morbidity and mortality are greatly affected by gestational age. Prior to 23 weeks' gestation, the neonate has essentially no chance of survival and even less chance of survival in the presence of significant medical complications. The risk of neonatal mortality and morbidity is so low after 34 completed weeks of gestation that tocolytics are not recommended in gestations greater than 34 weeks. Between 24 and 33 weeks' gestation, the neonate has a much better chance of benefiting from tocolytics.
DIAGNOSIS:
Contractions of sufficient strength and frequency to effect progressive effacement and dilation of the cervix are indicative of active preterm labor. If the diagnosis is suggested, obtain a vaginal fetal fibronectin sample before the pelvic cervical examination. If preterm labor obviously is present after the pelvic examination, the specimen can be discarded. If the etiology for the contractions is in question, the specimen is analyzed.
Criteria that indicate consideration of tocolytic therapy include more than 6 contractions per hour plus documented evidence of cervical change (preferably by the same observer). Cervical change is defined as a cervix that is less than 2.5 cm in length based on ultrasound measurement, greater than 80% effaced based on digital examination findings, 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 the results of the fetal fibronectin analysis are negative, the patient may be sent home, with appropriate follow-up evaluation.
ASSESSMENT AND MANAGEMENT PRIOR TO TOCOLYTIC THERAPY :
Review the 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 result from a pregnancy test (home or clinic) prior to the expected date of the second missed period
Consistent uterine size at less than 12 weeks' gestation
Electronically amplified fetal heart tones noted at 9-12 weeks' gestation
A consistent ultrasound-based estimation of gestational age (ie, first trimester within 1 wk, second trimester within 2 wk, and third trimester within 3 wk)
When the date of the 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-based estimation of gestation age is confirmed by consistent results from ultrasounds performed at 3- to 4-week intervals. Tocolytics are recommended for preterm labor between 22 and 34 weeks' gestation 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 present, such as the following:
Fetal growth restriction
Oligohydramnios
Nonreactive nonstress test results
Positive contraction stress test results
Absent or reversed diastolic flow upon Doppler examination of umbilical blood flow
Repetitive variable decelerations
Vaginal bleeding
A nonstress test, amniotic fluid index, estimation of fetal weight, fetal anatomy scan to rule out lethal abnormalities or placental position or abnormality (eg, abruption, grade), and measurement of cervical length at less than 31 weeks' gestation 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 (eg, chorioamnionitis) includes a temperature greater than 38.0Β°C (100.0Β°F) plus 2 of the 5 following signs:
WBC count greater than 15,000 cells/mm3
Maternal tachycardia greater than 100 beats per minute (bpm)
Fetal tachycardia greater than 160 bpm
Tender uterus
Foul-smelling discharge
In situations in which the diagnosis is not clear, an amniocentesis for fluid culture (aerobic/anaerobic bacteria), Gram stain (bacteria present if Gram stain is positive or if WBC count is >50 cells/mm3), glucose level (positive if <15 mg/dL), or leukocyte esterase evaluation may be indicated. Amniocentesis may result in a false-positive fetal fibronectin test result. Tocolytics are not indicated in the presence of any positive test result involving 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 gonorrhea and chlamydia
Vaginal fluid pH
Wet smear for BV and trichomonal infection
Potassium hydroxide smear for yeast and whiff test
Gram stain of the upper lateral vaginal wall for BV score
GBS culture from the lower third of the vagina and anus (same swab) selective for GBS media (ie, Todd-Hewitt or Lim broth) - Recommended for optimal isolation rates
Urinalysis 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 who require medication or have a history of congestive heart failure, cardiac surgery, significant pulmonary disease, renal failure, or maternal infection (eg, pneumonia, appendicitis, pyelonephritis). In these cases, consult with a maternal-fetal medicine specialist prior to the initiation of tocolytics.
Contraindications to the specific tocolytics are aspirin-induced asthma, coagulopathy, and significant liver disease (indomethacin); use of calcium channel blockers or gentamicin, myasthenia gravis, and neuromuscular disorders (magnesium sulphate); and cardiac arrhythmia, valvular disease, and ischemic heart disease (beta-mimetics, eg, ritodrine and terbutaline). Beta-mimetic tocolytics are relatively contraindicated in patients with diabetes. No tocolytic agent should be used in the presence of known allergy to that agent.
FETAL THERAPY :
Prophylactic steroids (glucocorticoids) are the standard of care when the threat of delivery of a fetus at 24-34 weeks' gestation is present in the absence of clinical infection. 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 at 12.5 mg every 24 hours for 2 doses or dexamethasone at 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 IV insulin drip) to maintain a blood sugar level of 70-110 mg/dL.
In the event of abnormal biophysical parameters (ie, nonreactive nonstress test result or positive contraction stress test result, 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 thoughtful 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 do not benefit from prophylactic steroids.
The benefit of repeated weekly courses of prophylactic steroids has not been proven, and retrospective data indicate 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 a previous dose of steroids. Other authors specifically believe that re-treatment 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 U IV, then 2.5 million U IV q4h), ampicillin (2 g IV q6h), or clindamycin for patients who are allergic to penicillin (600 mg IV q6h).
Initiate prophylactic antibiotics at diagnosis of preterm labor with cervical change, and continue administration until delivery or for 72 hours. Re-treat patients with recurrent preterm labor or term labor regardless of culture results.
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 for 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 be associated with more fetal and neonatal toxicity. Calcium channel blockers, such as nifedipine, have also been used for treatment of preterm labor, but these are not considered the standard of care.
Results from retrospective studies in which 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, 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. A more significant inflammatory response in the membranes and decidua is observed at gestational ages less than 30 weeks compared to 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 those associated with either magnesium sulphate or indomethacin. Currently, beta-mimetics are considered a second-line tocolytic.
Management with specific agents
Magnesium sulphate
Baseline labs include CBC count and serum creatinine level. Baseline observations include urine output greater than 30 mL/h, vital signs, mentation, cranial nerve examination, deep tendon reflexes (DTRs), and auscultation of lung fields. The dose is 4-6 g IV over 20 minutes, followed with a maintenance dose of 1-4 g/h.
Follow-up includes monitoring mentation, visual symptoms, DTRs, and cardiac rhythm and auscultation of lung fields every 4 hours for toxicity. Monitor urine output to maintain at greater than 50 mL/h. This requires Foley catheter placement. Limit intravenous intake to less than 125 mL/h. Oral intake is at the discretion of the provider. Total intake is limited to greater than 2000 mL/d. 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 intravenous magnesium sulfate is titrated to maintain a serum level of 4-8 mg/dL.
Regarding the duration of magnesium sulfate therapy, the primary therapeutic goal is to prevent preterm delivery within 48 hours from the initiation of steroid prophylaxis. Little evidence suggests that most 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 such that continuous therapy is justified. Consult a maternal-fetal medicine specialist if magnesium sulfate is continued for more than 72 hours. No evidence suggests that oral beta-mimetics, subcutaneous terbutaline pump, or oral magnesium compounds are effective in delaying preterm birth. Follow-up oral tocolysis is not recommended.
Regarding acute magnesium sulphate toxicity, if a mild overdose and good urine output occur, the magnesium sulphate is discontinued and the serum magnesium level and DTRs are monitored until they return to normal. If the symptoms are life threatening, administer 1 g of calcium gluconate by slow intravenous push.
Indomethacin
Baseline labs include CBC count and liver function tests (LFTs). Baseline observations include urine output, temperature, and amniotic fluid index (AFI). The dose is 100 mg PR followed by 50 mg PO every 6 hours for 8 doses. Follow-up includes AFI determination at 24 hours, LFTs at 24 hours, and urine output measurement. The duration of indomethacin therapy should be limited to 48 hours.
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 may have been modified. Little evidence indicates that oral beta-mimetic, subcutaneous 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 h/d 7 d/wk. Some unique situations exist 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 the following:
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
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 manage the rapid delivery of 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, 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 via phone calls and office visits. Genital tract infection may have played a role in the preterm labor; therefore, repeat a screen 2-4 weeks after discharge.
If tocolysis is unsuccessful, the patient and family need education concerning the etiology and risk of recurrence. Few etiologies exist for which prediction of subsequent preterm delivery in future pregnancies is 100% accurate. Time should be spent at the postpartum visit reviewing the patient's clinical history, laboratory data, and pathology reports. Preconceptual counseling may also be critical in the decision of the patient to get pregnant and in managing her pregnancy once a pregnancy has been identified.