Preterm Birth: Definitions and Risk Factors

• Preterm delivery is defined as delivery before 37 weeks of gestation, occurring in 5-9% of pregnancies in developed countries.
• Preterm delivery accounts for 75-80% of all neonatal deaths and significant neonatal morbidity.
• The cost associated with preterm birth in the US was at least $26.2 billion.
• In 2015, preterm delivery rates were 9.0% for non-Hispanic whites, 13.8% for non-Hispanic blacks, and 9.5% for Hispanics.
• Late preterm is defined as 34 0/7 to 36 6/7 weeks gestation.
• Early preterm is defined as less than 34 completed weeks of gestation.
• 15 million infants are born preterm worldwide yearly.
• Over 60% of preterm births occur in Africa and South Asia, with Malawi having the highest rate at 18.1 per 100 live births.
• The global neonatal mortality rate is 19 per 1000 live births.
• A preterm infant is born between 20 0/7 weeks and 36 6/7 weeks after the last menstrual period.
• ACOG defines peri-viable birth as birth between 20 weeks and 25 6/7 weeks gestation.
• Low birth weight (LBW) doesn't necessarily mean a neonate was born preterm; they may be small for gestational age (SGA).
• LBW is defined as a neonate weighing less than 2500g at birth.
• Very low birth weight (VLBW) is less than 1500g, and extremely low birth weight (ELBW) is less than 1000g.

Classification of Deliveries Based on Gestational Age

• Extremely preterm: Less than 28 weeks
• Very preterm: 28 0/7 to 31 6/7 weeks
• Moderate preterm: 32 0/7 to 33 6/7 weeks
• Late preterm: 34 0/7 to 36 6/7 weeks
• Early term: 37 0/7 to 38 6/7 weeks
• Full term: 39 0/7 to 40 6/7 weeks
• Late term: 41 0/7 to 41 6/7 weeks
• Post term: 42 0/7 weeks and beyond
• Neonatal survival increases with birth weight and gestational age.
• Male infants have a higher mortality rate than female infants after controlling for gestational age and weight.
• There has been significant improvement in preterm infant survival rates over the past 3 decades, especially for those with birth weights between 501 and 1250 grams.
• The survival rate is approximately 94% for infants born at 28 weeks gestation.
• Infants born at 22-24 weeks gestation have the greatest risk for poor outcomes.

Neonatal Mortality by Gestational Age

• 22 weeks: 93% deaths
• 23 weeks: 68% deaths
• 24 weeks: 38% deaths
• 25 weeks: 23% deaths
• 26 weeks: 15% deaths
• 27 weeks: 10% deaths
• 28 weeks: 8% deaths
• Neonatal survival was 9% at 22 weeks, 33% at 23 weeks, 65% at 24 weeks, 81% at 25 weeks, and 87% at 26 weeks gestation.
• Most women received antenatal corticosteroids, and most neonates received exogenous surfactant.
• Delaying delivery by even one week at this time in gestation leads to significantly better outcomes and reduced costs.
• Approximately 84% of preterm births occur between 32 0/7 and 36 6/7 weeks gestation.
• Morbidity is a relatively greater concern than mortality in the 32 0/7 and 36 6/7 weeks gestation age range.
• Individuals born between 34-37 weeks gestation had lower scores on neurocognitive performance tests in late adulthood compared to those born after 37 weeks gestation.
• As gestational age increases, most morbidity decreases in frequency.
• High-grade (III or IV) intraventricular hemorrhage incidence diminishes rapidly after 27 weeks gestation and is rare after 32 weeks gestation.

Outcomes for Extremely Preterm Infants (22-24 weeks gestation)

• Maternal corticosteroid administration: 64%
• Maternal antibiotic administration: 66%
• Cesarean Delivery: 38%
• Male gender: 52%
• Multiple birth: 27%
• Surfactant therapy after birth: 66%
• Death before discharge: 64%
• Survival without neurodevelopmental impairment: 20%
• Survival without neurosensory impairment: 29%
• Significant risk factors for preterm labor include a history of preterm delivery, non-Hispanic black race, and multiple gestation.
• Normal parturition involves increased uterine contractility, cervical ripening, and membrane/decidual activation; the fetus also plays a role.
• Approximately 25% of preterm deliveries result from preterm premature rupture of membranes (PPROM).
• Approximately 45% of preterm deliveries result from spontaneous preterm labor.
• Approximately 30% of preterm deliveries result from maternal or fetal indications for early delivery.
• Preterm labor is a syndrome with multiple causes influenced by various factors.
• Infection is thought to be present in up to 40% of preterm deliveries.
• Subclinical infection may precipitate preterm labor in women with no apparent risk factors, which can increase rates of neurologic injury.
• Multiple gestation accounts for 21.6% of all preterm births.
• The twinning rate rose 76% from 1980 to 2009 (18.9 to 33.2 per 1000).
• Multifetal pregnancy rates have recently started to decline.
• The twin birth rate peaked at 33.9 twins per 1000 births in 2014 and decreased to 33.4 in 2016.
• The triplet and higher-order multiple birth rate has fallen 48% since the 1998 peak (193.5) to a rate of 101.4 multiples per 100,000 births in 2016.
• ART contributed to 1.7% of all infants born in the United States and 17.0% of all multiple-birth infants in 2015.
• The risk for preterm birth is elevated even for singleton pregnancies conceived by ART.
• Placenta previa, gestational diabetes, pre-eclampsia, and neonatal intensive care unit admission were also more prevalent in the ART group.

Factors Associated with Spontaneous Preterm Labor - Demographic & Medical Characteristics

• Non-Caucasian race
• Extremes of age (less than 17 or greater than 35)
• Low socioeconomic status
• Low pre-pregnancy body mass index
• History of preterm delivery
• Periodontal disease
• Abnormal uterine anatomy
• Trauma
• Abdominal surgery during pregnancy

Factors Associated with Spontaneous Preterm Labor - Behavioral Factors

• Tobacco use
• Substance abuse

Factors Associated with Spontaneous Preterm Labor - Obstetric Factors

• Previous preterm birth
• Vaginal bleeding
• Infection (systemic, genital tract, periodontal)
• Short cervical length
• Multiple gestation
• Assisted reproductive technologies
• Preterm premature rupture of membranes
• Polyhydramnios
• Preventing spontaneous preterm birth would be easier by intervening prophylactically or treating preterm labor once it occurs.
• Accurate prediction of which asymptomatic patients will have spontaneous preterm delivery is required for prophylactic treatment.
• Short cervical length, assessed by transvaginal ultrasonography, is associated with a greater risk for preterm delivery.
• A history of cervical surgery has been thought to be a risk factor for preterm birth because of associated cervical injury.
• Few interventions have been shown to reduce the incidence of preterm labor and delivery.
• Prophylactic cervical cerclage in the early second trimester has been performed to prevent preterm birth in women with a history of mid-trimester pregnancy loss; evidence supporting efficacy is weak.
• Evidence does NOT support the administration of prophylactic antibiotics in asymptomatic women at risk for preterm labor.
• Evidence does not support the prophylactic use of beta-adrenergic receptor agonists to prevent preterm labor in high-risk women.
• Progesterone therapy may be effective in reducing the rate of preterm birth in some patient populations, especially women with a sonographically identified short cervix and twin pregnancies.
• Determining whether a woman is in early preterm labor or in false labor is often difficult.
• Criteria for diagnosing preterm labor include gestational age between 20 0/7 and 36 6/7 weeks and regular uterine contractions, accompanied by a change in cervical dilation, effacement, or both, or initial presentation with regular contractions and cervical dilation of 2 cm or more.
• Less than 10% of women with a clinical diagnosis of preterm labor give birth within 7 days of presentation.
• Initial assessment of possible preterm labor includes physical examination and external monitoring of contractions and fetal heart rate.
• Acute conditions associated with preterm labor, including infection and placental abruption, should be considered.
• Preterm uterine contractions will cease spontaneously in many women.
• Once preterm labor is diagnosed, the obstetric care provider must decide whether intervention is warranted.
• Administering antenatal corticosteroids for fetal lung maturation and magnesium sulfate for fetal neuroprotection improves neonatal outcomes.
• Acute tocolytic therapy is widely used before 34 weeks gestation but remains controversial.
• Tocolysis is currently recommended between 24 and 34 weeks gestation.
• There is no consistent evidence that acute tocolysis reduces the chance of preterm birth or improves neonatal outcomes.
• Acute tocolysis may prolong pregnancy for about 48 hours.
• This can facilitate transfer to a tertiary care facility and allow for maternal administration of corticosteroids and antibiotics to prevent neonatal group B streptococcal infection.
• ACOG supports acute tocolysis to allow for a complete course of antenatal corticosteroids but discourages continued use after corticosteroid administration is complete.
• Criteria for tocolytic therapy use include gestational age after viability (23 weeks) and before 34 weeks gestation, reassuring fetal status, and no overt clinical signs of infection.

Contraindications to Tocolytic Therapy for Preterm Labor

• Fetal death
• Fetal anomalies incompatible with life
• Non-reassuring fetal status
• Chorioamnionitis
• Severe hemorrhage
• Corticosteroid administration before preterm delivery has demonstrated neonatal benefit.
• Antenatal corticosteroid treatment significantly reduces the incidence of neonatal respiratory distress syndrome, intraventricular hemorrhage, and neonatal death.
• The reduction in neonatal morbidity and mortality from corticosteroid administration is additive to that seen with neonatal surfactant alone.
• A single course of corticosteroids administered to women at risk for preterm birth after 34 weeks but before 37 weeks gestation resulted in a significantly lower incidence of severe neonatal respiratory morbidity.

Antenatal Corticosteroid Therapy

• Betamethasone: 12 mg IM every 24 hours x 2 doses
• Dexamethasone: 6 mg IM every 12 hours x 4 doses
• Prophylactic antibiotic therapy in the management of preterm labor in patients with intact membranes is unsupported and may not reduce the likelihood of preterm birth.
• There was an increase in cerebral palsy in children born to mothers in preterm labor with intact membranes who received any prophylactic antibiotics versus no antibiotics.
• ACOG does NOT recommend empirical antibiotic therapy in this population.
• Prophylactic antibiotic administration remains appropriate in women who are positive for group B streptococcus (GBS) and who are thought to be in preterm labor.
• With PPROM, antimicrobial therapy prolongs pregnancy and reduces both maternal and neonatal morbidity; ACOG recommends a 7-day course.
• Maternal administration of magnesium sulfate provides fetal neuroprotection when given to women at risk for preterm delivery.
• ACOG states that magnesium sulfate reduces the risk of cerebral palsy in surviving infants when given before anticipated early preterm birth.
• Physicians should develop guidelines based on larger trials for magnesium sulfate administration for neuroprotection.
• Prophylactic cervical cerclage is typically performed when the cervix is closed.
• A rescue cerclage is a procedure to prolong gestation in women with cervical dilation and/or prolapsed membranes.
• The efficacy and safety of rescue cerclage remains controversial.

Contraindications to Rescue Cerclage

• Established preterm labor with impending preterm birth
• Chorioamnionitis
• Heavy vaginal bleeding
• Preterm PROM
• Fetal demise
• Major fetal anomalies
• Fetal death
• Prolapsing membranes need to be replaced in the uterine cavity to reduce the risk for iatrogenic preterm PROM when placing the cerclage.
• Purse-string sutures are placed around the circumference of the cervix.
• Improved outcomes were reported in the cerclage group, including prolongation of gestation by 4 weeks and reductions in the rates of neonatal intensive care unit admission and neonatal death.
• Cerclage removal does not routinely precipitate the labor process.
• It is recommended to proceed with removal at 36 to 37 weeks gestation when vaginal delivery is planned.
• It is permissible to defer cerclage removal until delivery in cases of planned cesarean delivery.
• Management of preterm labor should not be influenced by the presence of a cerclage; if the patient demonstrates cervical change, painful contractions, or vaginal bleeding, the cerclage should be removed.
• Given current evidence, it is reasonable to either remove or retain the cerclage after diagnosis of preterm PROM.
• If cerclage is retained, women should receive 7 days of antibiotic prophylaxis.
• Cerclage removal is usually a straightforward procedure using a speculum and scissors to transect the suture.
• Elective removal of a cerclage in an office setting is appropriate in most cases.
• Occasionally, neuraxial anesthesia may be required to facilitate cervical dissection and cerclage removal if the stitch becomes embedded within the cervical mucosa.

Tocolytic agents

• There are four classes of tocolytic agents currently in use: (1) beta-adrenergic receptor agonists, (2) calcium entry-blocking agents, (3) magnesium sulfate, and (4) nonsteroidal anti-inflammatory drugs.
• Magnesium sulfate is not efficacious and should not be used for tocolysis.

Tocolytic Drugs for Preterm Labor

Calcium Entry-Blocking Agents

• Contraindications: Cardiac disease, Renal disease, Maternal hypotension
• Maternal Side Effects: Transient hypotension, flushing, headache, dizziness, nausea
• Fetal Side Effects: None identified.

Cyclooxygenase Inhibitors (NSAIDs)

• Contraindications: Significant renal/hepatic impairment, Active PUD, Coagulation disorders, Thrombocytopenia, NSAID-sensitive Asthma, Other NSAID sensitivities
• Maternal Side Effects: Nausea, Heartburn
• Fetal Side Effects: Constriction of the ductus arteriosus, Pulmonary hypertension, Reversible renal dysfunction, Intraventricular hemorrhage, Hyperbilirubinemia, Necrotizing enterocolitis

Beta-Adrenergic Receptor Agonists

• Contraindications: Cardiac dysrhythmias, Poorly controlled thyroid disease, Poorly controlled diabetes mellitus
• Maternal Side Effects: Dysrhythmias, pulmonary edema, myocardial ischemia, hypotension, tachycardia, Hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, altered thyroid function, Palpitations, tremors, nervousness, nausea/vomiting, fever, hallucinations
• Fetal Side Effects: Fetal = tachycardia, hyperinsulinemia, hyperglycemia, myocardial and septal hypertrophy, myocardial ischemia. Neonatal = tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, intraventricular hemorrhage.

Magnesium Sulfate

• Contraindications: Myasthenia Gravis, Myotonic Dystrophy
• Maternal Side Effects: Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest
• Fetal Side Effects: Lethargy, hypotonia, respiratory depression, demineralization
• Myometrial smooth muscle consists of thick (myosin) and thin (actin) filaments.
• Electrical activity is spread by gap junctions between myometrial cells.
• A rise in intracellular calcium concentration leads to contractions; calcium binds to calmodulin, activating myosin light-chain kinase (MLCK).
• Phosphorylation allows actin to bind to myosin, activating myosin adenosine triphosphatase.
• Adenosine triphosphatase (ATP) is hydrolyzed, resulting in muscle shortening or contraction.
• Increases in intracellular cyclic adenosine monophosphate (cAMP) cause muscle relaxation by decreasing MLCK activity and reducing intracellular calcium concentration.
• Before labor, the uterus is in a state of functional quiescence due to inhibitors.
• Before term, the uterus goes through an activation phase with greater expression of contraction-associated proteins, activation of ion channels, and an increase in connexin-43 concentration. -Its levels increase during gestation, accumulate in the third trimester, and peak at labor onset.
• Human parturition may be triggered by a functional progesterone withdrawal.
• Parturition may also be related to changes in inflammation linked to functional progesterone withdrawal.
• Acute tocolytic therapy offers only limited benefits and does not reduce the rate of preterm birth.
• The probability of delaying delivery by 48 hours was highest with prostaglandin synthesis inhibitors, followed by magnesium sulfate, calcium entry-blocking agents, beta-adrenergic agonists, and the oxytocin receptor blocker, atosiban.
• No class of tocolytic was significantly superior to placebo in reducing neonatal respiratory distress syndrome.
• Calcium entry-blocking agents (nifedipine) have benefits over beta-adrenergic receptor agonists for prolonging pregnancy, serious neonatal morbidity, and maternal adverse effects.
• Beta-adrenergic receptor agonists (ritodrine, terbutaline) are used less than other tocolytic agents due to side effects.
• The FDA issued a warning in 2011 that injectable terbutaline should not be used in pregnant women for prolonged treatment of preterm labor due to the potential for marked maternal cardiac problems and death.
• Oral terbutaline should not be used for prevention or treatment of preterm labor because it was not effective and was associated with similar safety concerns.
• Prostaglandins increase intracellular calcium concentrations, increase activation of MLCK, and promote gap junction formation.
• Prolonged use of the non-selective cyclooxygenase inhibitor indomethacin can lead to constriction of the ductus arteriosus and oligohydramnios.
• The oxytocin receptor antagonist atosiban was not approved by the FDA due to a higher rate of fetal death in an RCT.
• Magnesium sulfate is ineffective in delaying or preventing preterm birth and may be associated with an increased risk for total fetal, neonatal, or infant mortality.
• The nitric oxide donor nitroglycerin does not result in significantly later gestational age at delivery or better neonatal outcomes.
• ACOG states that evidence supports the use of tocolytic treatment with beta-adrenergic receptor agonist therapy, calcium entry-blocking agents, or NSAIDs for short-term prolongation of pregnancy (up to 48 hours) to allow for antenatal maternal corticosteroid administration.
• Prolonged use of tocolytic agents does not alter outcomes.
• The risk for side effects appears to increase when more than one tocolytic agent is administered simultaneously.
• The preterm fetus has lower hemoglobin concentration and oxygen-carrying capacity than a term fetus.

Preterm infants

• Preterm infants are at risk for complications, including:
  • Respiratory distress syndrome
  • Hyperbilirubinemia
  • Necrotizing enterocolitis
  • Intraventricular hemorrhage
  • Perinatal infection
  • Retinopathy of prematurity
  • Patent ductus arteriosus
  • Pulmonary hypertension
  • Water and electrolyte imbalances
  • Acid-base disturbances
  • Anemia
  • Hypoglycemia
• Long term, preterm infants also are more likely to experience adverse outcomes:
  • Bronchopulmonary dysplasia
  • Reactive airway disease
  • Failure to thrive
  • Cerebral palsy
  • Neurodevelopmental delay
  • Hearing loss
  • Blindness
  • Pulmonary hypertension
  • Adult hypertension
  • Impaired glucose metabolism

Method of Delivery

• There is controversy regarding the best mode of delivery for very preterm infants, especially less than 26 weeks gestation.
• Preterm birth at any gestational age is NOT considered a contraindication for trial of labor.
• A systematic review found no difference in outcomes between elective with selective cesarean delivery for preterm infants.
• Preterm cesarean delivery may increase maternal risk in subsequent pregnancies.
• Obstetricians must decide whether to recommend cesarean delivery for fetal indications, such as non-reassuring fetal heart status or breech presentation.
• Antenatal corticosteroids, advanced neonatal ventilation techniques, neonatal surfactant therapy, and ECMO have reduced mortality and morbidity for preterm neonates.
• Survival is not typically possible below a certain gestational age (less than 22 0/7 to 23 0/7 weeks).
• The chance of survival and survival without long-term major adverse outcomes remains low and difficult to predict.
• Parents, obstetricians, and neonatologists should be involved in the decision-making process regarding resuscitation.
• Withholding and/or discontinuation of life-sustaining treatment are considered ethically equivalent, and withdrawal of support is considered reasonable when the possibility of functional survival is highly unlikely.
• Resuscitation is generally not indicated in cases of very early gestation (less than 22 to 23 weeks), extremely low birth weight (less than 400 grams), and life-limiting anomalies.
• Resuscitation is nearly always indicated in conditions associated with a high survival rate and acceptable morbidity, generally including infants with a gestational age of 25 weeks or above.
• Anesthesia providers often participate in the care of women with preterm delivery.
• Women who deliver preterm may request neuraxial analgesia for labor and vaginal delivery or require cesarean delivery with urgent administration of anesthesia.
• The preterm fetus is more vulnerable than the term fetus to the depressant effects of analgesic and anesthetic drugs:
  • Less protein available for drug binding.
  • Higher levels of bilirubin.
  • Greater drug access to the CNS because of the presence of an incomplete BBB.
  • Decreased ability to metabolize and excrete drugs.
  • A higher incidence of acidosis during labor and delivery.
• Neuraxial labor analgesia decreases maternal concentrations of catecholamines, ameliorates cycles of maternal hypoventilation and hyperventilation, and may thereby improve uteroplacental perfusion as long as hypotension is avoided.
• Thus, in some cases, it may be appropriate to establish neuraxial analgesia even before it is clear that a preterm delivery will soon occur.
• An advantage of early initiation of neuraxial analgesia is rapidly converting labor analgesia to surgical anesthesia if emergency cesarean delivery should be necessary. Administration of general anesthesia for preterm cesarean delivery is similar to that for parturients at term.
• Most anesthetic agents used for induction and maintenance of general anesthesia cross the placenta.
• If cesarean delivery is necessary, it is preferable to administer either epidural or spinal anesthesia to avoid the depressant effects of agents given for general anesthesia.
• Preterm infants exposed to epidural anesthesia for cesarean delivery had higher 1- and 5-minute APGAR scores than similar infants exposed to general anesthesia.
• Animal studies suggest that exposure of the immature brain to anesthetic agents can trigger significant brain cell apoptosis and cause functional learning deficits in later life.
• At the current time, there is minimal evidence to support altering the anesthetic technique for cesarean delivery merely because the infant is preterm.
• Cerclage placement requires a T10 level of surgical anesthesia.
• Shorter-acting spinal anesthetics may accelerate recovery and discharge for those going home.
• Cerclage removal does not usually require anesthesia, but surgical anesthesia may be necessary if the stitch is embedded under the cervical mucosa.
• Obstetric venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality.
• Antepartum hospitalization and prolonged immobility increase the risk for VTE.
• Pharmacologic VTE prophylaxis is recommended for prolonged antepartum admissions.
• Pregnant women will present for neuraxial analgesia or anesthesia in the context of pharmacologic anticoagulation with the wider adoption of VTE guidelines.

In Summary

• Despite improved antenatal care, the incidence of preterm delivery in the US remains approximately 10%.
• Preterm birth is a leading cause of neonatal mortality, and survivors have an increased chance of disability.
• Spontaneous preterm labor or preterm premature rupture of membranes accounts for the majority of preterm births.
• Treatment with tocolytic therapy may prolong labor by up to 48 hours and thereby facilitate the transfer of the patient, maternal administration of a corticosteroid to accelerate fetal lung maturity, and maternal administration of magnesium for fetal neuroprotection.
• Long-term tocolytic therapy does not improve neonatal outcomes.
• Nifedipine and Indomethacin are used commonly to treat preterm labor in the United States; oxytocin receptor antagonists are used in Europe. Magnesium sulfate is not an effective tocolytic but is considered beneficial when used specifically for neuroprotection in reducing rates of cerebral palsy in preterm infants.
• Terbutaline is associated with a high incidence of maternal and fetal side effects.
• Cyclooxygenase inhibitors reversibly inhibit cyclooxygenase, resulting in a transient effect on platelet function.
• However, their use does not necessitate the assessment of platelet or coagulation function before administration of neuraxial analgesia/anesthesia.