Preterm Labor

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Continuing Education Activity

Spontaneous preterm labor (sPTL) is characterized by cervical changes triggered by regular uterine contractions occurring between 20 0/7 and 36 6/7 weeks of gestational age (EGA). Diagnostic criteria vary, with the American College of Obstetricians and Gynecologists defining sPTL as cervical dilation of at least 2 cm before 37 weeks EGA, while international guidelines suggest a cutoff of 3 cm. Patients presenting with symptoms such as contractions, pelvic or back pain, vaginal bleeding, or fluid leakage undergo evaluations involving history, pelvic examination, and potentially transvaginal ultrasound or fetal fibronectin testing. Management strategies depend on gestational age and may include antenatal corticosteroids, tocolysis, magnesium sulfate, and group B Streptococcus prophylaxis to improve neonatal outcomes.

This course equips participants with a comprehensive understanding of sPTL, including its etiology, clinical presentation, diagnostic strategies, and evidence-based management approaches. Clinicians refine their skills in identifying at-risk patients and applying individualized treatment protocols. The curriculum emphasizes the importance of interprofessional collaboration among obstetricians, neonatologists, maternal-fetal medicine specialists, and nursing teams to ensure cohesive care. By fostering communication and coordinated management, participants improve decision-making, reduce preterm birth-related complications, and enhance neonatal outcomes. This interprofessional approach strengthens care delivery and enhances patient outcomes.

Objectives:

  • Identify risk factors for spontaneous preterm labor and underlying etiologies that can trigger the condition.

  • Apply the evaluation of preterm labor, including when to use fetal fibronectin testing and how to interpret the results.

  • Differentiate the management of preterm labor based on the patient's gestational age.

  • Communicate the role of collaboration among interprofessional team members to improve care coordination, leading to earlier recognition of preterm labor and optimal management and outcomes.

Introduction

Preterm labor (PTL) is defined as cervical change that develops in response to regular uterine contractions occurring between 20 0/7 and 36 6/7 weeks of estimated gestational age (EGA). The American College of Obstetricians and Gynecologists (ACOG) also states that PTL can be diagnosed in patients with regular contractions and cervical dilation of at least 2 cm before 37 weeks EGA, while the international guidelines from the World Association of Perinatal Medicine and the Perinatal Medicine Foundation (WAPM-PMF) recommend using a cutoff of at least 3 cm to diagnose spontaneous preterm labor (sPTL).[1][2] 

Spontaneous PTL is unlikely to resolve once the cervix reaches at least 3 cm. However, treatment also benefits patients who are at high risk of preterm delivery, even if they have not yet reached 3 cm dilation. Most patients presenting with symptoms of sPTL will usually deliver at term.[3] Therefore, when patients present with symptoms of sPTL, the evaluation should focus on attempting to identify patients whose labor will progress and result in preterm birth (PTB). PTL can be classified as extremely preterm. Spontaneous PTL with intact membranes is responsible for 40% to 45% of all PTBs, which, in turn, are associated with substantially higher rates of neonatal morbidity and mortality compared to neonates born after 37 weeks EGA.[4][5][6][7] For this reason, accurate diagnosis and management of sPTL is imperative for improving neonatal outcomes. 

Etiology

Causes of sPTL include decidual inflammation, decidual hemorrhage, pathologic uterine distention, and conditions that increase fetal and maternal stress.[7][8][9][10][11]

Risk factors for these underlying etiologies include the following:

  • History of prior PTB 
  • Preterm prelabor rupture of membranes 
  • Shortened cervical length 
  • Intrauterine or vaginal infection
  • Placental abruption
  • Placenta previa
  • Multifetal gestation
  • Abnormally high or low amniotic fluid volume
  • Conditions associated with uteroplacental insufficiency (eg, hypertensive disorders of pregnancy, diabetes mellitus, autoimmune disease)
  • Evidence of uteroplacental insufficiency (eg, fetal growth restriction, oligohydramnios, abnormal umbilical artery Doppler velocimetry)
  • Black race
  • Extremes of maternal age (40 years or older)
  • Poor nutrition
  • Low maternal body mass index
  • Inadequate prenatal care
  • Substance use [5][7][12]

Epidemiology

In patients presenting with signs or symptoms of PTL, only 5.5% deliver within 1 week.[3] Even in patients with a clinical diagnosis of sPTL, less than 10% give birth within 7 days of presentation.[1][3] The worldwide incidence of PTB is approximately 10%, with 40% to 45% of those births occurring secondary to sPTL with intact membranes.[7][13] This rate tends to be higher in lower-resource settings and lower in high-resource settings. Regarding racial disparities, results from a large retrospective analysis of patients treated at Kaiser Permanente in California between 2009 and 2020 found statistically significant differences in rates of sPTB by race.[14] In this study, the results showed that the incidence of sPTB in non-Hispanic Black individuals was 5.5% compared to 3.6% in non-Hispanic White individuals (P < 0.001).

Pathophysiology

The pathophysiology of sPTL is complex and multifactorial.[7][8] Labor is thought to be triggered by the activation of the decidua and fetal membranes, which can occur as a result of intrauterine inflammation, maternal vascular malperfusion of the placenta, uterine overdistension, maternal or fetal stress, and/or breakdown of maternal-fetal tolerance.[8] In sPTL, the processes that trigger this activation are pathologic and may develop acutely or over several weeks. Decidual activation appears to arise commonly in intrauterine infection or bleeding.[7] 

Bacteria from the vagina can bind to toll-like receptors on the cervix, placenta, and fetal membranes, inducing an inflammatory response. In addition to enhancing prostaglandin production, interleukin 1β and tumor necrosis factor stimulate matrix metalloproteinases, which degrade the extracellular matrix (ECM) of the cervix and membranes. Additionally, an influx of inflammatory cells into the cervical stroma releases cytokines and prostaglandins that stimulate further structural changes in the cervical collagen and glycosaminoglycans. These changes ultimately lead to cervical dilation and membrane rupture.[15] The degradation of ECM can be assessed by evaluating the cervicovaginal secretions for fetal fibronectin.

In patients with intact membranes, abnormalities in the maternal and fetal immunologic response to pregnancy can also lead to sterile inflammation characterized by elevated levels of pro-inflammatory cytokines in the amniotic fluid.[16] Although the underlying pathophysiology differs from the inflammation associated with intraamniotic infections, the molecular pathways ultimately lead to similar clinical outcomes.[8][16] Additionally, fetal, and to a lesser extent maternal, stress can trigger the release of placental corticotropin-releasing hormone (CRH). In addition to stimulating cortisol production in the pregnant person and fetus, placental CRH also triggers the secretion of prostaglandins from the amniochorion and decidua.[7] Prostaglandins then stimulate uterine contractions and cervical ripening; oxytocin release from the posterior pituitary gland results in coordinated myometrial contractions that cause labor to progress.

History and Physical

PTL is diagnosed clinically based on symptoms and physical findings. ACOG's Practice Bulletin on the management of PTL states that the diagnosis of PTL is "generally based on clinical criteria of regular uterine contractions accompanied by a change in cervical dilation, effacement, or both, or initial presentation with regular contractions and cervical dilation of at least 2 cm."[1] The threshold for defining "regular contractions" has varied in the literature, ranging from 4 to 12 contractions per hour.[2] ACOG does not include a threshold in their definition, though the WAPM-PMF joint guideline recommends requiring 6 or more contractions per 30 minutes.[1][2] WAPM-PMF recommends observing patients for at least 2 hours to assess contraction frequency and cervical change.

History

Patients in sPTL may present with menstrual-like cramping, regular contractions, pelvic pain or pressure, and/or low back pain. Patients should be asked about any contractions' duration, frequency, regularity, and intensity. Cervical change is more likely when contractions are frequent (every 2 to 3 minutes), regular, and strong—though preterm cervical change also occurs without these features. An increase in mucoid vaginal discharge and/or light bleeding or spotting can also be seen as the cervix dilates. A patient's history of past and present obstetric complications can also be informative, and the antenatal record should be thoroughly reviewed. 

Patients should be asked about potential PTL risk factors and signs and symptoms that would suggest a specific underlying etiology as follows:

  • Leakage of fluid suggests preterm premature rupture of membranes, PPROM.
  • Fever, uterine tenderness, or foul-smelling vaginal discharge suggests an infectious etiology.
  • Vaginal bleeding and abdominal pain are symptoms of placental abruption.
  • A prior history of sPTB, substance use, poor nutrition, suboptimal prenatal care, and extremes of maternal age are all risk factors for sPTL.
  • Medical and obstetric comorbidities, such as hypertensive disorders, diabetes, and autoimmune disease, increase the risk of uteroplacental insufficiency.

Physical Examination

In addition to assessing maternal vital signs, patients require abdominal and pelvic examinations. Importantly, in stable patients, the speculum exam should precede the digital exam, as a digital exam can affect the results of vaginal secretion testing and increase the risk of infection in patients with ruptured membranes. 

  • Abdominal examination: Contractions can often be palpated and are felt as a tightening of the gravid uterus. The uterus is typically nontender to palpation during labor; tenderness is seen in patients with intrauterine inflammation and/or bleeding. Fetal weight and position can also be assessed and estimated.
  • Speculum examination: Visual inspection should note the cervical dilation and effacement, membrane status, and the presence of any blood or abnormal discharge. Pooling of straw-colored fluid in the speculum or leakage of fluid from the cervical os suggests membrane rupture, which often occurs just before or during sPTL. When the membrane status is uncertain during the exam, it should be confirmed using standard methods. Blood can be seen in patients with placental abruption and placenta previa, both of which are risk factors for sPTL, though small amounts of bleeding can also be seen with normal cervical dilation. Foul-smelling or abnormal discharge suggests infection, and a sample should be obtained for appropriate testing.
  • Digital pelvic examination: After ruling out placenta previa and membrane rupture, a digital exam is typically performed to better assess cervical dilation, effacement, and station. If cervical dilatation is noted to be at least 3 cm before 34 weeks EGA, the patient is highly likely to deliver preterm. The placental location must be determined by chart review or bedside ultrasound before performing a digital cervical exam.                                                                                         
  • Cardiotocographic monitoring: Cardiotocographic monitoring provides information about fetal well-being and contraction patterns. The frequency and regularity of contractions should be documented, and clinicians and patients can determine if the symptoms correlate with contractions seen on the tocographic monitor. Additionally, fetal well-being should be confirmed in all patients presenting with symptoms of sPTL.

Evaluation

Beyond the history and examination, the evaluation of patients with threatened PTL includes collecting samples to test patients for ruptured membranes, urogenital infections, and the presence of fetal fibronectin (fFN) in cervicovaginal secretions, as well as transvaginal and limited obstetric ultrasounds. The selective use of fFN testing in patients with an indeterminate cervical length provides the best diagnostic accuracy for sPTL in the early to moderate preterm. However, neither of these tests is as helpful at late preterm gestational ages. The other tests help identify potential underlying etiologies and provide information necessary for appropriate intrapartum care should labor progress.[17][18] 

Basic Laboratory Testing

  • Confirming membrane status: The status of the fetal membranes must be determined, as management differs in patients with ruptured versus intact membranes. If rupture of membranes is not grossly apparent on the speculum exam, routine diagnostic evaluation is warranted. This testing may include microscopy, pH testing, and several commercially available tests that can detect the presence of amniotic fluid proteins, such as placental alpha microglobulin-1 and insulin-like growth factor binding protein 1, in a sample.[19][20][21][22][23] 
  • Group B Streptococcus rectovaginal culture: Knowledge of a patient's group B Streptococcus (GBS) status affects intrapartum management. A culture should be obtained in all patients presenting with symptoms of sPTL unless they have a GBS culture obtained within the past 5 weeks or if they already have an indication for intrapartum GBS prophylaxis, such as a positive GBS urine culture this pregnancy or a history of a neonate with invasive GBS disease.[24]                           
  • Urinalysis and urine culture: Asymptomatic bacteriuria and urinary tract infections (UTI) are associated with an increased risk of sPTL, and UTI symptoms may mimic those of sPTL. Urine culture with or without urinalysis is indicated in patients undergoing an evaluation for PTL.                                       
  • Testing for sexually transmitted infections: Patients with risk factors should be tested for chlamydia, gonorrhea, and syphilis if not recently tested, as these infections may cause inflammation leading to sPTL.                                       
  • Urine drug screen: This test can be considered in patients with risk factors and evidence of placental abruption causing sPTL.

Ultrasounds

  • Transvaginal ultrasound: A normal cervical length is 35 to 48 mm. An abnormally shortened cervical length before 34 weeks EGA is associated with an increased risk of sPTB in both singleton and multifetal gestations, with the shortest cervical lengths associated with the highest risks of sPTB.[17][25] Most studies have used cervical length thresholds of 25%. On the other hand, the risk of sPTB is less than 5% in patients with a cervical length 30 mm or more.[17][26]     
  • Obstetric ultrasound: A limited obstetric ultrasound is typically indicated to assess the amniotic fluid volume (both a sign of fetal well-being and, when abnormal, a risk factor for sPTL) and confirm the fetal position, which is critical for proper labor management. Additionally, an EFW should be obtained, as it allows the neonatal team to better anticipate the infant's needs after birth and provide more accurate prognostic information to the patient.

Biomarkers for PTL

  • Fetal fibronectin: Fetal fibronectin is an ECM glycoprotein present at the decidual-chorionic interface that gets released into cervicovaginal secretions when the ECM is degraded. ECM degradation can be triggered by numerous causes, including many that also trigger PTL. Notably, a digital cervical exam, blood, or recent intercourse can all lead to false-positive results (which is why this sample is best collected before any other pelvic assessments).[27] The primary utility of checking for fFN in cervicovaginal secretions is its negative predictive value; the absence of fFN is associated with a low risk of birth within 7 days.[28] The risk of sPTB is increased with a positive fFN, though the positive predictive value of this test is still relatively low, limiting its clinical utility in some patients.[17][29][30] Conversely, patients with a cervical length between 20 mm and 30 mm and a positive fFN should be considered at high risk of sPTB within the next 7 days and managed accordingly. Qualitative fFN tests are typically considered positive when the fFN concentration is 50 ng/mL or more in cervicovaginal fluid. When a quantitative test is used, higher fFN concentrations are associated with higher rates of sPTB within 14 days. For example, results from a prospective study found the positive predictive value of sPTB increased from 32% to 75% when the concentration of fFN used to define a positive result was increased from 50 ng/mL to 500 ng/mL.[31] Unfortunately, quantitative fFN testing is not always readily available, including in the United States.         
  • Other biomarkers for PTL: Positive PAMG-1 and IGFBP-1 tests, typically used to diagnose a rupture of membranes, are also associated with an increased risk of sPTB in patients with intact membranes. A prospective study of over 400 patients compared the use of placental alpha microglobulin-1 to insulin-like growth factor binding protein 1 in patients with PTL, intact membranes, and cervical lengths between 15 mm and 30 mm to determine their accuracy in identifying patients at risk of sPTB within 7 days.[32] This study's results showed that both biomarkers had a negative predictive value of approximately 97%, while the positive predictive value of placental alpha microglobulin-1 was significantly better at 61% compared to the positive predictive value of only 28% for insulin-like growth factor binding protein 1.

Treatment / Management

Management of sPTL is based on the EGA at presentation, cervical dilation, membrane status, and, in some cases, cervical length with or without fFN. Patients with threatened PTL are considered at high risk of sPTB within the next 7 days if they meet at least 1 criteria of the following:

  • Regular contractions and cervical dilation of 3 cm or more
  • Regular contractions with demonstrated cervical change over time
  • Symptoms of sPTL and a short cervical length (defined as less than 15 mm to 20 mm) regardless of fFN results
  • Symptoms of sPTL, an intermediate cervical length (defined as between 15 to 20 mm and 30 mm), and positive fFN
  • Ruptured membranes

These cases are managed based on EGA at presentation; treatment may include corticosteroids for fetal maturation, a 48-hour course of tocolysis (to allow time for the steroids to achieve maximal effect), magnesium sulfate for neuroprotection, and GBS prophylaxis (see Table. Summary of Preterm Labor Management in Patients with Intact Membranes Based on Gestational Age).[33] Latency antibiotics are indicated in patients with PPROM and are discussed in detail elsewhere. Additionally, every effort should be made to ensure patients in sPTL deliver at a facility that has the necessary resources to care for the preterm neonate, should their labor progress.

Table. Summary of Preterm Labor Management in Patients with Intact Membranes Based on Gestational Age

EGA (weeks) Steroids Tocolysis Magnesium sulfate for neuroprotection GBS Prophylaxis
22 to 31 6/7 Yes

IndomethacinNifedipineMagnesium sulfateTerbutaline

Yes Yes, if GBS is unknown or known positive
32 to 33 6/7 Yes Nifedipine or terbutaline No Yes, if GBS is unknown or known positive
34 to 36 6/7 Consider (guidelines vary) None No Yes, if GBS is unknown or known positive

 Corticosteroids

Antenatal corticosteroids improve neonatal outcomes when given to individuals at high risk of PTB; these are most effective between 48 hours and 7 days before PTB.[2] For these reasons, antenatal corticosteroids are universally recommended for patients at risk of PTB between viability and 34 weeks EGA. ACOG, the Society for Maternal-Fetal Medicine (SMFM), and the WAPM-PMF guidelines recommend considering antenatal corticosteroids in the periviable period, down to 22 0/7 weeks if neonatal resuscitation is planned.[2] However, beyond 34 weeks, recommendations vary across professional organizations.

The 2016 Antenatal Late Preterm Steroids (ALPS) trial was a double-blind, placebo-controlled, randomized controlled trial that studied the effect of antenatal betamethasone in 2831 patients with a singleton pregnancy between 34 and 36 6/7 weeks EGA at high risk of PTB within the next 7 days and before 37 weeks EGA who had not previously received steroids.[34] This study's results showed that antenatal betamethasone significantly reduced the risk of neonatal respiratory morbidity in the study population. However, a secondary analysis of this trial found that those with sPTL or PPROM had lower rates of neonatal respiratory complications when compared to those with indicated PTB, irrespective of betamethasone exposure in the late preterm period.[35]Antenatal corticosteroids also significantly increase the risk of neonatal hypoglycemia.[34] 

Furthermore, long-term neurodevelopmental and metabolic outcomes remain largely uncertain.[36] Results from a meta-analysis from 2022 involving over 1.25 million children exposed to antenatal steroids found a slight increase in the risk for neurocognitive disorders by age 1 (adjusted hazard ratio [aHR] 1.12 [95% CI, 1.05 to 1.20]) in children with a late-PTB, and the children born after 37 weeks EGA had an aHR of 1.47 (95% CI, 1.36-1.60) for mental or behavioral disorders.

International organizations have developed different guidelines in response to the results of these studies, including the following:

  • WAPM-PMF recommends individualizing treatment and suggests a 34 0/7 weeks EGA cutoff for treatment with antenatal corticosteroids.[2]
  • SMFM recommends counseling patients on the available data and offering those who meet inclusion criteria for the ALPS trial (singleton gestations between 34 and 36 6/7 weeks EGA) a single course of antenatal corticosteroids.[37] They also recommend against the use of antenatal steroids in late preterm patients with pregestational diabetes mellitus due to the risk of neonatal hypoglycemia.[37] 
  • ACOG supports SMFM's recommendations; they also recommend against administering steroids to patients with intraamniotic infection.[38]
  • The National Institute for Health and Care Excellence (NICE) guideline [NG25] recommends considering antenatal corticosteroids between 34 and 35 6/7 weeks EGA.
  • The Royal College of Obstetricians and Gynaecologists (RCOG) Green-Top Guideline Number 74 recommends offering antenatal corticosteroids up until 34 6/7 weeks EGA.[39]
  • The Society of Obstetricians and Gynecologists of Canada (SOGC) Technical Update No. 439 states that antenatal corticosteroids should be considered in patients between 34 and 36 6/7 weeks EGA.[40]
  • The World Health Organization (WHO) recommends antenatal corticosteroids from 24 to 34 weeks EGA, including patients with PPROM, multifetal gestations, hypertensive disorders, or fetal growth restriction. They advise against therapy for individuals with chorioamnionitis, as well as those undergoing a planned cesarean delivery between 34 and 36 6/7 weeks EGA.[41]

When given, 1 of 2 antenatal corticosteroid regiments should be used as follows:

  • Two doses of betamethasone 12 mg intramuscularly (IM), given 24 hours apart
  • Four doses of dexamethasone 6 mg IM, given every 12 hours [1][2]

ACOG and WHO recommend considering a single repeat course of antenatal corticosteroids (ie, "rescue steroids") in individuals who have received 1 previous course of steroids at least 7 to 14 days prior and are currently. A rescue course may consist of either a standard 48-hour regimen described above or a single dose of betamethasone, which evidence suggests is also effective after initial standard therapy.[42]

Tocolysis

Tocolytic agents decrease the strength and frequency of uterine contractions, which may briefly prolong pregnancy.[43] However, they do not treat the underlying causes of sPTL, have not been shown to delay birth until term, have not been shown to improve neonatal outcomes on their own, and are associated with a range of mild to severe adverse events.[44] For these reasons, their use should be limited to a 48-hour course of treatment and reserved for patients who would benefit from a 48-hour delay in birth, such as patients who need the time for a course of corticosteroids to achieve maximal effect.[1] A limited course of tocolytics may also be appropriate during patient transfers and in the case of self-limited or treatable conditions known to cause PTL, such as a urinary tract infection or intraabdominal procedures.[1]

Tocolytics are generally recommended for patients with threatened PTL between viability and 34 weeks EGA. In the periviable period, treatment with tocolytics should be individualized. In high-resource settings, experts recommend considering tocolysis down to 22 0/7 weeks EGA if neonatal resuscitation is planned.[1][2] If contractions occur despite adequate tocolytic therapy, then the clinician must reassess the patient for amniotic infection, fetal compromise, possible abruption, and whether cervical dilation is progressing or the membranes have ruptured. Contraindications to tocolysis include preeclampsia with severe features, intraamniotic infection, antepartum hemorrhage, intrauterine fetal demise, lethal fetal anomaly, and significant maternal cardiac disease.[1][2] Tocolytics are generally appropriate for patients with PPROM who lack evidence of maternal infection.

The drug classes with the best evidence to support their use for tocolysis include calcium channel blockers (CCBs, typically nifedipine), cyclooxygenase (COX) inhibitors (typically indomethacin), and beta-agonists (typically terbutaline).[1] Other tocolytic agents include oxytocin receptor antagonists (eg, atosiban), magnesium sulfate, and nitric oxide donors (eg, nitroglycerin). Combinations of tocolytics are generally not recommended.[2]

  • Calcium channel blockers: CCBs prevent intracellular calcium release from the sarcoplasmic reticulum, which prevents calcium-dependent myometrial contraction. Nifedipine has a better safety profile than other tocolytic medications and is often used for tocolysis, especially after 30 to 32 weeks of EGA.[45][46][47] Nifedipine is ACOG's recommended first-line agent for patients between 32 and 33 6/7 weeks and is the agent that the WHO, NICE, and WAPM-PMF recommend for tocolysis from 24 to 33 6/7 weeks EGA.[1][2][41] The most commonly used nifedipine regimen is an initial oral dose of 20 mg, then 10 mg orally every 6 hours.[1][2][41] CCBs do not have significant known adverse effects on fetal or newborn babies.[1] As a peripheral vasodilator, CCB therapy is associated with dizziness, palpitations, tachycardia, nausea, and flushing. This therapy is contraindicated in patients with hypotension and preload-dependent cardiac conditions.
  • Cyclooxygenase inhibitors: COX inhibitors prevent the conversion of arachidonic acid to prostaglandins, which stimulate contractions. Many experts prefer indomethacin for tocolysis before 32 weeks EGA based on the results of a large meta-analysis of 58 randomized clinical trials that showed it to be the superior first-line tocolytic agent due to its efficacy and tolerability.[44] The authors hypothesize that this may be due to the large proportion of sPTL resulting from inflammation and subclinical infection. A second systemic review from 2022 supported these results.[47] However, exposure to COX inhibitors beyond 48 hours increases the risk of constriction of the ductus arteriosus and oligohydramnios, though these complications are primarily seen in the third trimester. One study found that reversible narrowing of the ductus arteriosus can be detected in 50% of fetuses at an average of 5.1 days after therapy initiation and a mean gestational age of approximately 31 weeks EGA.[48] Results from a smaller study showed a dramatic increase in ductal constriction starting at an average of 32 weeks EGA and recommended limiting its use to patients.[53] However, prolonged use of indomethacin in the second trimester is associated with much lower rates of ductal constriction, occurring in only 6.5% of patients.[49] Results from older studies have also suggested several other neonatal complications associated with antenatal indomethacin. A 2015 systemic review and meta-analysis found that indomethacin used for labor tocolysis was associated with an increased risk of severe IVH, necrotizing enterocolitis, and periventricular leukomalacia.[50] This study also found no significant differences in the rates of patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia, sepsis, or neonatal mortality. These findings must be cautiously interpreted, as the trials included in this study included indomethacin exposure ranging from
  • Beta-2 receptor agonists: These agents lead to smooth muscle relaxation, reducing myometrial contractions. However, myometrial cells become desensitized to these drugs, limiting their effectiveness over time. Additionally, serious adverse effects are more common with these agents.[47][51] Although still used in some circumstances, beta-2 agonists are generally considered second-line tocolytics behind COX inhibitors and CCBs due to relatively lower efficacy and safety. NICE explicitly recommends against using these drugs for tocolysis. Importantly, beta-2 agonists increase maternal heart rate and cause peripheral vasodilation, bronchial relaxation, and hyperglycemia. Because of this, these drugs are relatively contraindicated in patients with significant tachycardia, cardiac disease sensitive to tachycardia, and poorly controlled diabetes mellitus.[1] Patients with diabetes require careful monitoring of their glucose and potassium levels and often require a continuous infusion of insulin if beta-2 agonists are used for tocolysis.
  • Oxytocin receptor antagonists: These drugs are commonly used in Europe and are unavailable in the United States. Atosiban is the most frequently used drug in this class and is considered an acceptable first-line alternative to nifedipine in the WAPM-PMF guidelines.[2] A randomized clinical trial of 510 individuals comparing 48-hour courses of oral nifedipine to intravenous atosiban in patients with threatened PTL found no difference in the percentage of patients still pregnant after 48 hours and in composite perinatal outcomes.[52] Atosiban has relatively few maternal adverse effects beyond injection site reactions, and there are no absolute contraindications to its use beyond allergy to the medication.           
  • Magnesium sulfate: Magnesium sulfate appears to be as effective as other tocolytic agents at delaying sPTB. However, it is generally considered a second-line tocolytic due to its higher potential for serious adverse maternal events.[43][44] However, its use has been shown to reduce the risk of moderate to severe cerebral palsy for fetuses delivered before 32 weeks EGA. For this reason, it is often given to patients in early sPTL for neuroprotection and can simultaneously function as the primary tocolytic. Despite generally recommending against combination tocolytic therapy, ACOG notes that a second tocolytic agent can be given to patients with persistent PTL despite being on magnesium sulfate for neuroprotection.[1] In these circumstances, indomethacin is often preferred. CCBs and beta-2 agonists should not be used concurrently with magnesium sulfate, as they can work synergistically, leading to profound smooth muscle relaxation and serious respiratory depression.[1]                                                                       
  • Nitric oxide donors: Nitric oxide is a potent smooth muscle relaxer, and the nitric oxide donor, nitroglycerin, has been studied for tocolysis. A 2014 Cochrane review of randomized clinical trials comparing nitroglycerin to placebo, nifedipine, or beta-2 agonists concluded that there is "insufficient evidence to support the routine administration of nitric oxide donors in the treatment of threatened preterm labor."[53]

Magnesium Sulfate for Neuroprotection

Magnesium sulfate provides neuroprotection for the neonate when given within 24 hours of early PTB.[54][55][56] Results from a 2024 Cochrane review confirmed that current evidence indicates predelivery magnesium sulfate reduces the risk of cerebral palsy and probably reduces rates of severe IVH when given to patients at imminent risk of PTB before 34 weeks EGA.[55] Similar to recommendations regarding antenatal corticosteroids, recommendations regarding when to offer magnesium sulfate for neuroprotection vary slightly across the globe. The WHO strongly recommends magnesium sulfate for women at risk of imminent PTB before 32 weeks.[57] ACOG’s practice bulletin on the management of PTL, which was reaffirmed in 2020, suggests that the evidence for magnesium sulfate is strongest before 32 weeks of EGA and recommends that hospitals develop uniform guidelines regarding its use.[1] NICE guidelines recommend offering magnesium sulfate between 24 and 29 6/7 weeks EGA and considering it between 30 and 33 6/7 weeks EGA. WAPM-PMF guidelines recommend its use up to 31 6/7 weeks and state it may be considered up to 33 6/7 weeks EGA in patients with a fetus below the 5th percentile for estimated weight.[2]

Magnesium sulfate is contraindicated in patients with myasthenia gravis and should be used with caution in patients with neuromuscular disease and heart block. This is excreted via the kidneys and thus requires renal dosing to prevent accumulation and magnesium toxicity in patients with renal dysfunction. All patients on magnesium sulfate should be carefully monitored for signs and symptoms of magnesium toxicity with regular assessments of their vital signs, urine output, deep tendon reflexes, and cardiopulmonary exams. With appropriate monitoring and care in high-resource settings, the 2024 Cochrane review found that magnesium sulfate did not increase rates of maternal death or cardiac or respiratory arrest when compared with placebo.[55] 

GBS Prophylaxis

GBS prophylaxis should be given to all patients according to standard recommendations for its use. Preterm delivery is considered a risk factor for early-onset GBS disease and is an indication for prophylaxis in patients with unknown GBS status. RCOG recommends intrapartum GBS prophylaxis in all preterm patients.[58]

Intrapartum and Postpartum Care

Continuous cardiotocography is typically used to monitor patients and their fetuses during PTL. GBS prophylaxis and magnesium sulfate for neuroprotection should be continued through delivery. Postpartum, delayed cord clamping is advantageous for preterm neonates. Delayed cord clamping is associated with higher initial hematocrits, diastolic blood pressures, and circulating blood volume but with lower resuscitation rates, blood transfusion, and death before discharge.[59][60][61] Results from a 2023 randomized clinical trial involving 204 neonates found that delayed cord clamping between 30 and 60 seconds is safe and effective. However, waiting 120 seconds was associated with higher rates of neonatal polycythemia and longer durations of phototherapy.[62]

Resolution of SPTL

In many cases, threatened PTL resolves spontaneously. After 34 weeks of EGA, patients can typically be discharged home with close follow-up if they have intact membranes and reassuring tests of fetal well-being. Before 34 weeks, care must be individualized, taking into account gestational age, cervical dilation and effacement, pregnancy complications, obstetric history, the patient's distance from the hospital at home, and patient preference. At home, patients can perform typical daily life activities, and bed rest is not recommended.[2][63] 

Results from a randomized clinical trial of 120 patients found that activity restriction (including pelvic rest and reduction of work) in patients with arrested PTL did not reduce sPTB.[64] However, patients should restrict recreational exercise and heavy lifting. ACOG recommends advising patients to discontinue exercise if they develop regular contractions, vaginal bleeding, abdominal pain, leakage of fluid, dyspnea before exertion, dizziness, headache, chest pain, muscle weakness, or calf pain.[63] 

Differential Diagnosis

The differential diagnosis for obstetric patients presenting with lower abdominal, pelvic, or back pain includes the following:

  • Spontaneous preterm labor
  • Braxton-Hicks contractions (ie, false labor pains)
  • Musculoskeletal or round ligament pain
  • Urinary tract infection
  • Gastrointestinal disorder
  • Placental abruption
  • Uterine rupture

Prognosis

Approximately 30% of sPTL cases resolve spontaneously, and approximately 50% of patients hospitalized with sPTL ultimately deliver at term. Furthermore, less than 10% of individuals presenting with preterm contractions progress to active labor and sPTB within 7 days.[1][65] Cervical length and fFN can be used to stratify patients into high- and low-risk categories. 

Complications

Complications of PTL can significantly affect both the mother and baby. These complications are often influenced more by the underlying causes of PTL and the degree of prematurity than by PTL itself, highlighting the importance of addressing maternal health and optimizing neonatal care.

Maternal Complications

SPTB has been associated with modest cardiovascular mortality and morbidity risks that remain elevated more than 40 years later.[66] The reason for this association remains unclear.

Complications in Offspring

The risk of neonatal complications is primarily dependent on the gestational age at delivery. Neonates born in the late preterm period are at risk for respiratory distress, hypothermia, hypoglycemia, hyperbilirubinemia, feeding difficulties, and failure to thrive. The administration of antenatal corticosteroids increases the risk of hypoglycemia in neonates.[34] Neonates born at earlier gestations are also at increased risk of necrotizing enterocolitis, IVH, sepsis, bronchopulmonary dysplasia, patent ductus arteriosus, hypotension, retinopathy of immaturity, anemia of prematurity, and poor growth. 

With improvements in obstetric and neonatal care, short-term neonatal morbidity and mortality rates have decreased over the past 2 decades.[67] Long-term complications include impaired neurodevelopmental outcomes, such as cognitive or motor deficits, vision or hearing loss, and cerebral palsy.[68][69] Behavioral issues such as anxiety, depression, autism spectrum disorders, and attention deficit hyperactivity disorder are also associated with PTB. These risks increase with decreasing gestational age at birth. With patient-specific education and follow-up, the long-term sequelae and disability have also improved.

Deterrence and Patient Education

Patients with a history of sPTB have an increased risk for recurrent sPTB, especially if their cervical length is shortened. Recent studies have shown that vaginal progesterone supplementation does not reduce the risk of recurrent sPTB unless the patient also has a shortened cervical length.[70][71] Vaginal progesterone supplementation is not recommended in asymptomatic individuals. Intramuscular progesterone therapy is no longer recommended for the prevention of PTB. In patients without a history of a prior sPTB, early cervical length screening is not recommended. The cervix should be assessed as part of the routine anatomy scan performed at 18 to 22 weeks EGA. 

Patients should be counseled on how to improve modifiable risk factors for sPTL. This counseling includes discussing the importance of proper nutrition, hydration, and weight gain during pregnancy and encouraging all patients to avoid tobacco and substance use. Additionally, patients should be encouraged to attend regular prenatal visits, obtain recommended screening tests, and follow treatment recommendations when abnormalities are encountered. 

Enhancing Healthcare Team Outcomes

When evaluating and caring for a patient in PTL, collaboration among obstetricians, midwives, nurses, maternal-fetal medicine specialists, neonatologists, laboratory technicians, and obstetric sonographers is crucial for ensuring maternal and fetal well-being. The evaluation typically involves a history, physical examination, review of the antenatal record, transvaginal ultrasound, and collection of several additional specimens for testing. Once PTL is confirmed or suspected, management depends on gestational age and may include prolonged observation, antenatal corticosteroids, tocolysis, GBS prophylaxis, and/or magnesium sulfate for neuroprotection.  

Nurses are often the patient's first point of contact with the healthcare system and are critical in obtaining the initial history. They can help triage patients over the phone and advise them when an evaluation is necessary. For example, recommending a period of hydration and rest may be appropriate for some patients at low risk with mild irregular contractions. In contrast, patients with bleeding, severe pain, or certain pregnancy complications should be advised to present immediately. Once patients arrive for evaluation, nurses typically perform the initial assessment, obtain the patient's vital signs, and initiate cardiotocographic monitoring. Their timely assessment of the patient and appropriate communication with the primary obstetric clinician is pivotal in initiating the patient's evaluation and treatment.

The primary obstetric clinician (eg, obstetrician, midwife, or family medicine physician) typically leads the care team, assessing the patient's clinical presentation and determining the urgency of necessary interventions. Obstetric sonographers may assist in the evaluation by performing ultrasounds to assess cervical length, fetal weight, fetal position, amniotic fluid levels, and signs of distress, providing critical data to guide decisions. Laboratory technicians contribute by promptly processing essential tests, such as fetal fibronectin, complete blood counts, and infection screenings, which all aid in diagnosis and management. Nurses play a pivotal role in monitoring maternal and fetal vital signs, contraction patterns, and patient symptoms and administering critical medications such as tocolytics and corticosteroids. 

Maternal-fetal medicine specialists often consult on complex cases, offering expertise in managing high-risk pregnancies and recommending interventions to prolong gestation that balance maternal and neonatal risks. Neonatologists are also frequently engaged early when PTB is anticipated, especially at earlier gestational ages. This contact allows them to anticipate neonatal risks and prepare the neonatal intensive care unit for the infant's arrival. They can also provide parents with important prognostic information that may influence their decision to pursue aggressive resuscitation after birth. Communication between team members is crucial to ensuring testing and management are performed correctly and promptly. Together, this interprofessional team ensures comprehensive, patient-centered care by integrating diagnostic findings, clinical expertise, and advanced technology to optimize outcomes for both mother and baby.


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References


[1]

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 171: Management of Preterm Labor. Obstetrics and gynecology. 2016 Oct:128(4):e155-64. doi: 10.1097/AOG.0000000000001711. Epub     [PubMed PMID: 27661654]


[2]

Dagklis T, Akolekar R, Villalain C, Tsakiridis I, Kesrouani A, Tekay A, Plasencia W, Wellmann S, Kusuda S, Jekova N, Prefumo F, Volpe N, Chaveeva P, Allegaert K, Khalil A, Sen C. Management of preterm labor: Clinical practice guideline and recommendation by the WAPM-World Association of Perinatal Medicine and the PMF-Perinatal Medicine Foundation. European journal of obstetrics, gynecology, and reproductive biology. 2023 Dec:291():196-205. doi: 10.1016/j.ejogrb.2023.10.013. Epub 2023 Oct 10     [PubMed PMID: 37913556]

Level 1 (high-level) evidence

[3]

Waks AB, Martinez-King LC, Santiago G, Laurent LC, Jacobs MB. Developing a risk profile for spontaneous preterm birth and short interval to delivery among patients with threatened preterm labor. American journal of obstetrics & gynecology MFM. 2022 Nov:4(6):100727. doi: 10.1016/j.ajogmf.2022.100727. Epub 2022 Aug 19     [PubMed PMID: 35995363]


[4]

Dagklis T, Sen C, Tsakiridis I, Villalaín C, Allegaert K, Wellmann S, Kusuda S, Serra B, Sanchez Luna M, Huertas E, Volpe N, Ayala R, Jekova N, Grunebaum A, Stanojevic M. The use of antenatal corticosteroids for fetal maturation: clinical practice guideline by the WAPM-World Association of Perinatal Medicine and the PMF-Perinatal Medicine foundation. Journal of perinatal medicine. 2022 May 25:50(4):375-385. doi: 10.1515/jpm-2022-0066. Epub 2022 Mar 11     [PubMed PMID: 35285217]

Level 1 (high-level) evidence

[5]

Hoffman MK. Prediction and Prevention of Spontaneous Preterm Birth: ACOG Practice Bulletin, Number 234. Obstetrics and gynecology. 2021 Dec 1:138(6):945-946. doi: 10.1097/AOG.0000000000004612. Epub     [PubMed PMID: 34794160]


[6]

Hall M, Valencia CM, Soma-Pillay P, Luyt K, Jacobsson B, Shennan A, FIGO Preterm Birth Committee. Effective and simple interventions to improve outcomes for preterm infants worldwide: The FIGO PremPrep-5 initiative. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2024 Jun:165(3):929-935. doi: 10.1002/ijgo.15269. Epub 2024 Jan 24     [PubMed PMID: 38264849]


[7]

Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet (London, England). 2008 Jan 5:371(9606):75-84. doi: 10.1016/S0140-6736(08)60074-4. Epub     [PubMed PMID: 18177778]


[8]

Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science (New York, N.Y.). 2014 Aug 15:345(6198):760-5. doi: 10.1126/science.1251816. Epub 2014 Aug 14     [PubMed PMID: 25124429]


[9]

Preston M, Hall M, Shennan A, Story L. The role of placental insufficiency in spontaneous preterm birth: A literature review. European journal of obstetrics, gynecology, and reproductive biology. 2024 Apr:295():136-142. doi: 10.1016/j.ejogrb.2024.02.020. Epub 2024 Feb 10     [PubMed PMID: 38359634]


[10]

Sen C. Preterm labor and preterm birth. Journal of perinatal medicine. 2017 Nov 27:45(8):911-913. doi: 10.1515/jpm-2017-0298. Epub     [PubMed PMID: 29055176]


[11]

Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, Chaiworapongsa T, Mazor M. The preterm parturition syndrome. BJOG : an international journal of obstetrics and gynaecology. 2006 Dec:113 Suppl 3(Suppl 3):17-42     [PubMed PMID: 17206962]


[12]

O'Hara S, Zelesco M, Sun Z. Cervical length for predicting preterm birth and a comparison of ultrasonic measurement techniques. Australasian journal of ultrasound in medicine. 2013 Aug:16(3):124-134. doi: 10.1002/j.2205-0140.2013.tb00100.x. Epub 2015 Dec 31     [PubMed PMID: 28191186]


[13]

Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, Okwaraji YB, Mahanani WR, Johansson EW, Lavin T, Fernandez DE, Domínguez GG, de Costa A, Cresswell JA, Krasevec J, Lawn JE, Blencowe H, Requejo J, Moran AC. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet (London, England). 2023 Oct 7:402(10409):1261-1271. doi: 10.1016/S0140-6736(23)00878-4. Epub     [PubMed PMID: 37805217]

Level 1 (high-level) evidence

[14]

Mensah NA, Fassett MJ, Shi JM, Kawatkar AA, Xie F, Chiu VY, Yeh M, Avila CC, Khadka N, Sacks DA, Getahun D. Examining recent trends in spontaneous and iatrogenic preterm birth across race and ethnicity in a large managed care population. American journal of obstetrics and gynecology. 2023 Jun:228(6):736.e1-736.e15. doi: 10.1016/j.ajog.2022.11.1288. Epub 2022 Nov 18     [PubMed PMID: 36403861]


[15]

Oner C, Schatz F, Kizilay G, Murk W, Buchwalder LF, Kayisli UA, Arici A, Lockwood CJ. Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and -3 expression in term decidual cells: implications for treatment of chorioamnionitis-induced preterm delivery. The Journal of clinical endocrinology and metabolism. 2008 Jan:93(1):252-9     [PubMed PMID: 17940116]


[16]

Gomez-Lopez N, Galaz J, Miller D, Farias-Jofre M, Liu Z, Arenas-Hernandez M, Garcia-Flores V, Shaffer Z, Greenberg JM, Theis KR, Romero R. The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal-fetal homeostasis. Reproduction (Cambridge, England). 2022 Jun 20:164(2):R11-R45. doi: 10.1530/REP-22-0046. Epub 2022 Jun 20     [PubMed PMID: 35559791]


[17]

DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. American journal of obstetrics and gynecology. 2013 Mar:208(3):233.e1-6. doi: 10.1016/j.ajog.2012.12.015. Epub 2012 Dec 12     [PubMed PMID: 23246314]

Level 1 (high-level) evidence

[18]

Creswell L, Rolnik DL, Lindow SW, O'Gorman N. Preterm Birth: Screening and Prediction. International journal of women's health. 2023:15():1981-1997. doi: 10.2147/IJWH.S436624. Epub 2023 Dec 21     [PubMed PMID: 38146587]


[19]

Yılmaz Semerci S, Yücel B, Erbas IM, Gunkaya OS, Talmac M, Çetinkaya M. The utility of amniotic fluid pH and electrolytes for prediction of neonatal respiratory disorders. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2020 Jan:33(2):253-257. doi: 10.1080/14767058.2018.1488961. Epub 2018 Jul 22     [PubMed PMID: 30033781]


[20]

Riedewald S, Kreutzmann IM, Heinze T, Saling E. Vaginal and cervical pH in normal pregnancy and pregnancy complicated by preterm labor. Journal of perinatal medicine. 1990:18(3):181-6     [PubMed PMID: 2384841]


[21]

Cousins LM, Smok DP, Lovett SM, Poeltler DM. AmniSure placental alpha microglobulin-1 rapid immunoassay versus standard diagnostic methods for detection of rupture of membranes. American journal of perinatology. 2005 Aug:22(6):317-20     [PubMed PMID: 16118720]


[22]

Lee SE, Park JS, Norwitz ER, Kim KW, Park HS, Jun JK. Measurement of placental alpha-microglobulin-1 in cervicovaginal discharge to diagnose rupture of membranes. Obstetrics and gynecology. 2007 Mar:109(3):634-40     [PubMed PMID: 17329514]


[23]

Thomasino T, Levi C, Draper M, Neubert AG. Diagnosing rupture of membranes using combination monoclonal/polyclonal immunologic protein detection. The Journal of reproductive medicine. 2013 May-Jun:58(5-6):187-94     [PubMed PMID: 23763001]


[24]

. Prevention of Group B Streptococcal Early-Onset Disease in Newborns: ACOG Committee Opinion, Number 797. Obstetrics and gynecology. 2020 Feb:135(2):e51-e72. doi: 10.1097/AOG.0000000000003668. Epub     [PubMed PMID: 31977795]

Level 3 (low-level) evidence

[25]

Prodan N, Wagner P, Sonek J, Abele H, Hoopmann M, Kagan KO. Single and repeat cervical-length measurement in twin gestation with threatened preterm labor. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2020 Apr:55(4):496-501. doi: 10.1002/uog.20306. Epub     [PubMed PMID: 31066097]


[26]

Gomez R, Romero R, Medina L, Nien JK, Chaiworapongsa T, Carstens M, González R, Espinoza J, Iams JD, Edwin S, Rojas I. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. American journal of obstetrics and gynecology. 2005 Feb:192(2):350-9     [PubMed PMID: 15695971]


[27]

McLaren JS, Hezelgrave NL, Ayubi H, Seed PT, Shennan AH. Prediction of spontaneous preterm birth using quantitative fetal fibronectin after recent sexual intercourse. American journal of obstetrics and gynecology. 2015 Jan:212(1):89.e1-5. doi: 10.1016/j.ajog.2014.06.055. Epub 2014 Jun 30     [PubMed PMID: 24992691]


[28]

Son M, Miller ES. Predicting preterm birth: Cervical length and fetal fibronectin. Seminars in perinatology. 2017 Dec:41(8):445-451. doi: 10.1053/j.semperi.2017.08.002. Epub 2017 Sep 19     [PubMed PMID: 28935263]


[29]

Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. American journal of obstetrics and gynecology. 2007 Oct:197(4):426.e1-7     [PubMed PMID: 17904989]

Level 1 (high-level) evidence

[30]

van Baaren GJ, Vis JY, Wilms FF, Oudijk MA, Kwee A, Porath MM, Oei G, Scheepers HCJ, Spaanderman MEA, Bloemenkamp KWM, Haak MC, Bolte AC, Bax CJ, Cornette JMJ, Duvekot JJ, Nij Bijvanck BWA, van Eyck J, Franssen MTM, Sollie KM, Vandenbussche FPHA, Woiski M, Grobman WA, van der Post JAM, Bossuyt PMM, Opmeer BC, Mol BWJ. Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor. Obstetrics and gynecology. 2014 Jun:123(6):1185-1192. doi: 10.1097/AOG.0000000000000229. Epub     [PubMed PMID: 24807328]


[31]

Abbott DS, Radford SK, Seed PT, Tribe RM, Shennan AH. Evaluation of a quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. American journal of obstetrics and gynecology. 2013 Feb:208(2):122.e1-6. doi: 10.1016/j.ajog.2012.10.890. Epub 2012 Nov 16     [PubMed PMID: 23164760]


[32]

Nikolova T, Uotila J, Nikolova N, Bolotskikh VM, Borisova VY, Di Renzo GC. Prediction of spontaneous preterm delivery in women presenting with premature labor: a comparison of placenta alpha microglobulin-1, phosphorylated insulin-like growth factor binding protein-1, and cervical length. American journal of obstetrics and gynecology. 2018 Dec:219(6):610.e1-610.e9. doi: 10.1016/j.ajog.2018.09.016. Epub 2018 Sep 18     [PubMed PMID: 30240653]


[33]

Dayal S, Jenkins SM, Hong PL. Preterm and Term Prelabor Rupture of Membranes (PPROM and PROM). StatPearls. 2025 Jan:():     [PubMed PMID: 30422483]


[34]

Gyamfi-Bannerman C, Thom EA. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The New England journal of medicine. 2016 Aug 4:375(5):486-7. doi: 10.1056/NEJMc1605902. Epub     [PubMed PMID: 27518669]


[35]

Deshmukh US, Lundsberg LS, Pettker CM, Rouse DJ, Reddy UM. Neonatal outcomes by delivery indication after administration of antenatal late preterm corticosteroids. AJOG global reports. 2022 Nov:2(4):100097. doi: 10.1016/j.xagr.2022.100097. Epub 2022 Sep 15     [PubMed PMID: 36536839]


[36]

Kamath-Rayne BD, Rozance PJ, Goldenberg RL, Jobe AH. Antenatal corticosteroids beyond 34 weeks gestation: What do we do now? American journal of obstetrics and gynecology. 2016 Oct:215(4):423-30. doi: 10.1016/j.ajog.2016.06.023. Epub 2016 Jun 21     [PubMed PMID: 27342043]


[37]

Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org, Reddy UM, Deshmukh U, Dude A, Harper L, Osmundson SS. Society for Maternal-Fetal Medicine Consult Series #58: Use of antenatal corticosteroids for individuals at risk for late preterm delivery: Replaces SMFM Statement #4, Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery, August 2016. American journal of obstetrics and gynecology. 2021 Nov:225(5):B36-B42. doi: 10.1016/j.ajog.2021.07.023. Epub 2021 Aug 5     [PubMed PMID: 34363784]


[38]

Committee on Obstetric Practice. Committee Opinion No. 713: Antenatal Corticosteroid Therapy for Fetal Maturation. Obstetrics and gynecology. 2017 Aug:130(2):e102-e109. doi: 10.1097/AOG.0000000000002237. Epub     [PubMed PMID: 28742678]

Level 3 (low-level) evidence

[39]

Stock SJ, Thomson AJ, Papworth S, Royal College of Obstetricians and Gynaecologists. Antenatal corticosteroids to reduce neonatal morbidity and mortality: Green-top Guideline No. 74. BJOG : an international journal of obstetrics and gynaecology. 2022 Jul:129(8):e35-e60. doi: 10.1111/1471-0528.17027. Epub 2022 Feb 16     [PubMed PMID: 35172391]


[40]

Liauw J, Foggin H, Socha P, Crane J, Joseph KS, Burrows J, Lacaze-Masmonteil T, Jain V, Boutin A, Hutcheon J. Technical Update No. 439: Antenatal Corticosteroids at Late Preterm Gestation. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2023 Jun:45(6):445-457.e2. doi: 10.1016/j.jogc.2022.12.006. Epub 2022 Dec 23     [PubMed PMID: 36572248]


[41]

Vogel JP, Ramson J, Darmstadt GL, Qureshi ZP, Chou D, Bahl R, Oladapo OT. Updated WHO recommendations on antenatal corticosteroids and tocolytic therapy for improving preterm birth outcomes. The Lancet. Global health. 2022 Dec:10(12):e1707-e1708. doi: 10.1016/S2214-109X(22)00434-X. Epub     [PubMed PMID: 36400080]


[42]

Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS, Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet (London, England). 2006 Jun 10:367(9526):1913-9     [PubMed PMID: 16765760]

Level 1 (high-level) evidence

[43]

Wilson A, Hodgetts-Morton VA, Marson EJ, Markland AD, Larkai E, Papadopoulou A, Coomarasamy A, Tobias A, Chou D, Oladapo OT, Price MJ, Morris K, Gallos ID. Tocolytics for delaying preterm birth: a network meta-analysis (0924). The Cochrane database of systematic reviews. 2022 Aug 10:8(8):CD014978. doi: 10.1002/14651858.CD014978.pub2. Epub 2022 Aug 10     [PubMed PMID: 35947046]

Level 1 (high-level) evidence

[44]

Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstetrics and gynecology. 2009 Mar:113(3):585-594. doi: 10.1097/AOG.0b013e318199924a. Epub     [PubMed PMID: 19300321]

Level 1 (high-level) evidence

[45]

Conde-Agudelo A, Romero R, Kusanovic JP. Nifedipine in the management of preterm labor: a systematic review and metaanalysis. American journal of obstetrics and gynecology. 2011 Feb:204(2):134.e1-20. doi: 10.1016/j.ajog.2010.11.038. Epub     [PubMed PMID: 21284967]

Level 1 (high-level) evidence

[46]

Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. The Cochrane database of systematic reviews. 2014 Jun 5:2014(6):CD002255. doi: 10.1002/14651858.CD002255.pub2. Epub 2014 Jun 5     [PubMed PMID: 24901312]

Level 1 (high-level) evidence

[47]

Xiong Z, Pei S, Zhu Z. Four kinds of tocolytic therapy for preterm delivery: Systematic review and network meta-analysis. Journal of clinical pharmacy and therapeutics. 2022 Jul:47(7):1036-1048. doi: 10.1111/jcpt.13641. Epub 2022 Mar 18     [PubMed PMID: 35304748]

Level 1 (high-level) evidence

[48]

Vermillion ST, Scardo JA, Lashus AG, Wiles HB. The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age. American journal of obstetrics and gynecology. 1997 Aug:177(2):256-9; discussion 259-61     [PubMed PMID: 9290437]


[49]

Savage AH, Anderson BL, Simhan HN. The safety of prolonged indomethacin therapy. American journal of perinatology. 2007 Apr:24(4):207-13     [PubMed PMID: 17447185]


[50]

Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. American journal of obstetrics and gynecology. 2015 Apr:212(4):505.e1-13. doi: 10.1016/j.ajog.2014.10.1091. Epub 2014 Oct 30     [PubMed PMID: 25448524]

Level 1 (high-level) evidence

[51]

Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ (Clinical research ed.). 2012 Oct 9:345():e6226. doi: 10.1136/bmj.e6226. Epub 2012 Oct 9     [PubMed PMID: 23048010]

Level 1 (high-level) evidence

[52]

van Vliet EOG, Nijman TAJ, Schuit E, Heida KY, Opmeer BC, Kok M, Gyselaers W, Porath MM, Woiski M, Bax CJ, Bloemenkamp KWM, Scheepers HCJ, Jacquemyn Y, Beek EV, Duvekot JJ, Franssen MTM, Papatsonis DN, Kok JH, van der Post JAM, Franx A, Mol BW, Oudijk MA. Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. Lancet (London, England). 2016 May 21:387(10033):2117-2124. doi: 10.1016/S0140-6736(16)00548-1. Epub 2016 Mar 2     [PubMed PMID: 26944026]

Level 1 (high-level) evidence

[53]

Duckitt K, Thornton S, O'Donovan OP, Dowswell T. Nitric oxide donors for treating preterm labour. The Cochrane database of systematic reviews. 2014 May 8:2014(5):CD002860. doi: 10.1002/14651858.CD002860.pub2. Epub 2014 May 8     [PubMed PMID: 24809331]

Level 1 (high-level) evidence

[54]

Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, Iams JD, Wapner RJ, Sorokin Y, Alexander JM, Harper M, Thorp JM Jr, Ramin SM, Malone FD, Carpenter M, Miodovnik M, Moawad A, O'Sullivan MJ, Peaceman AM, Hankins GD, Langer O, Caritis SN, Roberts JM, Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. The New England journal of medicine. 2008 Aug 28:359(9):895-905. doi: 10.1056/NEJMoa0801187. Epub     [PubMed PMID: 18753646]

Level 1 (high-level) evidence

[55]

Shepherd ES, Goldsmith S, Doyle LW, Middleton P, Marret S, Rouse DJ, Pryde P, Wolf HT, Crowther CA. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. The Cochrane database of systematic reviews. 2024 May 10:5(5):CD004661. doi: 10.1002/14651858.CD004661.pub4. Epub 2024 May 10     [PubMed PMID: 38726883]

Level 1 (high-level) evidence

[56]

Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks' gestation: a systematic review and metaanalysis. American journal of obstetrics and gynecology. 2009 Jun:200(6):595-609. doi: 10.1016/j.ajog.2009.04.005. Epub     [PubMed PMID: 19482113]

Level 1 (high-level) evidence

[57]

. WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. 2015:():     [PubMed PMID: 26447264]


[58]

. Prevention of Early-onset Neonatal Group B Streptococcal Disease: Green-top Guideline No. 36. BJOG : an international journal of obstetrics and gynaecology. 2017 Nov:124(12):e280-e305. doi: 10.1111/1471-0528.14821. Epub 2017 Sep 13     [PubMed PMID: 28901693]


[59]

Fogarty M, Osborn DA, Askie L, Seidler AL, Hunter K, Lui K, Simes J, Tarnow-Mordi W. Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis. American journal of obstetrics and gynecology. 2018 Jan:218(1):1-18. doi: 10.1016/j.ajog.2017.10.231. Epub 2017 Oct 30     [PubMed PMID: 29097178]

Level 1 (high-level) evidence

[60]

Seidler AL, Aberoumand M, Hunter KE, Barba A, Libesman S, Williams JG, Shrestha N, Aagerup J, Sotiropoulos JX, Montgomery AA, Gyte GML, Duley L, Askie LM, iCOMP Collaborators. Deferred cord clamping, cord milking, and immediate cord clamping at preterm birth: a systematic review and individual participant data meta-analysis. Lancet (London, England). 2023 Dec 9:402(10418):2209-2222. doi: 10.1016/S0140-6736(23)02468-6. Epub 2023 Nov 14     [PubMed PMID: 37977169]

Level 1 (high-level) evidence

[61]

Chartrand L, Barrington KJ, Dodin P, Villeneuve A. Delayed cord clamping in preterm twin infants: a systematic review and meta-analysis. American journal of obstetrics and gynecology. 2024 Oct 28:():. pii: S0002-9378(24)01085-8. doi: 10.1016/j.ajog.2024.10.024. Epub 2024 Oct 28     [PubMed PMID: 39477050]

Level 1 (high-level) evidence

[62]

Chaudhary P, Priyadarshi M, Singh P, Chaurasia S, Chaturvedi J, Basu S. Effects of delayed cord clamping at different time intervals in late preterm and term neonates: a randomized controlled trial. European journal of pediatrics. 2023 Aug:182(8):3701-3711. doi: 10.1007/s00431-023-05053-6. Epub 2023 Jun 6     [PubMed PMID: 37278737]

Level 1 (high-level) evidence

[63]

Mota P, Bø K. ACOG Committee Opinion No. 804: Physical Activity and Exercise During Pregnancy and the Postpartum Period. Obstetrics and gynecology. 2021 Feb 1:137(2):376. doi: 10.1097/AOG.0000000000004267. Epub     [PubMed PMID: 33481514]

Level 3 (low-level) evidence

[64]

Saccone G, Della Corte L, Cuomo L, Reppuccia S, Murolo C, Napoli FD, Locci M, Bifulco G. Activity restriction for women with arrested preterm labor: a randomized controlled trial. American journal of obstetrics & gynecology MFM. 2023 Aug:5(8):100954. doi: 10.1016/j.ajogmf.2023.100954. Epub 2023 Apr 18     [PubMed PMID: 37080296]

Level 1 (high-level) evidence

[65]

Fuchs IB, Henrich W, Osthues K, Dudenhausen JW. Sonographic cervical length in singleton pregnancies with intact membranes presenting with threatened preterm labor. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2004 Oct:24(5):554-7     [PubMed PMID: 15386604]


[66]

Crump C, Sundquist J, Sundquist K. Adverse Pregnancy Outcomes and Long-Term Mortality in Women. JAMA internal medicine. 2024 Jun 1:184(6):631-640. doi: 10.1001/jamainternmed.2024.0276. Epub     [PubMed PMID: 38619848]


[67]

Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB, Walsh MC, Vohr BR, Stoll BJ, Carlo WA, Van Meurs KP, Rysavy MA, Patel RM, Merhar SL, Sánchez PJ, Laptook AR, Hibbs AM, Cotten CM, D'Angio CT, Winter S, Fuller J, Das A, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. JAMA. 2022 Jan 18:327(3):248-263. doi: 10.1001/jama.2021.23580. Epub     [PubMed PMID: 35040888]


[68]

Ward RM, Beachy JC. Neonatal complications following preterm birth. BJOG : an international journal of obstetrics and gynaecology. 2003 Apr:110 Suppl 20():8-16     [PubMed PMID: 12763105]


[69]

Moore T, Hennessy EM, Myles J, Johnson SJ, Draper ES, Costeloe KL, Marlow N. Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. BMJ (Clinical research ed.). 2012 Dec 4:345():e7961. doi: 10.1136/bmj.e7961. Epub 2012 Dec 4     [PubMed PMID: 23212880]


[70]

Nelson DB, Lafferty A, Venkatraman C, McDonald JG, Eckert KM, McIntire DD, Spong CY. Association of Vaginal Progesterone Treatment With Prevention of Recurrent Preterm Birth. JAMA network open. 2022 Oct 3:5(10):e2237600. doi: 10.1001/jamanetworkopen.2022.37600. Epub 2022 Oct 3     [PubMed PMID: 36315147]


[71]

Conde-Agudelo A, Romero R. Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis. American journal of obstetrics and gynecology. 2022 Sep:227(3):440-461.e2. doi: 10.1016/j.ajog.2022.04.023. Epub 2022 Apr 20     [PubMed PMID: 35460628]

Level 1 (high-level) evidence