Preterm Labor

Etiology

The following are etiologies that may contribute to preterm labor: stress, infection, placental abruption, placenta previa, substance use, history of preterm birth or abortion, inadequate prenatal care, smoking, maternal age <18 or >40, poor nutrition, low body mass index, fetal anomaly, fetal growth restriction, oligohydramnios, polyhydramnios, vaginal bleeding, premature preterm rupture of membranes (PPROM), and environmental factors. This list is not comprehensive, and various other factors contribute to preterm labor. However, it encompasses the most common reasons patients present in clinical settings.[2]

It is important to familiarize oneself with PPROM as it affects about 3% of all pregnancies in the United States. Membrane rupture can be physiologic or pathologic. The intra-amniotic infection has been most commonly associated with PPROM, especially at earlier gestational ages. Other causes contributing to PPROM include short cervical length, second and third trimester bleeding, low BMI, low socioeconomic status, cigarettes, and illicit drug use. Typically, about half of mothers with PPROM deliver within a week of ROM.

The main concern with PPROM is prematurity. The most common complication of preterm birth is respiratory distress. However, one must consider sepsis, intraventricular hemorrhage, and necrotizing enterocolitis. PPROM with intrauterine inflammation can lead to neurodevelopmental impairment, and early gestational age at membrane rupture has an association with an increased risk of neonatal white matter damage. Infection and umbilical cord accidents contribute to 1-2% risk of antenatal fetal demise after preterm PROM.

Epidemiology

In 2005, the WHO illustrated that preterm births accounted for about 9.5% of births worldwide. That equates to almost 13 million births. In the United States, the number hovers around 11.4% as of 2013. The rate peaked at 12.8% in 2006 due to increased pregnancy dating by ultrasound, increased use of assisted reproductive technology, and showed preterm labor induction. Since then, it has declined with better fertility practices now in place. The rates of preterm labor vary across the different states in the United States. African Americans have almost twice the rate of preterm labor compared to other racial/ethnic groups.[3]

Pathophysiology

Three main components contribute to labor: cervical changes, persistent uterine contractions, and activation of the decidua and membranes. The difference between labor at term and preterm is that the former occurs via a normal physiologic process and the latter is pathological. Some processes are acute, and some can take several weeks leading up to preterm labor.

One of the key events to occur in preterm labor that is pathological is the fetal inflammatory response syndrome (FIRS) which involves systemic inflammation and elevation of fetal plasma interleukin-6, typically in response to a trigger such as chorioamnionitis.[4] A signal is sent by the fetal hypothalamus leading to secretion of CRH, stimulating the release of ACTH and therefore cortisol production by the fetal adrenal glands, which triggers the parturition pathway to activate. An influx of inflammatory cells into the cervical stroma leads to the release of cytokines and prostaglandins which stimulate cervical ripening. These changes influence the structures of the collagen and glycosaminoglycans that make up cervical tissue. Estrogen stimulates collagen degradation whereas progesterone inhibits it. Therefore, progesterone is used to prevent or delay ripening. Both hormones are implicated in regulating the gap-junction formation and the upregulation of connexin 43 proteins which contribute to parturition.

Additionally, contractions are an integral contributor to labor. The change from uncoordinated myometrial contractions to coordinated uterine contractions is attributed to neural control. Oxytocin plays an essential role in the circadian rhythm of these contractions.

The degradation of the extracellular matrix is assessed by fetal fibronectin detection in cervicovaginal secretions and is also part of the parturition process. When detected between 22 and 37 weeks gestational age, it indicates the disruption of the decidual-chorionic interface and increased risk of preterm labor. Evidence implicates apoptosis as a critical factor leading in the above process.

History and Physical

As mentioned above, preterm labor is diagnosed primarily by history, symptoms, and physical exam. Pertinent history regarding past and present obstetrical complications can be informative. If an early gestational age ultrasound is not available, fetal biometry should be performed. Maternal vital signs, fetal heart rate, assessment of uterine contractions, frequency, duration, and intensity are very important in the assessment of a patient in labor 

A physical exam is done to assess firmness, abdominal tenderness, fetal size, and position. The cervical exam can identify asymptomatic cervical dilatation and effacement. Symptoms of preterm labor include regular contractions before term gestational age associated with cervical change, pelvic pressure, menstrual like cramps, watery vaginal discharge, and lower back pain. Although lower back pain is present in normal pregnancy as well, if occurring before term, it has an established association with impending preterm labor.

If cervical dilatation is noted to be at least 2 or 3 cm at less than 34 weeks, then the patient is highly likely to deliver preterm. Another indicator is short cervix as assessed by transvaginal ultrasound. Normal cervical length is 35-48 mm. The definition of a short cervix is cervical length <25mm at 16-24 weeks of gestation. Of note, a transvaginal ultrasound can help to distinguish cervical effacement due to cervical insufficiency versus due to active labor.[5]

Evaluation

If PPROM is suspected, diagnosis involves a speculum examination to visualize amniotic fluid passing from the cervical canal and pooling in the vagina. Fern and pH testing of the pooled vaginal secretions can indicate rupture of membranes. The PH of amniotic fluid is 7.1 to 7.3.

Fetal fibronectin gets released as a result of the breakdown of the cervical extracellular matrix is also an indicator of preterm labor though, it is a specific but not a sensitive test. If the result is negative, it is strongly indicative of an intact membrane, but if positive, it does not necessarily indicate premature rupture of membranes.

Finally, laboratory evaluation can assist in eliciting the etiology of preterm labor and guide management. These include a rectovaginal group B streptococcal culture. If not performed within the previous 5 weeks, then antibiotic prophylaxis would be required. A urine culture, since asymptomatic bacteriuria has associations with an increased risk of preterm labor and birth. In patients with substance abuse, a urine drug screen would be beneficial as there is a link between cocaine use and placental abruption. Fetal fibronectin testing is necessary for women <34 weeks gestation, cervical dilation of <3 cm and with a cervical length of 20-30mm on transvaginal ultrasound. Testing for sexually transmitted infections as they can contribute to preterm labor etiology.

Treatment / Management

Management is implemented based on the gestational age at which the mother presents to the hospital. At >34 weeks, if the mother presents with preterm labor, she is admitted. After observation for 4-6 hours, if she does not have progressive cervical dilation and effacement, fetal well-being is noted on a reactive non-stress test, and complications in pregnancy have been excluded, she can be sent home with instructions for follow-up in 1-2 weeks and return if there are additional signs and symptoms of preterm labor or other pregnancy concerns.

Mothers presenting at <34 weeks with signs and symptoms of preterm labor are hospitalized. In preterm labor with intact membranes, tocolytic drugs for up to 48 hours are used to inhibit labor.[6](A1)

Guidelines for tocolytic drugs: typically, tocolytics are a consideration between 22 and 34 weeks of gestational age and only when there are no contraindications.

The classes of these drugs include:

• Calcium channel blockers – Nifedipine is preferred as it has fewer side effects than other drugs
• Beta adrenergics– most commonly used beta-2 agonist is terbutaline
• COX inhibitors – indomethacin is safest if given no longer than the recommended 48 hours due to the risk of PDA closure
• Nitric oxide donors.
• Weaker tocolytic drugs
  • Atosiban (oxytocin-vasopressin receptor antagonist) – not available in the United States
  • Magnesium sulfate – of note, this is one of the most commonly used drugs in preterm labor. Mothers on this medication should have monitoring for the following: Deep tendon reflexes, vital signs, magnesium levels, urine output, and respiratory depression
  • Glyceryl trinitrate

Contraindications to tocolytic drug use include preeclampsia with severe features, intrauterine fetal demise, lethal fetal anomaly, chorioamnionitis, hemorrhage, and significant maternal cardiac disease.[1]

Once the membranes have ruptured, pregnancy cannot typically be prolonged enough for further intrauterine growth and maturation. However, appropriate therapy should reduce neonatal morbidity and mortality; this includes the following:

• Transferring the mother to a hospital with advanced obstetric and neonatal capabilities for care
• Administering appropriate antibiotics in labor to prevent GBS
• Antenatal administration of steroids to the mother to reduce morbidity and mortality of the fetus secondary to respiratory distress
• Intraventricular hemorrhage
• Necrotizing enterocolitis
• PDA
• Administration of magnesium sulfate in preterm labor before 32 weeks for neuroprotection

If contractions occur despite adequate tocolytic therapy, then the clinician must reassess the patient for amniotic infection, fetal compromise, possible abruption, and question whether the cervix is still changing.

In some instances, preterm labor induction may necessary. These instances can include intra-amniotic infection, fetal growth restriction, oligohydramnios, placental abruption, elevated blood pressures secondary to preeclampsia/eclampsia. In these cases, the fetus is monitored similarly as term fetuses, i.e., via fetal heart tracings. Monitoring has shown to reduce intrapartum death and neonatal seizures. Additionally, the neonatal care team should be informed of the status of the patient to ensure appropriate personnel and equipment are available if required.

It would be worth mentioning that after birth, delayed cord clamping (DCC) has been deemed advantageous for preterm infants. DCC has associations with higher initial hematocrits, high diastolic blood pressures, higher circulating blood volume, and a lower rate of resuscitation.

Differential Diagnosis

• Abruptio placentae

• Fetal growth restriction

• Multifetal pregnancy 

• Preeclampsia

• Premature rupture of membranes

• Preterm labour

Complications

Maternal Complications

Preterm labor has been associated with an increased risk for cardiovascular mortality and morbidity, typically years after the delivery due to unclear reasons.

Infant Complications

Preterm labor and delivery are associated with the impaired neurodevelopmental outcome which includes impaired cognitive abilities, motor deficits, cerebral palsy, and vision and hearing losses. These risks increase with decreasing gestational age. Behavioral issues such as anxiety, depression, autism spectrum disorders, and ADHD also associate to preterm labor.

Neonatal Complications

These include necrotizing enterocolitis, intraventricular hemorrhage, bronchopulmonary dysplasia, retinopathy of immaturity, weak growth, and the presence of congenital anomalies.

With improved obstetric and neonatal care, the rate of complications in preterm births has decreased. With patient-specific education and follow up, the long-term sequelae and disability have improved.