PRETERM LABOR
From Boston University School of Medicine’s 9th Annual Practical Issues in Obstetrics, Gynecology and Women’s
Health
Errol R. Norwitz, MD, PhD, Associate Professor, Department of Obstetrics, Gynecology, and Reproductive
Sciences, Yale University School of Medicine; Director of Perinatal Research, Associate Director, Division of
Maternal-Fetal Medicine, Yale-New Haven Hospital, New Haven, CT
| MECHANISMS OF PRETERM LABOR
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| General: preterm labor complicates 8% to 12% of deliveries; leading cause of perinatal mortality and morbidity; preterm
birth rate 13.1% in 2003; overall incidence slowly increasing; incidence of high-risk preterm births (<34 wk) and extreme
preterm births (<28 wk) also slowly increasing; birth defects constitute highest cause of perinatal mortality in developed
countries (5 of top 9 causes related directly to prematurity); health care costs—in 2002, overall cost $15.5 billion in
United States (half of hospital charges related to prematurity)
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| Causes of labor: rodents—ovary maintains pregnancy through maintenance of high progesterone levels; study showed
that at end of gestation (21 days), prostaglandin production increases through release of surfactant protein A (SP-A) from
pup’s lung; SP-A causes pup’s white blood cells to move into maternal decidua, leading to upregulation of prostaglandin;
prostaglandin production leads to decrease in progesterone and start of labor; sheep—fetus triggers labor through activation
of fetal hypothalamic-pituitary-adrenal (HPA) axis; surge of cortisol 1 to 2 days before onset of parturition; cortisol
travels to placenta and selectively upregulates enzyme, 17 α-hydroxylase/17,20 lyase (CYP17), catalyzing conversion of
progesterone to estrogen; switch in prostaglandin/estrogen ratio causes prostaglandin production and labor; steroids
given to sheep cause preterm labor; steroids given to rhesus monkeys (higher-order primates) to induce preterm labor resulted
in 71% of monkeys being postterm; CYP17 absent in human placenta; parturition cascade in humans—
activation of fetal HPA axis with surge of cortisol; cortisol prepares organ systems for maturation and upregulates selective
enzymes in placenta (placental corticotropin-releasing hormone [CRH]); placental CRH goes back to fetal HPA axis
and creates feedforward loop, driving axis further; surge from intermediate zone of fetal adrenal glands (fetal androgen
[fetal dehydroepiandrosterone]); fetal androgens serve as precursor for estrogen (estriol) production in placenta; estrogen-dominant
environment upregulates contraction-associated proteins, leads to prostaglandin production, rupture of
membranes, contractions, and labor
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| Preterm birth: syndrome; 20% of preterm births iatrogenic; indications include maternal concerns (eg, preeclampsia,
poorly controlled diabetes), fetal concerns (eg, nonreassuring fetal testing), or placental issues (eg, placenta previa or
abruption); 80% of preterm births equally divided between premature rupture of membranes (PROM), intra-amniotic infection
(no way to treat babies in utero), and idiopathic preterm labor
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| Pathways involved in prematurity: stress—maternal or fetal; stress acts through fetal HPA axis or placental CRH
expression; infection or inflammation—inflammation key problem; inflammatory response from fetus can induce preterm
labor directly through prostaglandin upregulation or indirectly through cytokines or chemokines; uterine stretch—
can cause prostaglandin production (patients with multiple pregnancy or polyhydramnios); hemorrhage—thrombin can
cause preterm contractions and preterm labor (enough thrombin in 1 mL of clotted blood to cause contractions)
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| Screening for preterm labor: home uterine activity monitoring—data show no improvement in outcome; overdiagnosis
with this technology; obstetric intervention increased; risk factor scoring—previous preterm birth and ethnicity examples
of risk factors that cannot be changed; illicit drug use and cigarette smoking; recent data suggest that uterine
contraction not risk factor; clinical features of preterm labor (symptoms and examination) very poor predictors of preterm
birth; >60% of women with signs and symptoms of preterm labor deliver at term without treatment; history of preterm deliveries,
illicit drug use, alcohol use, and cigarette smoking important, but risk factors alone not sufficient predictors (poor
sensitivity and low predictive value); cervical length measurements—useful in high-risk women; inverse correlation between
length of cervix and risk for preterm birth; if cervical length <15 mm at 22 to 24 wk gestation, 60% of women deliver
by 28 wk and 90% by 32 wk; biochemical and endocrine markers—CRH (study showed that single measurement
at 15 wk can predict risk for preterm birth); estrogen test not available clinically; fetal fibronectin (fFN; fetal glycoprotein
that serves as glue between amniochorion and maternal decidua) only test currently established as screening test; premature
leakage of fFN into cervicovaginal discharge suggests premature separation of membranes and increased risk for preterm
delivery (normally present in high concentrations early in pregnancy; test reports positive or negative with 50 ng/mL
as cut-off); window to screen symptomatic women from 24 to 37 wk gestation (American Academy of Obstetrics and Gynecology
[ACOG] has 6 criteria defining women symptomatic for preterm labor, including regular contractions increasing
in intensity and frequency, substantial pelvic pressure, and woman who does not feel well in pregnancy; definition of
“symptomatic” varies); test approved for asymptomatic high-risk women at 22 to 30 wk gestation; positive test at 22 to 24
wk associated with delivery rates of 13% by 28 wk and 36% by 37 wk; high negative predictive value (99.9% with negative
test still pregnant in 1 wk; 98.9% still pregnant at 2 wk; 89% still pregnant in 3 wk; 80% of high-risk symptomatic
women have negative fFN); fFN best test for predicting preterm labor; combining tests—fFN and measurement of cervical
length additive in value, but not synergistic; if long cervical length, discard fFN; if short cervical length, run fFN; patient
with short cervical length, negative fFN, and contractions can be sent home
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| Summary: no overall decrease in incidence of preterm birth in last 30 yr; etiologies multiple; clinical features unreliable;
fFN single best test for predicting preterm labor; fFN and cervical length used together
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| MANAGEMENT OF PRETERM LABOR
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| Strategies: single healthy pregnancy goal of artificial reproductive technology, with prevention of multifetal pregnancy
effective strategy for preventing preterm birth; cervical cerclage—indications rapidly decreasing; study showed cerclage
for shortened cervical length not effective in preventing preterm birth; cerclage appropriate in women with 2 unexplained
second trimester losses with classical presentation of cervical insufficiency; prevention and early diagnosis of genitourinary
tract infections and sexually transmitted diseases (STDs)—pyelonephritis or appendicitis can activate cytokine
cascade and lead to premature delivery; routine screening for asymptomatic bacteriuria and appropriate treatment
helpful; cigarette use and substance abuse cessation—appropriate; strategies without proven benefit for preterm
delivery—data show intensive prenatal care does not make difference (beneficial in screening for conditions like preeclampsia);
no proven benefit with bed rest (except, babies grow ≈200 g larger with improved uteroplacental circulation
postulated as reason); screening asymptomatic women for lower genital tract infections (bacterial vaginosis and Trichomonas
vaginalis) not beneficial; who should be treated—women with confirmation of preterm labor (regular uterine
contractions increasing in frequency and intensity with cervical change); examination of patient with regular
contractions, especially if nulliparous, with 80% effacement or 2 cm dilatation of cervix can make diagnosis
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| Contraindications to tocolysis and expectant management: necessary to exclude contraindications; unexplained
vaginal bleeding (possible underlying abruption); nonreassuring fetal testing; intrauterine fetal demise (IUFD);
maternal contraindications to tocolysis; intra-amniotic infection (most important contraindication); diagnosis of intra-
amniotic infection in preterm labor—amniocentesis (controversial); 2 of 4 standard clinical criteria for diagnosis (fetal
tachycardia; maternal tachycardia; uterine tenderness between contractions; maternal fever); pus coming out of uterus on
speculum examination
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| Treatment: steroids—prednisone does not cross placenta; betamethasone useful; proven benefit at <34 wk gestation; no
proven benefit at >34 wk; recent data suggest benefit lasts to term; controversial in PROM at 32 to 34 wk gestation (no
good studies); antibiotics—routine evaluation includes checking group B Streptococcus (GBS) status; if patient intrapartum
rather than antepartum, give antibiotic prophylaxis (penicillin antibiotic of choice)
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 | Tocolysis: traditionally cornerstone of management; realization that does not work well (by time patient contracting with
cervical dilatation, diagnosis missed by weeks or months); no reliable data that tocolytic agent can delay delivery >24
to 48 hr, with exception of nonselective cyclooxygenase (COX)-inhibitor indomethacin (Indocin) and nifedipine;
choice of agent depends on side-effect profile of drug; Royal College of Obstetricians and Gynaecologists states 2 reasons
to give tocolysis include getting patients to tertiary care center and first course of antenatal steroids administered;
traditionally, magnesium sulfate first agent of choice; meta-analyses suggest nifedipine as first-line agent and possibly
as maintenance tocolytic agent; atosiban (oxytocin-receptor inhibitor) used in Europe; management strategies shown
not to confer benefit—concurrent use of 2 tocolytic drugs (increases side-effect profile); generally, maintenance tocolysis
>24 hr not recommended, however meta-analyses on nifedipine changing recommendations; tocolysis in setting
of PROM does not work (broad-spectrum antibiotics first-line treatment in this setting); strategies that may have
benefit—sequential therapy if one agent fails (tailor therapy to cascade that caused preterm labor; if magnesium sulfate
started and it fails, do not add another agent; stop magnesium sulfate and give another agent); evidence that patient
with advanced cervical examination (3 to 4 cm dilated with contractions) benefits from tocolysis by giving time for steroid
administration; broad-spectrum antibiotics proven efficacious in PROM to prolong latency, but not proven with
intact membranes
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| Progesterone: critical for early pregnancy maintenance; between 5 and 8 wk of gestation, luteal-placental shift occurs
(placenta takes over making progesterone, with large increase in levels); recent studies suggest that supplemental progesterone
later in pregnancy may prevent preterm labor; in humans, guinea pigs, and armadillos, systemic withdrawal of
progesterone not prerequisite for labor; withdrawal of progesterone action at level of uterus occurs before onset of labor;
progesterone necessary to maintain uterine quiescence; labor not caused by sudden surge of uterotonic agents but by
withdrawal of substances like progesterone that maintain uterine quiescence; mechanism of action—study showed certain
metabolites of progesterone get into membrane and distort oxytocin receptor, preventing oxytocin action; possible
that at end of pregnancy when metabolites disappear, oxytocin can then exert its action; differential expression of progesterone
receptors A and B seems determined in part by progesterone (2 isoforms of same gene, and ratio of pure A to pure
B seems important for labor); progesterone may interfere with cortisol-mediated regulation of placental gene expression,
especially CRH (stops feedforward loop that drives fetal HPA axis); 1990 data—meta-analysis suggested that progesterone
(17 α-hydroxyprogesterone caproate; 17P) could decrease overall incidence of preterm birth by 15% to 70% but no
difference in perinatal mortality or morbidity (use fell out of favor); Meis (2003)—randomized double-blind placebo-
controlled study of high-risk patients for preterm delivery (previous preterm deliveries) given weekly injections of 17P or
placebo from 16 to 20 wk gestation until 36 wk; study showed substantial reduction in risk for preterm delivery; improved
perinatal outcome (decreased incidence of necrotizing enterocolitis, intraventricular hemorrhage, and need for
supplemental O2 ); side effects include injection site discomfort, itching, and bruising; no increase in congenital anomalies;
conclusion that 17P can reduce preterm delivery in women at risk; need to treat 5 to 6 patients to prevent 1 premature
birth (<37 wk; 12 for 1 <32 wk); treatment recommended in women specifically with history of preterm deliveries;
hypospadias—2 recent studies pointed to association between progesterone supplementation given at 11 to 14 wk gestation
and hypospadias; Da Fonseca (2003)—double-blind randomized placebo-controlled study of women at high risk
for preterm delivery given daily supplementation with progesterone vaginal suppositories or placebo from 24 to 34 wk;
showed decrease in preterm birth and improvement in perinatal outcome; patients monitored for contractions every week
for 1 hr; study showed decrease in uterine contractions; ACOG recommends further studies for optimal route of administration,
dose, and long-term safety; potentially useful in women who had previous preterm deliveries, not in everyone;
not Food and Drug Administration (FDA)-approved; recent study indicates benefit in women with previous unexplained
preterm deliveries at <34 wk, benefit at 34 to 37 wk not established; 17P difficult to obtain (specially formulated and stable
for 11 wk)
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| Conclusions: physicians getting better at identifying women at risk for preterm delivery but not at preventing it because
20% to 40% of preterm births have element of genetic predisposition (fetal genotype important in timing of gestation);
familial clustering of preterm births; ethnicity plays role (black women at substantial risk for premature delivery); women
with previous preterm delivery at risk for another preterm delivery; genetic predisposition—not just genetics of mother
or baby, but gene environment interaction; known that lower genital tract infections associated with preterm birth;
speaker suggests infection not cause, woman’s genetic complement confers risk for lower genital tract infections, preterm
labor, and gingival infection; woman has genetic predisposition to sensitivity to inflammatory stimulus and mounts
proinflammatory response that triggers parturition cascade prematurely; actions—confirm diagnosis of preterm labor;
exclude contraindications to tocolysis; consider tocolytic agents; give steroids; give GBS chemoprophylaxis when appropriate;
follow literature on progesterone supplementation
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Educational Objectives
| The goal of this program is to provide the listener with information on the mechanisms and management of preterm labor.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the underlying mechanisms responsible for the onset of term and preterm labor.
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| 2. Recognize women at increased risk for preterm delivery.
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| 3. Discuss the risks and benefits of tocolytic therapy.
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| 4. Discuss the possible role of progesterone in prevention of preterm labor.
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| 5. Initiate treatment for a woman in preterm labor.
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Discussed on This Program
Atosiban [Tractocile, Antocin] (not available in United States)
Betamethasone [several trade names and formulations]
Indomethacin [Indocin, Indocin SR, Indomethacin Extended-Release]
Magnesium sulfate
Nifedipine [Adalat, Adalat CC, Nifedical XL, Procardia, Procardia XLs]
Penicillin G [Bicillin C-R, Bicillin C-R 900/300, Bicillin L-A, Permapen, Pfizerpen, Wycillin]
Prednisone [several trade names]
Progesterone [Crinone, Progesterone In Oil, Prometrium]
Ritodrine HCl [Yutopar]
Suggested Reading
Buhimschi CS, et al: Clinical Proteomics: A Novel Diagnostic Tool for the New Biology of Preterm Labor, Part I: Proteomics
Tools. Obstet Gynecol Surv 61:481, 2006; Bukowski R, et al: Labor-associated gene expression in the human
uterine fundus, lower segment, and cervix. PloS Med 3:e169, 2006; Carvajal JA, et al: Mechanisms of paracrine regulation
by fetal membranes of human uterine quiescence. J Soc Gynecol Investig 13:343, 2006; Challis JR, et al: Fetal
signals and parturition. J Obstet Gynaecol Res 31:492, 2005; Hassan S, et al: A sonographic short cervix as the only
clinical manifestation of intra-amniotic infection. J Perinat Med 34:13, 2006; Jones JS, et al: The interval spontaneous
delivery following discontinuation of maintenance tocolysis. J Matern Fetal Neonatal Med 19:331, 2006; Lyndon A:
Preterm labor and birth: where are we now? J Perinat Neonatal Nurs 20:82, 2006; Mackenzie R, et al: Progesterone
for the prevention of preterm birth among women at increased risk: a systematic review and meta-analysis of randomized
controlled trials. Am J Obstet Gynecol 194:1234, 2006; Maxwell NC, et al: Antenatal infection and inflammation:
what’s new? Curr Opin Infect Dis 19:253, 2006; Ness A, et al: Progesterone for preventing premature birth: practice
patterns of board-certified maternal-fetal medicine specialists in the United States. J Reprod Med 51:411, 2006; Papatsonis
D, et al: Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 20:CD004452,
2005; Sheehan PM: A possible role for progesterone metabolites in human parturition. Aust N Z J Obstet Gynaecol
46:159, 2006; Swamy GK, et al: Clinical utility of fetal fibronectin for predicting preterm birth. J Reprod Med 50:851,
2005; Tan TC, et al: Tocolytic treatment for the management of preterm labour: a systematic review. Singapore Med J
47:361, 2006; Vidaeff AC, Ramin SM: From concept to practice: the recent history of preterm delivery prevention.
Part II: Subclinical infection and hormonal effects. Am J Perinatol 23:75, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Norwitz is on the Speakers’ Bureau for Adeza Biomedical.
Dr. Norwitz was recorded at Practical Issues in Obstetrics, Gynecology, and Women’s Health, held November 11,
2005, in Waltham, MA, and sponsored by Boston University School of Medicine. The Audio-Digest Foundation
thanks the speaker and the sponsor for their cooperation in the production of this program.
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