An expert resource for medical professionals
Provided FREE as a service to women’s health

The Global Library of Women’s Medicine’s
Welfare of Women
Global Health Programme

An Educational Platform for

The global voice for women’s health

This chapter should be cited as follows:
Lalani ZV, Wanyonyi S, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.414173

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 10

Common obstetric conditions

Volume Editor: Professor Sikolia Wanyonyi, Aga Khan University Hospital, Nairobi, Kenya

Chapter

Preterm Labor

First published: February 2021

AUTHORS

Dr Zoya Virji Lalani, BMedSci, BMBS
Department of Obstetrics and Gynecology, Aga Khan University Hospital, Nairobi, Kenya
Dr Sikolia Wanyonyi, MMED, MRCOG
Consultant in Obstetrics/Gynaecology and Fetal Medicine, Department of Obstetrics and Gynecology, Aga Khan University Hospital, Nairobi, Kenya
Dr Charles Muteshi, MMed
Department of Obstetrics and Gynecology, Aga Khan University Hospital, Nairobi, Kenya

Study Assessment Option

By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
See end of chapter for details

INTRODUCTION

Preterm labor is the onset of labor before 37 weeks’ gestation. This accounts for about 5–18% of births worldwide and the highest proportion of perinatal mortality following preterm birth. There are also significant long-term health consequences for survivors of preterm birth. Preterm birth may be a result of preterm labor, premature preterm rupture of membranes (PPROM) or medically indicated preterm delivery for maternal or neonatal reasons. Neonatal and long-term risks depend upon the severity of prematurity and are inversely proportional to the gestational age at birth. Gestation at birth is categorized as extreme prematurity (<28 weeks’ gestation), severe prematurity (28–32 weeks’ gestation), moderate prematurity (32–34 weeks’ gestation) and near term (34–36 weeks’ gestation). Perinatal mortality increases markedly as gestational age and birth weight decline.

EPIDEMIOLOGY

Despite advances in neonatal care, perinatal mortality and morbidity appears to have remained stable over the past 40 years in preterm born neonates globally. This may be due to increasing access to assisted reproductive technologies (ART) and an increasing proportion of extremely premature deliveries. There is also an increasing proportion of pregnant women with advanced maternal age, high body mass index and medical conditions such hypertension and diabetes especially in developed countries. Due to variation in the lower cut-off gestation for preterm birth and miscarriage, previous studies have reported varied proportions of preterm labor and birth depending on geographical location.

Although the proportion of preterm labor at less than 28 weeks is low, accounting for about 5% of all preterm births perinatal, childhood and long-term complications are disproportionately high in this gestational age band.

Neonatal survival following preterm birth is higher in developed countries compared to developing countries. In developing countries half of all babies born at or before 32 weeks’ gestation die, whereas nearly all survive in developed countries. It is estimated that 15 million babies are born preterm worldwide with more than one million dying of prematurity complications. Globally, ten countries with the highest number of preterm births are developing countries except the USA.54

RISK FACTORS

Seventy five per cent of preterm births happen following spontaneous preterm labor and PPROM. Preterm labor is considered to be quite similar to term labor in its physiological mechanisms that include regular uterine contractions, progressive cervical dilation and membrane rupture. Whereas the mechanisms of labor may be similar at both term and preterm, the former is physiological and the latter a pathological activation of labor mechanisms.

Not all preterm labor is associated with identifiable antecedent risk factors, and this may differ between high-income countries and low- and middle-income countries. Table 1 summarizes known risk factors for preterm labor and PPROM.

Epidemiological evidence consistently shows that Black women compared to their Caucasian counterparts are at increased risk of preterm birth with an even higher risk of severe preterm birth in the USA.1 It is not completely understood why this is the case; however, it is postulated that Black women are likely to be more socially deprived and at higher risk of psychological morbidity and stress. In addition, the prevalence of bacterial vaginosis appears to be higher in Black than Caucasian women.2,3,4 These factors are associated with a higher risk for preterm birth; however, it is difficult to disentangle the actual reasons for the disparity due to confounding factors. Clearly, there is no biological explanation as studies have reported the risk of preterm birth increases with the duration of time spent in the USA by foreign-born women.

The single most significant risk factor for preterm birth is a history of previous preterm birth with recurrences often occurring at the same gestational age.5 The risk being inversely proportional to the gestation at which the previous birth occurred. It is estimated that the risk for subsequent preterm birth may be 2.5-fold higher following a previous preterm birth. Whereas persistent factors have not been elucidated that may account for this residual risk, it forms the basis for cervical length measurement during pregnancy.

Women at extremes of maternal age have higher rates of preterm birth, this could be due to younger adults being physiologically immature or impacting socioeconomic factors, whilst older mothers have a higher prevalence of pre-existing conditions and obesity.6

The proportion of multiple pregnancies spontaneously conceived remains low, however, with advent of ART, pregnancies following ART are increasingly becoming common even in developing countries. Pregnancies conceived by ART are at a higher risk of preterm birth even if they result in a singleton gestation.7 The highest risk follows multiple embryo transfer, even though there seems to be an increase in the risk of monozygotic multifetal pregnancy with blastocyst or embryo manipulation techniques. Twins carry a substantial risk of preterm birth of nearly 60% and account for 15–20% of all preterm births. More than three-quarters of higher order multiple pregnancies will be born preterm, more likely in the severe preterm gestational age bracket.

The majority of these preterm births will be a result of spontaneous preterm labor. Uterine over-distension is the mechanism behind preterm labor initiation. Moreover, twin pregnancies are likely to be complicated by maternal conditions such as hypertension, pre-eclampsia and gestational diabetes that require iatrogenic preterm delivery.

Generally, the interval for a subsequent pregnancy is likely to be longer following a term pregnancy with a good outcome. Women with a shorter inter-pregnancy interval of <6 months have a two-fold increased risk of preterm birth.8 The mechanism for this increased risk is unknown, though it could be due to a higher risk of preterm birth in the preceding pregnancy. Women who conceive using ART may be in haste to conceive following delivery so they can complete their families sooner due to a variety of reasons, not the least being maternal age.

Social factors such as maternal smoking and alcohol consumption are associated with adverse pregnancy outcomes. In the USA, up to 15% of women who become pregnant while smoking will continue to smoke throughout pregnancy. There are many chemical compounds found in tobacco smoke though no specific chemical has been identified as responsible for how the 2-fold increased risk of preterm birth is conferred. Women who smoke or use substances are also at increased risk of other factors such as social deprivation, psychological disturbances or extremes of body mass index, confounders which are difficult to separate from the attributable risk from the substance abuse.9,10

Early pregnancy bleeding is not uncommon and is associated with increased risk of preterm labor, PPROM, placental abruption and severe pre-eclampsia.11 In addition, women with placental abruption, previa or who experience unexplained vaginal bleeding after the first trimester have a higher risk of preterm delivery.

Cervical surgery and cervical irregularities also contribute greatly to the increased risk of preterm labor, whilst cervical length measurement has become an important surveillance method in these women. Surgeries to the cervix include cold knife conization and loop electrosurgical excision procedures. Women with a short cervix, as measured by transvaginal ultrasound between 16 and 28 weeks' gestation, have an inversely related to the risk of preterm birth in both singletons and twins. Furthermore, cervical dilation of >1 cm before 24 weeks' gestation is associated with an increased risk of preterm birth. Congenital uterine abnormalities can affect the cervix and/or the uterine corpus with the risk of preterm birth of up to 25–50% depending on the specific abnormality. The presence of large (>5–6 cm) or multiple uterine leiomyomas is an important risk factor for preterm birth with those with a submucosal location further contributing to pregnancy loss.12,13

Infections in pregnancy have been associated with preterm labor and birth. These include asymptomatic bacteriuria and genital tract infections. Studies are unclear on whether asymptomatic bacteriuria is an independent risk factor for preterm birth;14 however, practice guidelines suggest a first trimester urine culture be performed on all pregnant women with antenatal screening performed on those at high risk for asymptomatic bacteriuria. Colonization of the genital tract with group B streptococci (GBS), Chlamydia trachomatis, bacterial vaginosis (BV), Neisseria gonorrhoea, syphilis, Trichomonas vaginalis, Ureaplasma species, and unencapsulated Haemophilus influenza have all been associated with an increased risk of preterm birth.

1

Risk factors for preterm birth.

Maternal

Pregnancy characteristics

Black race

Previous preterm birth

<17 or >35 years of age

Assisted conception, e.g. IVF

Psychological stress

Multiple pregnancy

Low socioeconomic status

PPROM

Behavior: smoking/alcohol/cocaine/heroin

Antepartum hemorrhage

Low pre-pregnancy BMI

Polyhydramnios

Cervical conization or multiple D&Es

Interpregnancy interval <6 months

Uterine anomalies

Medical conditions: hypertension, diabetes, thyroid disease, asthma


Infections in pregnancy

PPROM, preterm premature rupture of the membranes; BMI, body mass index.

PATHOPHYSIOLOGY OF PRETERM LABOR

The mechanisms of labor are similar at both term and preterm; however, the former is physiological and the latter a pathological activation of labor mechanisms. Preterm labor likely occurs when local uterine factors are prematurely stimulated or there is a premature withdrawal of the factors that maintain uterine quiescence.

During pregnancy, uterine quiescence is maintained by progesterone hormone acting to reduce up regulation of the contraction associated proteins and prostaglandin activity, hence inhibition of uterine activity and cervical changes. It is not known how labor is initiated in human term pregnancy. Similarly, the exact mechanisms of the onset of preterm labor are unknown, though it is thought to be a heterogeneous process. Complex mechanisms converge and lead to cervical ripening and dilation, membrane activation and rupture, and increased uterine contractility ending as the final process of labor both in term and preterm pregnancy.

Four major factors leading to preterm labor are intrauterine infection, decidual hemorrhage, excessive uterine stretch and maternal or fetal stress. This pathophysiological construct of uterine distension, placental ischemia and chorio-decidual activation or inflammation has been proposed as the trigger of preterm labor. Central to this is an inflammatory process that results in prostaglandin release. Prostaglandins are well known in the propagation mechanisms in the process of labor. Pathological activation of these pathways manifests clinically in the form of cervical insufficiency, preterm uterine contractions or PPROM.

A significant amount of scientific work demonstrates that infection underlies preterm labor in nearly 40% of cases. The amniotic fluid environment is considered sterile with less than 1% of women at term having bacteria in the amniotic fluid. Interestingly, women who had bacteria (Mycoplasma hominis and Ureaplasma urealyticum) incidentally isolated from the amniotic fluid during amniocentesis went on to have preterm birth. The earlier the gestational age at preterm birth, the more likely that microbial invasion of the amniotic cavity is present.

Evidence for infection causing preterm birth is strengthened by the increased level of inflammatory markers present. These protect the host against infection but are similar to mediators that trigger parturition thus in the setting of infection, the onset of preterm labor is likely a host defence mechanism.

Maternal BV is a consistently reported risk factor for spontaneous preterm delivery, yet treatment of BV does not reliably prevent preterm birth in women with BV.15 Emerging evidence has shown that pregnancy alters the vaginal microbiome in favor of Lactobacillus spp. compared to BV organisms with the exception of BV-associated bacterium 1 (BVAB1) which has been found to be more prevalent in African women. This gene–environment interaction contributes to the manifestation of preterm labor.

After inflammation, the most common abnormality seen in placental pathology from preterm births is vascular lesions, both in the maternal and fetal circulation.16 Uteroplacental ischemia caused by failure of physiological transformation of maternal spiral arteries (similar to the pathogenesis of pre-eclampsia and intrauterine growth restriction) has been shown in women with preterm labor. Furthermore, abnormal uterine artery Doppler velocimetry has been reported in women with apparently idiopathic preterm labor. The decidua is a rich source of tissue factor which is the principal initiator of coagulation and thrombin activation, decidual necrosis and hemorrhage can activate labor mechanisms through the production of thrombin which stimulates uterine contractility in a dose–dependent manner. This accounts for the clinical association of vaginal bleeding and hemorrhage with preterm labor and PPROM.17,18

Uterine over distension linked to multiple gestation, polyhydramnios, etc. is a well described risk factor for preterm birth. The stretch effect on the myometrium induces the formation of gap junctions, upregulation of oxytocin receptors, increased production of inflammatory cytokines and prostaglandins, and myosin light chain kinase, culminating in uterine contractions and cervical dilation.19 Stretch can also affect the fetal membranes causing an increase in production of collagenase, interleukin-8 and prostaglandin E2 which contribute to membrane rupture.

Premature activation of the maternal or fetal hypothalamus–pituitary–adrenal (HPA) axis related to stress is the fourth major factor in the pathogenesis of preterm birth. The main fetal stressor leading to preterm birth is uteroplacental ischemia,20,21 this is due to increased corticotropin-releasing hormone,22 binding to the ligand binding site on the progesterone receptor23 and increased release of fetal pituitary adrenocorticotropic hormone.24 Severe maternal psychosocial stress has also been implicated in the activation of the maternal HPA axis with worsening of symptoms increasing the risk of preterm birth.25,26,27

Pathological cervical change leading to a sonographic short cervix and subsequent preterm birth results from activation of both the hemorrhagic and the inflammatory pathways, whilst maintaining myometrial quiescence resulting in cervical changes without preterm labor. Cerclage may be helpful in selected instances.

Fetal fibronectin (fFN) is an extracellular matrix protein that is present at the decidual–chorionic interface. Dissolution of the extracellular fibronectins is thought to be responsible for the process that allows the membranes to separate from the decidua after birth. Detection of fFN between 22 and 37 weeks' gestation is evidence of disruption of the decidual–chorionic interface and is associated with an increased risk of preterm labor.28 Disruption can occur due to infection, inflammation, abruption or uterine contractions.

CLINICAL FINDINGS

True labor is defined by regular contractions plus cervical change whether this is at term or preterm. It is important to distinguish this from false labor where contractions do not result in cervical change. Symptoms include:

  • Abdominal cramping;
  • Contractions (these increase in both frequency and duration in true labor);
  • Pressure sensation in the pelvis;
  • Vaginal discharge, e.g. mucus plug or bloody show.

Any acute conditions that threaten the health of the mother and the fetus should be assessed and may mandate delivery, e.g. acute pyelonephritis, asthma, pneumonia, trauma, severe pre-eclampsia, placental abruption or previa and chorioamnionitis. Fetal compromise may be acute and manifest as an abnormal cardiotocogram or chronic manifesting as fetal growth restriction or oligohydramnios.

DIAGNOSTIC EVALUATION

This is performed on the labor unit:

  • History and assessment:
    • Review of past and present obstetric history – looking for any risk factors for preterm birth;
    • Ensure correct assessment of gestational age;
    • Evaluate for clinical signs of labor;
    • Take maternal vital signs;
    • Examine uterus for firmness, tenderness, fetal size and position;
    • Perform a cardiotocogram;
    • Assess maternal contractions in terms of frequency, intensity and duration.
  • Speculum examination:
    • Estimate cervical dilation (≥3 cm supports preterm labor);
    • Assess per vaginal bleeding if any;
    • Assess for PPROM:
      • Pooling of amniotic fluid observed;
      • If pooling is not observed, perform an insulin-like growth factor binding protein-1 or placental alpha-microglobulin-1 test of vaginal fluid;
      • Do not use nitrazine to diagnose PPROM;
    • Swab cervicovaginal fluid for fetal fibronectin (fFN) testing;
    • Culture swab for chlamydia/gonorrhea (cervix) and group B streptococcus (rectovaginal).
  • Digital cervical examination:
    • Assessment of cervical dilation;
    • Perform if placenta previa and PPROM have been ruled out.
  • Transvaginal ultrasound (TVS) examination:
    • Measurement of cervical length:29
      • A short cervix of <3 cm before 34 weeks has an increased risk of preterm birth.
  • Obstetrical ultrasound examination:
    • Assessment of; 
      • Fetus: anomalies, presentation, size, weight;
      • Placenta: position, abnormalities;
      • Amniotic fluid: volume;
      • Maternal: anatomic anomalies;
      • Dopplers: in the case of fetal growth restriction.
  • Laboratory evaluation:
    • Rectovaginal group B streptococcal culture;
    • Culture for chlamydia/gonorrhea;
    • Urine culture to diagnose asymptomatic bacteriuria;
    • fFN in women <34 weeks, cervical dilation <3 cm and cervical length between 2 and 3 cm on TVS:
      • Measurement of fFN is performed to distinguish women in true preterm labor from those with false labor so as to avoid unnecessary intervention for the 50% of patients that will ultimately have a term birth without tocolysis.30
      • Qualitative result is positive or negative: A positive fFN test refers to a fFN concentration ≥50 ng/mL in cervicovaginal fluid between 22+0 and 34+6 weeks' gestation in women with intact membranes, cervical dilation <3 cm, and no gross vaginal bleeding. A positive fFN result correlates with an increased risk of preterm delivery within 7 days.31
      • Quantitative result: uses a 50 ng/mL threshold. A threshold of 10, 50, 200, and 500 ng/mL predict preterm birth within 14 days by 11, 20, 37, and 46%, respectively.32
      • If fFN testing is negative (concentration 50 ng/ml or less), it is unlikely to be preterm labor.

DIAGNOSIS

Specific criteria used for diagnosis of preterm labor:33

Uterine contractions: ≥4 every 20 minutes or ≥8 in 60 minutes

plus

Cervical dilation ≥3 cm or

Cervical length <20 mm on transvaginal ultrasound or

Cervical length 20–<30 mm on transvaginal ultrasound and positive fetal fibronectin.

TREATMENT

  • ≥34 weeks' gestation:
    • Admit for delivery after observation for 6 hours if progressive cervical dilation and effacement are documented.
  • <34 weeks' gestation
    • Maternal antenatal transfer: Women who are at risk of preterm delivery especially prior to 32 weeks should be assessed to be transferred to a unit where there is an NICU to ensure care for the preterm infant.
    • Administer antenatal corticosteroids to reduce neonatal morbidity and mortality due to respiratory distress syndrome, intraventricular hemorrhage, and other causes.
    • Administer antibiotics for GBS chemoprophylaxis, because preterm infants have a greater risk of neonatal GBS infection than those born at term, intrapartum prophylaxis with penicillin is recommended.
    • Administer tocolytic drugs for up to 48 hours to delay delivery, so that antenatal steroids given to the mother can achieve its maximum fetal effect.
    • Administer magnesium sulfate for pregnancies at 24–32 weeks' gestation. In utero exposure to magnesium sulfate provides neuroprotection against cerebral palsy and other types of severe motor dysfunction in offspring born preterm.

Antenatal corticosteroids

  • Evidence has shown that a single dose course of antenatal corticosteroid therapy administered to women at risk for preterm birth reduces the risk of respiratory distress syndrome, intraventricular hemorrhage and necrotizing enterocolitis.34
  • Gestational age at administration:
    • 22+0 to 33+6 weeks: if delivery in the next 1–7 days is anticipated with planned neonatal care. Evidence has shown that the risk of major morbidity is still high even with the administration of the antenatal steroids
      • If not delivered, a single repeat course of antenatal corticosteroids may be needed later in gestation when the treatment is thought to be more effective.
    • >34+0 weeks: use of antenatal steroids is controversial because of the inconsistent data available; however, clinical approaches vary and some clinicians will still administer corticosteroids prior to delivery due to the reduction in neonatal respiratory morbidity especially if the mode of delivery is by cesarean section as respiratory problems are less common after labor and vaginal birth.
      • 34+0 to 36+6 weeks: The American College of Obstetricians and Gynecologists (ACOG) recommends the administration of antenatal corticosteroids for women with singleton pregnancy at risk of imminent preterm birth within 7 days.35

Antibiotics for GBS chemoprophylaxis

  • Women with a known positive GBS culture within the previous 5 weeks should be given GBS prophylaxis if admitted in preterm labor.
  • If colonization status is unknown, GBS cultures are obtained at the time of presentation and then antibiotic prophylaxis is administered
  • GBS prophylaxis is continued until delivery if true preterm labor; however, if after a period of observation and the patient is not in true labor then the antibiotics should be discontinued.
  • If the culture result is negative, no GBS prophylaxis is needed if preterm labor recurs within the next 5 weeks.
  • If the patient is undelivered at 36+0 to 37+6 weeks' gestation, a vaginal–rectal culture should be repeated

Tocolysis

  • Administration of tocolytic drugs (Table 2) can reduce the strength and frequency of uterine contractions.
  • Evidence has shown that tocolytic drugs are more effective than placebo/control for delaying delivery for a maximum of 48 hours to 7 days. Tocolysis therapy should not be used continuously until term gestation is reached.30
  • The goal of tocolysis is to delay delivery by at least 48 hours, so that corticosteroids have time to achieve their maximal effects, transfer the mother to a facility where there is appropriate neonatal care or to prolong the pregnancy in the case where conditions that cause labor are treated and are unlikely to cause recurrent preterm labor, e.g. pyelonephritis.
  • Give tocolysis to women:
    • In early phase of preterm labor, where cervical dilation is still <3 cm;
    • Gestational age of ≥2436–34 weeks' gestation.
  • Contraindications to tocolysis include:
    • Intrauterine fetal demise;
    • Lethal fetal anomaly;
    • Non-reassuring fetal status;
    • Pre-eclampsia with severe features or eclampsia;
    • Maternal hemorrhage with hemodynamic instability;
    • Intraamniotic infection;
    • Preterm prelabor rupture of membranes;
    • Medical contraindications to the tocolytic drug.

2

Types of tocolytic drugs.

Drug

Mode of action

Efficacy

Maternal side- effects

Fetal side-effects

Contraindications

Cyclooxygenase inhibitors, e.g. indomethacin

Cyclooxygenase is the enzyme responsible for conversion of arachidonic acid to prostaglandins, which are critical in parturition, thus cyclooxygenase inhibitors reduce prostaglandin production

Reduces the risk of delivery within 48 hours of initiation compared to any beta-agonist, but as effective as nifedipine

Nausea, esophageal reflux, gastritis, and emesis; platelet dysfunction (rare)

In utero closure of ductus arteriosus (risk associated with use for >48 h) and oligohydramnios. PDA in neonate

Platelet dysfunction or bleeding disorder, hepatic or renal dysfunction, gastrointestinal or ulcerative disease, asthma (in women with hypersensitivity to aspirin)

Calcium channel blockers, e.g. nifedipine

Directly block the influx of calcium ions through the cell membrane and inhibit release of intracellular calcium from the sarcoplasmic reticulum and increase calcium efflux from the cell. The resulting decrease in intracellular free calcium inhibits calcium-dependent myosin light-chain kinase phosphorylation, leading to myometrial relaxation

Reduces the risk of delivery within 48 hours. Benefits over beta-agonists with respect to prolongation of pregnancy, neonatal morbidities and maternal adverse effect

Dizziness, flushing, headache, palpitations, elevation of hepatic aminotransferase levels


Hypotension, preload-dependent cardiac lesions (e.g. aortic insufficiency)

Beta-agonists, e.g. ritodrine and terbutaline

The beta-2 receptor agonists cause myometrial relaxation by binding with beta-2 adrenergic receptors and increasing intracellular adenyl cyclase

Decreases the number of women giving birth within 48 h

Tachycardia and hypotension, tremor, shortness of breath, chest discomfort, pulmonary edema, hypokalemia, hyperglycemia

Tachycardia

Tachycardia-sensitive maternal cardiac disease, poorly controlled diabetes mellitus

Oxytocin-receptor antagonists, e.g. atosiban

Selective oxytocin-vasopressin receptor antagonist

Use of these drugs does not reduce the risk of birth within 48 hours of initiation of treatment, the risk of preterm birth at less than 28 weeks' gestation or the risk of preterm birth at <37 weeks

Hypersensitivity injection-site reactions

For atosiban, an increased rate of fetal or infant death (may be attributable to the lower gestational age of infants in the atosiban group)

None

Nitric oxide donors, e.g. glyceryl trinitrate

Nitric oxide is produced in a variety of cells and is essential for maintenance of normal smooth muscle tone. Extracellular stimuli of NO formation to the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP). The increase in cGMP content in smooth muscle cells activates myosin light chain kinases leading to smooth muscle relaxation

Use of glyceryl trinitrate does not significantly prolong pregnancy by ≥48 h, reduce preterm birth, or result in improved neonatal outcomes compared to placebo, beta agonists and nifedipine

Dizziness, flushing, hypotension


Hypotension, preload-dependent cardiac lesions (e.g., aortic insufficiency)

Magnesium sulfate

Competes with calcium at the level of the plasma membrane voltage-gated channels and inhibits myosin light-chain kinase activity, reducing myometrial contractility

Administration does not result in a statistical reduction in birth <48 h. Neither more nor less effective than other tocolytics

Flushing, diaphoresis, nausea, loss of deep-tendon reflexes (serum levels of 9.6–12 mg/dL), respiratory paralysis (at serum levels of 12–18 mg/dL), cardiac arrest (at serum levels of 24–30 mg/dL); when used with calcium channel blockers, suppression of heart rate, contractility, and left ventricular systolic pressure and neuromuscular blockade


Myasthenia gravis

  • Clinical practice dictates which tocolytic is used.
    • 24–32 weeks: indomethacin has been suggested as first-line therapy for labor inhibition due to its reduced side-effect profile and its compatibility with magnesium sulfate which is used concomitantly for neuroprotection.
    • 32–34 weeks: nifedipine is used as first-line therapy, followed by terbutaline as second-line therapy.

Magnesium sulfate for neuroprotection

Multiple large studies have shown that antenatal administration of magnesium sulfate has been associated with a reduction in cerebellar hemorrhage in preterm infants37 with a reduction in cerebral palsy.38,39,40,41 The mechanism of action is poorly understood; however, several have been proposed including stabilization of the cerebral circulation and protection against oxidative, inflammatory and excitatory injury.

Candidates:

  • Women at high risk of imminent (within 24 hours) preterm birth
  •  >24–<32 weeks’ gestation

Administer for 24 hours (even if delivery has not occurred), repeat doses are not advised.

Prevention of preterm birth

When a woman presents acutely in established preterm labor, efforts to delay delivery are somewhat unsuccessful. A lot of research has therefore been performed in prevention strategies.

Progesterone supplementation

Physiologically, progesterone helps maintain pregnancy in many ways; its production from the corpus luteum is critical in early pregnancy until the placenta takes over, it helps maintain uterine quiescence and prevents apoptosis in the fetal membranes in pro-inflammatory conditions.

The efficacy of progesterone supplementation depends on appropriate patient selection which is summarized in Table 3.

Pregnancies likely to benefit include:

  • Women with a singleton pregnancy who have had a previous spontaneous preterm singleton birth.
    • A meta-analysis in 2013 showed that in women with a past history of preterm birth, progesterone supplementation resulted in a lower risk of subsequent preterm birth and a lower risk of neonatal morbidity including use of assisted ventilation, incidence of necrotizing enterocolitis and NICU admission.42
    • The use of hydroxyprogesterone caproate injection is supported by a randomized controlled trial by Meis et al., where active prophylaxis with progesterone injections reduced the risk of preterm delivery at all gestational ages studied.43 However, the PROLONG trial reported no significant reduction in preterm birth or neonatal morbidity when women were supplemented with hydroxyprogesterone caproate injection.44
    • There have been conflicting studies regarding the use of vaginal progesterone pessaries. A Brazilian trial showed that daily supplementation with vaginal progesterone gel from 24 to 34 weeks’ gestation significantly reduced the risk of preterm delivery.45 Again, two studies the OPPTIMUM and PROGRESS studies both subsequently showed that supplementation with vaginal progesterone did not reduce fetal death/birth before 34 weeks, neonatal respiratory distress syndrome and other morbidities.46,47
  • Women with a short cervix on ultrasound examination in the current pregnancy.
    • A recent systematic review has found that supplemental vaginal progesterone in women with a short cervix of <25 mm before 24 weeks reduces the risk of preterm birth, neonatal morbidity including respiratory distress, reduced birth weight and reduced admission to NICU.48

3

Patient selection for progesterone supplementation. Adapted from Committee on Practice Bulletins-Obstetrics TACoO, Gynecologists.49

Indication

Progesterone supplementation indicated

Management

Singleton pregnancy, prior spontaneous singleton preterm birth, normal cervical length

Yes


Hydroxyprogesterone caproate 250 mg intramuscularly weekly beginning between 16 and 20 weeks' gestation and continuing through 36 weeks' gestation or until delivery and monitor cervical length. Natural progesterone administered vaginally is a reasonable alternative.

Short (≤25 mm) cervix → consider performing cerclage

Singleton pregnancy, prior spontaneous twin preterm birth, normal cervical length

Possibly

Hydroxyprogesterone caproate 250 mg intramuscularly weekly beginning between 16 and 20 weeks' gestation and continuing through 36 weeks' gestation or until delivery and monitor cervical length. Natural progesterone administered vaginally is a reasonable alternative.

Short (≤25 mm) cervix → consider performing cerclage

Singleton pregnancy, no prior spontaneous preterm birth, short cervix (≤20 mm)

Yes

Progesterone suppository 90–200 mg vaginally each night from time of diagnosis through 36 weeks' gestation.

A vaginal suppository can be prepared by a compounding pharmacy utilizing a commercially available standardized kit.

Other options include a 100 mg micronized progesterone vaginal tablet or an 8% vaginal gel containing 90 mg micronized progesterone per dose. Both preparations are commercially available in US, but not approved for prevention of preterm birth in cervical shortening

Multiple pregnancy (twins or triplets) without prior preterm birth, normal cervical length

No

No progesterone, no cerclage

Twins, prior preterm birth

Possibly

Hydroxyprogesterone caproate 250 mg intramuscularly weekly beginning between 16 and 20 week' gestation and continuing through 36 weeks' gestation or until delivery. Natural progesterone administered vaginally is a reasonable alternative.

Twins, short cervix

Possibly

Vaginal progesterone, no cerclage

Preterm premature rupture of membranes

No

Positive fetal fibronectin test

No

Undelivered after an episode of preterm labor

No



Evaluation of cervical length

Cervical shortening is one of the first steps leading to labor. This process usually begins at the level of the internal os and progresses downwards towards the external os, therefore it is often detected on ultrasound rather than on physical examination.50 Most women do not have a short cervix and of those who do, only 30% will deliver prior to 35 weeks;51 however, cervical length screening can still be cost-effective.

The diagnosis of a short cervix is when cervical length is ≤25 mm before 24 weeks' gestation. The threshold that triggers treatment varies worldwide. The diagnosis of a short cervix is when cervical length is ≤25 mm before 24 weeks' gestation. The threshold that triggers treatment varies worldwide for example The American College of Obstetricians and Gynecologists (ACOG) use a cervical length of ≤20 mm in women with no prior spontaneous birth and <25 mm in women with a prior spontaneous preterm birth at <34 weeks' gestation in order to initiate treatment.49

Treatments triggered include:

  • Vaginal progesterone: in singleton pregnancies without a prior spontaneous preterm birth;
  • Cervical cerclage (ultrasound indicated): in singleton pregnancies with a prior spontaneous preterm birth.

Universal screening of cervical length is supported by one study which showed that up to 40% of women with a short cervix are missed when selective cervical screening is performed52 and screening women without a history of preterm birth reduces the frequency of spontaneous preterm birth at <37, <34 and <32 weeks’ gestation. A 2019 meta-analysis of randomized trials did not find sufficient evidence to recommend routine cervical length screening for all pregnant women;53 however, there is a consensus for screening high-risk women with singleton pregnancies.

Screening with transvaginal ultrasound

  • Women with no prior spontaneous preterm birth are screened once at approximately 20 weeks ' gestation (18–24 weeks);
  • Women with a prior spontaneous preterm birth usually begin screening at approximately 16 weeks' gestation and the frequency depends on the measurement.

PRACTICE RECOMMENDATIONS

  • Identification of the many risk factors that can contribute to preterm labor is essential before conception or early in pregnancy to allow for interventions.
  • A history of prior preterm birth is the strongest risk factor for future preterm birth.
  • Diagnosis of preterm labor is based on specific clinical criteria that includes both regular painful contractions of the uterus and cervical dilation and/or effacement.
  • Women >34 weeks’ gestation in preterm labor are admitted for delivery as perinatal morbidity and mortality are low compared to the potential complications and costs that can result from labor inhibition at this gestation. 
  • For women diagnosed in preterm labor, consider maternal transfer to a facility with a NICU, administer tocolytic drugs for 48 hours, antibiotics for group B streptococcal chemoprophylaxis, antenatal corticosteroids and magnesium sulfate for neuroprotection (between 24 and 32 weeks’ gestation)
  • Tocolysis:
    • 24–32 weeks: indomethacin as first-line therapy and nifedipine as second-line therapy;
    • 32–34 weeks: nifedipine as first-line therapy and terbutaline as second-line therapy.
  • Prevention:
    • Progesterone supplementation in a woman with a history of preterm birth reduces the risk of recurrent preterm birth by 30%'
    • Screening with transvaginal ultrasound:
      • Women with no prior spontaneous preterm birth are screened once at approximately 20 weeks' gestation (18–24 weeks).
      • Women with a prior spontaneous preterm birth usually begin screening at approximately 16 weeks' gestation and the frequency depends on the measurement.
          • For women with no previous history of preterm delivery who develop a short cervix, progesterone supplementation may prolong gestation.
          • For women with a history of preterm delivery, who develop a short cervix despite progesterone supplementation, placement of a cerclage may prolong gestation.

CONFLICTS OF INTEREST

The authors of this chapter declare that they have no interests that conflict with the contents of the chapter.

REFERENCES

1

Srinivasjois RM, Shah S, Shah PS, Knowledge Synthesis Group on Determinants Of Preterm LBWB. Biracial couples and adverse birth outcomes: a systematic review and meta-analyses. Acta Obstet Gynecol Scand 2012;91(10):1134–46.

2

Wen A, Srinivasan U, Goldberg D, et al. Selected vaginal bacteria and risk of preterm birth: an ecological perspective. J Infect Dis 2014;209(7):1087–94.

3

Fettweis JM, Brooks JP, Serrano MG, et al. Differences in vaginal microbiome in African American women versus women of European ancestry. Microbiology 2014;160(Pt 10):2272–82.

4

Hyman RW, Fukushima M, Jiang H, et al. Diversity of the vaginal microbiome correlates with preterm birth. Reprod Sci 2014;21(1):32–40.

5

Bhattacharya S, Raja EA, Mirazo ER, et al. Inherited predisposition to spontaneous preterm delivery. Obstet Gynecol 2010;115(6):1125–33.

6

Fuchs F, Monet B, Ducruet T, et al. Effect of maternal age on the risk of preterm birth: A large cohort study. PLoS One 2018;13(1):e0191002.

7

Kiely JL. What is the population-based risk of preterm birth among twins and other multiples? Clin Obstet Gynecol 1998;41(1):3–11.

8

Wong LF, Wilkes J, Korgenski K, et al. Risk factors associated with preterm birth after a prior term delivery. BJOG : an international journal of obstetrics and gynaecology. 2016;123(11):1772–8.

9

Ney JA, Dooley SL, Keith LG, et al. The prevalence of substance abuse in patients with suspected preterm labor. Am J Obstet Gynecol 1990;162(6):1562–5; discussion 5–7.

10

Spence MR, Williams R, DiGregorio GJ, et al. The relationship between recent cocaine use and pregnancy outcome. Obstet Gynecol 1991;78(3 Pt 1):326–9.

11

Lykke JA, Dideriksen KL, Lidegaard O, et al. First-trimester vaginal bleeding and complications later in pregnancy. Obstet Gynecol 2010;115(5):935–44.

12

Rice JP, Kay HH, Mahony BS. The clinical significance of uterine leiomyomas in pregnancy. Am J Obstet Gynecol 1989;160(5 Pt 1):1212–6.

13

Koike T, Minakami H, Kosuge S, et al. Uterine leiomyoma in pregnancy: its influence on obstetric performance. J Obstet Gynaecol Res 1999;25(5):309–13.

14

Schnarr J, Smaill F. Asymptomatic bacteriuria and symptomatic urinary tract infections in pregnancy. Eur J Clin Invest 2008;38 Suppl 2:50–7.

15

Leitich H, Brunbauer M, Bodner-Adler B, et al. Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol 2003;188(3):752–8.

16

Kelly R, Holzman C, Senagore P, et al. Placental vascular pathology findings and pathways to preterm delivery. American journal of epidemiology 2009;170(2):148–58.

17

Harger JH, Hsing AW, Tuomala RE, et al. Risk factors for preterm premature rupture of fetal membranes: a multicenter case-control study. Am J Obstet Gynecol 1990;163(1 Pt 1):130–7.

18

Salafia CM, Lopez-Zeno JA, Sherer DM, et al. Histologic evidence of old intrauterine bleeding is more frequent in prematurity. Am J Obstet Gynecol 1995;173(4):1065–70.

19

Adams Waldorf KM, Singh N, Mohan AR, Young RC, Ngo L, Das A, et al. Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates. Am J Obstet Gynecol 2015;213(6):830 e1- e19.

20

Arias F, Rodriquez L, Rayne SC, et al. Maternal placental vasculopathy and infection: two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol 1993;168(2):585–91.

21

Salafia CM, Ghidini A, Lopez-Zeno JA, et al. Uteroplacental pathology and maternal arterial mean blood pressure in spontaneous prematurity. J Soc Gynecol Investig 1998;5(2):68–71.

22

Korebrits C, Ramirez MM, Watson L, et al. Maternal corticotropin-releasing hormone is increased with impending preterm birth. J Clin Endocrinol Metab 1998;83(5):1585–91.

23

Schatz F, Guzeloglu-Kayisli O, Basar M, et al. Enhanced Human Decidual Cell-Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal. Am J Pathol 2015;185(9):2402–11.

24

Challis JR, Hooper S. Birth: outcome of a positive cascade. Baillieres Clin Endocrinol Metab 1989;3(3):781–93.

25

Copper RL, Goldenberg RL, Das A, et al. The preterm prediction study: maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks' gestation. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1996;175(5):1286–92.

26

Wadhwa PD, Sandman CA, Porto M, et al. The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am J Obstet Gynecol 1993;169(4):858–65.

27

Ding XX, Wu YL, Xu SJ, et al. Maternal anxiety during pregnancy and adverse birth outcomes: a systematic review and meta-analysis of prospective cohort studies. J Affect Disord 2014;159:103–10.

28

Feinberg RF, Kliman HJ, Lockwood CJ. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Pathol 1991;138(3):537–43.

29

Berghella V, Palacio M, Ness A, et al. Cervical length screening for prevention of preterm birth in singleton pregnancy with threatened preterm labor: systematic review and meta-analysis of randomized controlled trials using individual patient-level data. Ultrasound Obstet Gynecol 2017;49(3):322–9.

30

Haas DM, Imperiale TF, Kirkpatrick PR, et al. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009;113(3):585–94.

31

Sanchez-Ramos L, Delke I, Zamora J, et al. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol 2009;114(3):631–40.

32

Abbott DS, Radford SK, Seed PT, et al. Evaluation of a quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. Am J Obstet Gynecol 2013;208(2):122 e1–6.

33

Lockwood CJ. Preterm labor: Clinical findings, diagnostic evaluation, and initial treatment 2019 [updated Aug 02, 2019. Available from: https://www.uptodate.com/contents/preterm-labor-clinical-findings-diagnostic-evaluation-and-initial-treatment?search=preterm%20labour&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 – H1331942419.

34

Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50(4):515–25.

35

Committee on Obstetric P. Committee Opinion No. 713: Antenatal Corticosteroid Therapy for Fetal Maturation. Obstet Gynecol 2017;130(2):e102-e9.

36

American College of O, Gynecologists, the Society for Maternal-Fetal M, Ecker JL, Kaimal A, Mercer BM, et al. #3: Periviable birth. Am J Obstet Gynecol 2015;213(5):604–14.

37

Gano D, Ho ML, Partridge JC, et al. Antenatal Exposure to Magnesium Sulfate Is Associated with Reduced Cerebellar Hemorrhage in Preterm Newborns. J Pediatr 2016;178:68–74.

38

Costantine MM, Weiner SJ, Eunice Kennedy Shriver National Institute of Child H, Human Development Maternal-Fetal Medicine Units N. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Obstet Gynecol 2009;114(2 Pt 1):354–64.

39

Doyle LW, Crowther CA, Middleton P, et al. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol 2009;113(6):1327–33.

40

Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009(1):CD004661.

41

Zeng X, Xue Y, Tian Q, et al. Effects and Safety of Magnesium Sulfate on Neuroprotection: A Meta-analysis Based on PRISMA Guidelines. Medicine (Baltimore). 2016;95(1):e2451.

42

Dodd JM, Jones L, Flenady V, et al. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev. 2013(7):CD004947.

43

Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348(24):2379–85.

44

Blackwell SC, Gyamfi-Bannerman C, Biggio JR, et al., Chauhan SP, Hughes BL, Louis JM, et al. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial. Am J Perinatol. 2019.

45

da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188(2):419–24.

46

Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 2016;387(10033):2106–16.

47

Crowther CA, Ashwood P, McPhee AJ, et al. Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): A multicentre, randomised, placebo-controlled trial. PLoS Med 2017;14(9):e1002390.

48

Romero R, Conde-Agudelo A, Da Fonseca E, O'Brien JM, Cetingoz E, Creasy GW, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol 2018;218(2):161–80.

49

Committee on Practice Bulletins-Obstetrics TACoO, Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol 2012;120(4):964–73.

50

Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996;334(9):567–72.

51

Berghella V, Odibo AO, To MS, et al. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005;106(1):181–9.

52

Son M, Grobman WA, Ayala NK, et al. A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate. Am J Obstet Gynecol 2016;214(3):365 e1–5.

53

Berghella V, Saccone G. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database Syst Rev 2019;9:CD007235.

54

WHO (2018). Preterm birth. [online] Available at: https://www.who.int/news-room/fact-sheets/detail/preterm-birth [Accessed 17 Jan. 2020

Online Study Assessment Option
All readers who are qualified doctors or allied medical professionals can now automatically receive 2 Continuing Professional Development credits from FIGO plus a Study Completion Certificate from GLOWM for successfully answering 4 multiple choice questions (randomly selected) based on the study of this chapter.
Medical students can receive the Study Completion Certificate only.

 

(To find out more about FIGO’s Continuing Professional Development awards programme CLICK HERE)