Preterm birth refers to the delivery that occurs after 28 weeks but before 37 weeks of gestation, and neonates born during this period are called preterm infants. In some countries, the lower gestational age limit for preterm birth is defined as 24 or even 20 weeks of gestation. The organs of preterm infants are underdeveloped, and the earlier the gestational age at birth and the lower the birth weight, the poorer the prognosis. Preterm birth accounts for over one-third of neonatal deaths and remains the leading cause of death among children under the age of five worldwide.
The incidence of preterm birth is approximately 5%–10%. Advances in the care and monitoring of preterm infants have significantly improved survival rates and reduced rates of disability.
Classification and Etiology
Classification
Based on etiology, preterm birth can be classified as spontaneous preterm birth (sPTB) and indicated preterm birth.
- Spontaneous preterm birth refers to preterm labor or preterm premature rupture of membranes (PPROM) resulting in preterm delivery before 37 weeks of gestation.
- Indicated preterm birth arises from medical or fetal conditions that preclude continuation of pregnancy, leading to induction of labor or cesarean delivery before 37 weeks.
Based on gestational age at delivery, preterm birth can be further classified as early preterm birth and late preterm birth.
- Early preterm birth occurs between 28 and less than 34 weeks of gestation.
- Late preterm birth occurs between 34 and less than 37 weeks of gestation.
Etiology
Preterm birth has a multifactorial etiology with mechanisms that remain incompletely understood. Common risk factors include a history of prior spontaneous preterm birth or mid-trimester pregnancy loss, extremes of maternal age, low body mass index, short interpregnancy interval, multiple pregnancies, uterine abnormalities, vaginal bleeding, pregnancy complications, and comorbidities. Possible mechanisms include infection, decidual hemorrhage, immune tolerance disruption between the mother and fetus, uterine overdistension, maternal-fetal stress, and genetic factors.
Prediction
Preterm birth is a multifactorial syndrome, and no definitive or highly effective predictive method exists. Clinically, cervical length measurement is often used, sometimes combined with risk factors or biochemical markers for risk stratification.
High-Risk Factors
High-risk factors include:
- Maternal Factors: Extremes of maternal age, low body weight, short interpregnancy intervals (<18 months), smoking, and psychological factors.
- Obstetric History: History of mid-trimester pregnancy loss or prior preterm birth.
- Uterine and Cervical Anatomy: Congenital reproductive tract anomalies, history of uterine dilation and curettage, cervical surgery or trauma, cervical shortening, or cervical insufficiency.
- Current Pregnancy Factors: Conception through assisted reproductive technology, multiple pregnancies, antepartum hemorrhage, infections, fetal or amniotic fluid abnormalities, and pregnancy-related complications or comorbidities.
Cervical Length
The standard method for cervical length (CL) measurement involves transvaginal ultrasound after bladder emptying. A cervical length ≤25 mm measured before 24 weeks of gestation is defined as a short cervix, indicating an increased risk of preterm birth. Cervical lengths <15 mm and >30 mm have greater positive and negative predictive value, respectively, for preterm birth.
Biochemical Markers
Common markers include fetal fibronectin (fFN), phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1), and placental alpha-microglobulin-1 (PAMG-1). Among these, fFN is widely used in clinical practice, primarily to enhance the accuracy of preterm birth prediction when combined with cervical length. fFN has particularly high negative predictive value.
Clinical Manifestations and Diagnosis
The primary clinical manifestation of preterm birth is uterine contractions. Initially, these contractions are irregular and may be accompanied by mild vaginal bleeding or blood-tinged discharge. Over time, they may progress to regular contractions, similar to the initiation of term labor. Clinically, preterm birth can be divided into two stages: threatened preterm labor and preterm labor.
- Threatened preterm labor refers to regular uterine contractions (≥4 contractions in 20 minutes) accompanied by progressive cervical shortening.
- Preterm labor is defined as regular contractions (≥4 contractions in 20 minutes) with both progressive cervical shortening and cervical dilation ≥2 cm.
Diagnosing preterm birth is usually straightforward. However, it is important to distinguish it from physiological uterine contractions in late pregnancy (Braxton Hicks contractions). Physiological contractions are typically irregular, painless, and not associated with cervical shortening or dilation; this is sometimes referred to as false preterm labor.
Treatment
The principles of treatment prioritize maternal and fetal safety. For cases with intact membranes, expectant management is conducted until 34 weeks of gestation, while premature rupture of membranes is handled according to the guidelines for preterm premature rupture of membranes. The main therapeutic interventions include suppression of uterine contractions, promotion of fetal lung maturation, fetal neuroprotection, prevention and treatment of intrauterine infection when necessary, timely intrauterine transfer, and appropriate cessation of preterm labor treatment.
General Management
General management involves providing adequate rest, maintaining a healthy diet, offering psychological support, and strengthening maternal-fetal monitoring with dynamic assessments.
Suppression of Uterine Contractions
For patients with threatened preterm labor, controlling uterine contractions may help prolong gestation. For patients in preterm labor, tocolytics cannot prevent preterm delivery but may provide time for interventions such as promoting fetal lung maturation and intrauterine transfer. Common tocolytic agents include the following:
Calcium Channel Blockers
Drugs such as nifedipine selectively reduce the inward flow of calcium ions through slow channels, interfere with intracellular calcium levels, and inhibit uterine contractions. Nifedipine is administered orally with an initial dose of 20 mg, followed by adjustments of 10–20 mg per dose every 6–8 hours based on contraction patterns. Monitoring of the maternal heart rate and blood pressure during treatment is required.
Prostaglandin Synthetase Inhibitors
These drugs inhibit prostaglandin synthesis and release, suppressing uterine contractions. Given their ability to cross the placenta, prolonged use or high doses may cause premature closure of the fetal ductus arteriosus, pulmonary hypertension, fetal renal impairment, reduced amniotic fluid, and oligohydramnios as severe side effects. Therefore, they should be used only for short durations before 32 weeks of gestation. Indomethacin is commonly used, with an initial rectal dose of 50–100 mg or oral administration, followed by 25 mg every 6 hours for 48–72 hours. Close monitoring of amniotic fluid volume and fetal ductus arteriosus blood flow is necessary during treatment.
Beta-Adrenergic Agonists
These are beta-2 receptor agonists on uterine smooth muscle cell membranes that activate intracellular adenylate cyclase, enhance cyclic AMP synthesis, reduce intracellular calcium levels, and suppress uterine muscle contractility. Although effective in inhibiting contractions, their receptor selectivity is low, leading to side effects such as increased maternal and fetal heart rates, elevated myocardial oxygen demand, hyperglycemia, water and sodium retention, hypokalemia, and, in severe cases, pulmonary edema and heart failure, which may be life-threatening. Caution or avoidance is advised for patients with heart disease, hypertension, uncontrolled diabetes, severe preeclampsia, significant antepartum hemorrhage, or multiple pregnancies. Ritodrine is a commonly used beta agonist by intravenous infusion starting at 50–100 µg/min, increasing by 50 µg/min every 10 minutes up to a maximum of 350 µg/min or until uterine contractions cease, for up to 48 hours. Continuous monitoring of maternal complaints, heart rate, and fluid balance is conducted, with intravenous fluids limited to 2,000 ml/day to prevent pulmonary edema. If the heart rate exceeds 120 bpm, infusion rate adjustments or discontinuation is required; heart rates exceeding 140 bpm or the presence of chest pain necessitate discontinuation. Prolonged use requires monitoring of blood potassium, glucose levels, liver function, and echocardiography.
Oxytocin Receptor Antagonists
Atosiban competes for oxytocin receptors on uterine smooth muscle cells, thereby inhibiting oxytocin-induced contractions. The regimen includes an initial intravenous bolus of 6.75 mg, followed by an infusion at 18 mg/h for 3 hours, and then a maintenance dose of 6 mg/h for 45 hours. This medication has mild side effects and no definite contraindications.
Promotion of Fetal Lung Maturation
In cases where the gestational age is less than 34 weeks and delivery is likely within one week, glucocorticoids are used to promote fetal lung maturity. For gestational ages between 34 and 36 weeks, the decision to use glucocorticoids is based on patient and family preferences following informed consent. The options include intramuscular injection of 6 mg dexamethasone every 12 hours for a total of 4 doses, or 12 mg betamethasone every 24 hours for a total of 2 doses. If more than 1–2 weeks pass after treatment and preterm delivery remains probable at less than 34 weeks of gestation, a repeat course may be administered.
Fetal Neuroprotection
The administration of magnesium sulfate before delivery reduces the risk and severity of cerebral palsy in preterm neonates. Its routine use is recommended for pregnancies at risk of preterm birth before 34 weeks. The regimen includes an intravenous loading dose of 4 g over 20–30 minutes, followed by a maintenance dose of 1 g/hour for 24 hours or until delivery. If labor does not progress after 24 hours, treatment may be discontinued; it may be resumed once labor begins. High-concentration magnesium ions directly act on uterine smooth muscle cells to counteract the effects of calcium ions on contraction, providing additional uterine tocolysis when used for less than 48 hours.
Infection Monitoring
Infection serves as a major underlying etiology of preterm birth. Screening and prevention of infection, particularly group B streptococcus (GBS), remain key components of management.
Time to Cessation of Preterm Birth Treatment
Treatment is discontinued under the following conditions:
- Progressive uterine contractions that remain uncontrolled despite treatment.
- When the risks of continuing pregnancy outweigh the risks of delivery after careful consideration of maternal and fetal health.
- Gestational age reaching or exceeding 34 weeks.
Intrapartum Management and Mode of Delivery
Preterm neonates, especially those born before 32 weeks of gestation, require access to advanced neonatal care. Whenever feasible, delivery should occur at a facility capable of managing preterm neonates, with intrauterine transfer preferred when appropriate.
Most preterm neonates can be delivered vaginally. Epidural anesthesia is considered relatively safe for labor analgesia. Drugs such as morphine and pethidine, which suppress the newborn respiratory center, should be used with caution. Continuous monitoring of fetal status during labor is essential. For breech presentations, particularly footling breech, the mode of delivery should be decided based on local neonatal care conditions and a balanced assessment of the benefits and risks of cesarean section. The decision should be made under the premise of informed consent.
For preterm neonates not requiring resuscitation, delayed umbilical cord clamping for at least 30 to 60 seconds is recommended. This practice has been shown to reduce the need for neonatal blood transfusions and lower the incidence of intraventricular hemorrhage.
Prevention
Effective prevention of preterm birth is one of the key measures to reduce perinatal mortality rates.
Enhancing Preconception and Prenatal Care
Preterm birth risk factors should be identified as early as possible during preconception or prenatal care. Identified high-risk factors should be assessed and managed accordingly.
Specific Preventive Measures
Cervical Cerclage
Cervical cerclage includes transvaginal cervical cerclage and transabdominal cervical cerclage.
Transvaginal Cervical Cerclage
Transvaginal cerclage can be further divided into the following categories:
- History-Indicated Cerclage: This is recommended for patients with a history of three or more mid-trimester pregnancy losses or spontaneous preterm births, or at least one instance of painless cervical dilation during the mid-trimester. Typically, the procedure is performed between 12 and 14 weeks of gestation and is also known as prophylactic cerclage.
- Ultrasound-Indicated Cerclage: This procedure is recommended for patients with a history of mid-trimester pregnancy loss or spontaneous preterm birth, and a cervical length of ≤25 mm before 24 weeks of gestation in the current pregnancy.
- Physical Examination-Indicated Cerclage: This procedure is performed when physical examination during the mid-trimester reveals cervical dilation or protrusion of the amniotic sac through the cervical os, provided that labor, placental abruption, infection, and uterine contractions have been ruled out. This is also referred to as emergency cervical cerclage.
Following cervical cerclage, the removal of cerclage sutures is usually recommended between 36 and 38 weeks of gestation. If inevitable miscarriage or preterm labor occurs, immediate suture removal is necessary.
Transabdominal Cervical Cerclage
This technique, performed either via laparotomy or laparoscopy, is mainly reserved for patients with confirmed cervical insufficiency where transvaginal cerclage has failed previously or is anatomically unfeasible due to cervical resection history or other anatomical abnormalities.
Progesterone Therapy
Progesterone has shown efficacy in some cases in preventing preterm birth. It is typically used in pregnant women with a short cervix during the mid-trimester or a history of mid-trimester pregnancy loss or spontaneous preterm birth. Vaginal administration is recommended, with common medications being micronized progesterone capsules and progesterone gels. The effectiveness of other oral or intramuscular formulations requires further clinical evidence.
Cervical Pessaries
Although reports have suggested potential benefits, the efficacy and clinical application of cervical pessaries remain highly controversial.
The above preventive measures primarily apply to singleton pregnancies, and there is insufficient evidence from clinical studies to support their use for multiple pregnancies.