Preterm Labor

WILLIAM G. SAYRES, JR.

WILLIAM G. SAYRES, JR., MD

Am Fam Physician. 2010;81(4):477-484

A more recent article on preterm labor is available.

Author disclosure: Nothing to disclose.

Preventing preterm delivery remains one of the great challenges in modern medicine. Preterm birth rates continue to increase and accounted for 12.7 percent of all U.S. births in 2005. The etiology of preterm delivery is unclear, but is likely to be complex and influenced by genetics and environmental factors. Women with previous preterm birth are at increased risk of subsequent preterm delivery and may be candidates for treatment with antenatal progesterone. Fetal fibronectin testing and endovaginal ultrasonography for cervical length are useful for triage. For the patient in preterm labor, only antenatal corticosteroids and delivery in a facility with a level III neonatal intensive care unit have been shown to improve outcomes consistently. Tocolytic agents may delay delivery for up to 48 hours, enabling the administration of antenatal corticosteroids or maternal transfer. Routine use of antibiotics in preterm labor is not indicated except for group B streptococcus prophylaxis or treatment of chorioamnionitis.

In 2005, 12.7 percent of American births were preterm, defined as occurring before 37 weeks' gestation.¹ The rate of preterm delivery has increased 20 percent since 1990; recent increases have been associated primarily with late preterm (i.e., 34 to 36 weeks' gestation) deliveries (Figure 1).¹ Rates of preterm delivery differ among socioeconomic groups and races. For example, black women had an 18.4 percent rate of preterm delivery in 2005 compared with non-Hispanic white women, who had a rate of 11.7 percent, and Hispanic women, who had a rate of 12.1 percent.¹ Increased rates of preterm delivery are also noted among demographic groups delaying pregnancy and those using assisted reproductive technology.² About one half of preterm deliveries are the result of spontaneous labor with intact membranes, one fourth are associated with preterm premature rupture of membranes (PPROM), and one fourth are iatrogenic.³ Iatrogenic factors include elective preterm delivery by induction of labor or cesarean delivery for medical indications, such as hypertensive diseases of pregnancy, intra-uterine growth restriction, placental abruption, or nonreassuring fetal surveillance.⁴ This review focuses primarily on spontaneous preterm labor with intact membranes.

Clinical recommendation	Evidence rating	References
Antenatal progesterone supplementation decreases the incidence of preterm delivery in high-risk patients.	A	²⁸, ⁶³
Administration of corticosteroids in women with preterm labor between 26 and 34 weeks' gestation reduces the incidence of neonatal death, respiratory distress syndrome, and intraventricular hemorrhage.	A	⁴⁴, ⁴⁵
Corticosteroids are effective in women with premature labor with intact membranes, preterm premature rupture of membranes, and hypertensive disorders of pregnancy.
If delivery is not imminent, maternal transfer to a facility with a level III neonatal intensive care unit is indicated.	C	⁵⁰, ⁵⁹
In symptomatic patients, calcium channel blockers reduce the risk of delivery within seven days and before 34 weeks' gestation. Calcium channel blockers are better tolerated than beta mimetics.	A	⁵⁷
In symptomatic patients, beta mimetics decrease the risk of delivery within 48 hours. They are associated with significant adverse effects.	A	⁵⁸

Despite improvements in neonatal care, infants born prematurely have increased rates of mortality, and those who survive may have neurodevelopmental and medical disabilities.⁵ Infant mortality rates are a function of gestational age at birth and increase significantly before 32 weeks' gestation (Figure 2).⁵ Although neonatal morbidity and mortality increase at earlier gestational ages, the high proportion of preterm deliveries at 34 to 36 weeks' gestation results in the majority of admissions to neonatal intensive care units (NICUs), primarily from respiratory complications.

Risk Factors for Preterm Delivery

Table 1 lists risk factors for preterm delivery.⁶ An interpregnancy interval of less than six months increases the risk of preterm delivery (odds ratio = 2.2; 95% confidence interval [CI], 1.3 to 3.6).⁷ A history of previous preterm birth is the most important historical risk factor for subsequent preterm delivery, with a relative risk (RR) of 2.5 (95% CI, 1.9 to 3.2).⁸ A shorter penultimate (previous) pregnancy or a history of more than one preterm birth confer an even greater likelihood of subsequent preterm delivery.⁹

Maternal characteristics

Black race

Interpregnancy interval of less than six months

Physically strenuous or stressful work

Prepregnancy body mass index = 19 kg per m²

Pregnancy history

Previous preterm delivery

Pregnancy characteristics

Bacterial vaginosis, Chlamydia infection

Cocaine or heroin use

History of cervical cone biopsy or loop electrosurgical excision procedure

Intrauterine infection

Maternal abdominal surgery

Maternal medical disorders such as thyroid disease, diabetes mellitus, or hypertension

Multiple gestation

Nongenital tract infection (asymptomatic bacteriuria, pneumonia, appendicitis)

Periodontal disease

Polyhydramnios or oligohydramnios

Shortened cervix (< 3.0 cm)

Tobacco use

Uterine anomalies

Vaginal bleeding caused by placental abruption or placenta previa

A history of cervical conization or loop electrosurgical excision procedure of the cervical transformation zone increases the risk of preterm delivery (RR = 1.99; 95% CI, 1.81 to 2.20).¹⁰ Tobacco use is moderately associated with preterm birth (RR = 1.2 to 1.6).¹¹ Smoking is also associated with higher rates of recurrent preterm birth.⁶ Infection is one of the primary biologic pathways leading to preterm labor.⁶ Bacterial vaginosis (BV; RR = 1.5 to 3.0) and genitourinary infection with Chlamydia (RR = 2.2; 95% CI, 1.03 to 4.78) are associated with preterm delivery.¹² Maternal periodontal infection also increases the risk of preterm delivery (RR = 1.6; 95% CI, 1.1 to 2.3).¹³

A shortened cervix (i.e., generally less than 3.0 cm) or a funneling configuration at the internal os observed in second trimester transvaginal ultrasonography (Figure 3) increases the likelihood of preterm delivery.^14,15 Measurements before 14 weeks' gestation lack predictive value. Cervical effacement begins in normal pregnancies at about 32 weeks' gestation, limiting the usefulness of measurement in asymptomatic patients after 32 weeks' gestation.¹⁶ Table 2 lists predictive values of cervical length for preterm delivery.¹⁴ A shorter cervix confers a higher risk of preterm delivery.¹⁴

Cervical length (cm)*	Positive predictive value (%)	Negative predictive value (%)
At 24 weeks' gestation†
≤ 2.0	25.7	96.5
≤ 2.5	17.8	97.0
≤ 3.0	9.3	97.4
At 28 weeks' gestation‡
≤ 2.0	16.7	97.6
≤ 2.5	11.3	98.0
≤ 3.0	7.0	98.5

Prevention of Preterm Delivery

Smoking cessation interventions decrease the RR for delivering infants with low birth weight (RR = 0.81; 95% CI, 0.70 to 0.94), and for preterm birth (RR = 0.84; 95% CI, 0.72 to 0.98).¹⁷

Treatment of asymptomatic bacteriuria in pregnancy reduces the incidence of subsequent pyelonephritis and low birth weight, but does not affect preterm delivery.¹⁸ Treatment of periodontal disease does not decrease the risk of preterm delivery.¹⁹

Screening and treatment of BV for the prevention of preterm delivery remains controversial. In patients with a history of preterm birth, screening for and treatment of BV result in a decreased rate of PPROM and low–birth-weight newborns without affecting the incidence of preterm birth.²⁰ When asymptomatic, low-risk women were screened early in the second trimester and infected patients treated with clindamycin (Cleocin, administered vaginally in two studies and orally in one), rates of preterm delivery and second trimester miscarriage were reduced.^21–24 However, the U.S. Preventive Services Task Force recommends against screening low-risk patients for BV and rates the evidence as insufficient to recommend for or against screening and treatment of high-risk patients.²⁵ Routine screening and treatment of BV in low-risk patients should wait until best practices for timing and methods of screening, as well as treatment of infection, have been established.

Although most studies used Gram stain for the diagnosis of BV, most physicians use the Amsel criteria. For a BV diagnosis using the Amsel criteria, at least three of the following factors must be present: amine odor with potassium hydroxide; clue cells on normal saline wet mount; pH greater than 4.5; and a thin, homogenous vaginal discharge.²⁶

Centers for Disease Control and Prevention suggestions for the treatment of BV in pregnancy include oral clindamycin at a dosage of 300 mg twice daily for seven days, metronidazole (Flagyl) at a dosage of 500 mg twice daily for seven days, or metronidazole at a dosage of 250 mg three times daily for seven days.²⁷ Patients should be reevaluated one month after treatment.²⁷ Clindamycin is preferred.

Antenatal progesterone prevents the formation of cellular gap junctions and maintains uterine quiescence. A meta-analysis of randomized controlled trials involving women at an increased risk of preterm delivery showed that progesterone therapy decreased the risk of delivery before 37 weeks' gestation (RR = 0.57; 95% CI, 0.36 to 0.90; number needed to treat = 6) without an increase in fetal congenital anomalies.²⁸ One of the trials included in the analysis used 17-alpha hydroxyprogesterone caproate (250 mg intramuscularly weekly from 16 to 20 weeks' gestation through 36 weeks' gestation),²⁹ whereas another trial used natural progesterone suppositories (100 mg vaginally daily from 24 to 34 weeks' gestation).³⁰ Overall, the analysis found that the trials' effect on neonatal mortality was uncertain,²⁸ although 17-alpha hydroxyprogesterone injections resulted in lower rates of necrotizing enterocolitis and intraventricular hemorrhage, and less need for supplemental oxygen.²⁹ Prophylactic vaginal progesterone from 24 to 34 weeks' gestation in women with a cervical length of less than 15 mm at 22 weeks' gestation resulted in decreased rates of preterm birth (RR = 0.56; 95% CI, 0.56 to 0.86).³¹ However, progesterone treatment in twin pregnancies did not improve outcomes.³² The American College of Obstetricians and Gynecologists recommends limiting antenatal progesterone prophylaxis to women with a previous spontaneous birth at less than 37 weeks' gestation.³³

Initial Evaluation of the Patient with Preterm Contractions

Only 30 to 60 percent of women presenting with preterm contractions go on to deliver prematurely.³⁴ The three antenatal interventions that have been proven effective in premature labor are transfer to a facility with a NICU, maternal corticosteroid administration, and antibiotic prophylaxis for group B streptococcus (GBS).³⁵ The physician should obtain a thorough history and assess fetal well-being, membrane integrity, and the possibility of underlying infection. Table 3 summarizes the steps involved in the initial assessment of patients with premature contractions.

Assessment questions	Comments
What is the gestational age?	Verify dates by clinical history and ultrasonography
Are the membranes ruptured?	History of leaking fluid; observed leakage of fluid from cervical os on sterile speculum examination; nitrazine-positive reaction of fluid; ferning of fluid; ultrasonography for oligohydramnios; amnioinfusion of indigo carmine, if available
Is the patient in labor?	Observe for contractions accompanied by cervical effacement and dilation
Is there an infection?	Group B streptococcus carrier status; urinary tract infection; bacterial vaginosis; trichomoniasis; gonorrhea or chlamydia
What is the likelihood that the patient will deliver prematurely?	Consider endovaginal ultrasonography of cervical length and/or fetal fibronectin testing

ASSESS FOR RUPTURE OF MEMBRANES

Sterile speculum examination is recommended to assess whether the membranes have ruptured, as well as to collect a sample for fetal fibronectin analysis.³⁶ If pooled fluid is not visible and suspicion remains high for rupture of the fetal membranes, the patient should be reexamined after prolonged recumbency.³⁷ A sample of fluid can be tested for alkalinity using the nitrazine test (accuracy of 97 percent) and ferning (accuracy of 84 to 100 percent).³⁸ False-positive nitrazine results can be obtained in the presence of blood, semen, alkaline urine, and vaginal infections. To evaluate for ferning, a sample of fluid from the vaginal pool is placed on a glass slide and allowed to air dry for 10 minutes. The development of a fern-like crystalline pattern strongly suggests the presence of amniotic fluid. Cervical mucus may also cause ferning and may lead to an incorrect diagnosis of rupture of membranes.³⁸

Oligohydramnios on ultrasonography supports the presence of ruptured membranes, but it is not diagnostic. When there is high suspicion of ruptured membranes despite negative findings on speculum examination, diagnosis may be confirmed with observation of passage of blue fluid through the cervical os after an ultrasound-guided, transabdominal amnioinfusion of indigo carmine (1 mL in 9 mL of normal saline).³⁷ This test may not be available in all institutions.

ASSESS FOR INFECTION

Because bacteriuria and pyelonephritis are associated with preterm delivery, urine should be obtained for microscopic analysis and culture.³⁶ If the patient has not already been screened, a rectovaginal culture should be obtained for determination of GBS-carrier status, and prophylaxis should be initiated, if necessary. Screening for gonorrhea and chlamydia should be considered if not performed previously. Symptomatic patients should be evaluated for BV and trichomoniasis, although treatment of these infections will not affect pregnancy duration.²⁵

DETERMINE THE LIKELIHOOD OF TRUE LABOR

Labor is defined as regular uterine contractions that are accompanied by descent of the presenting fetal part, and progressive dilation and effacement of the cervix. Accuracy of clinical diagnosis is increased when there are at least six contractions per hour, the cervix is dilated to at least 3.0 cm, effacement is at least 80 percent, membranes are ruptured, or there is vaginal bleeding.³⁵ However, patients may present with an incomplete picture. Fetal fibronectin testing and cervical ultrasonography help determine the likelihood of preterm delivery.

Fetal Fibronectin Testing. Oncofetal fibronectin is a placental glycoprotein that is thought to play a role in implantation and maintenance of choriodecidual attachment throughout pregnancy. The fetal fibronectin assay is superior to cervical dilatation and contraction frequency in predicting preterm delivery in symptomatic women.³⁹ The negative predictive value of fetal fibronectin testing is greater than 99 percent for delivery within 14 days.⁴⁰ The positive predictive value is 13 to 30 percent for delivery within seven to 10 days.⁴⁰ The test should not be done if the patient had a vaginal examination, sexual intercourse, or endovaginal ultrasonography within the previous 24 hours.⁴⁰ Other confounders to fetal fibronectin testing include vaginal bleeding, rupture of membranes, abnormal vaginal flora, and use of vaginal lubricants or disinfectants.⁴¹

Cervical Ultrasonography. As with the fetal fibronectin testing, cervical ultrasonography is more useful in ruling out than diagnosing preterm labor. Decreased cervical length is associated with increased risk of subsequent delivery among patients presenting with premature contractions.¹⁵ Patients with a cervical length of at least 3.0 cm are unlikely to deliver within seven days (1 percent in one study).⁴² However, it is more problematic establishing a cervical length that is usefully predictive of eventual preterm birth.¹⁵ In one study, most deliveries within seven days occurred when the cervical length was less than 1.5 cm.⁴³

Fetal Fibronectin Testing and Cervical Ultrasonography. The use of combined cervical ultrasonography and fetal fibronectin testing is more accurate than the use of either test alone.⁴² In one study of 215 symptomatic patients, 23.1 percent of those with a cervical length less than 3.0 cm delivered within seven days.⁴² Within that same group, 11.4 percent delivered when the fetal fibronectin test was negative, and 44.7 percent delivered when it was positive.

Management of Preterm Labor

Management of preterm labor consists of corticosteroids to improve fetal outcomes, antibiotics for prophylaxis of GBS infection, and limited tocolysis.

ANTENATAL CORTICOSTEROID THERAPY FOR FETAL MATURATION

When administered to women with preterm labor between 24 and 34 weeks' gestation, betamethasone (two 12-mg intramuscular doses 24 hours apart) or dexamethasone (6 mg intramuscularly every 12 hours for four doses) results in a decreased incidence of neonatal mortality, respiratory distress syndrome, and intra-ventricular hemorrhage.⁴⁴ Antenatal corticosteroids also benefit patients with PPROM and those with hypertensive syndromes. Repeat courses of corticosteroids are not recommended.⁴⁵

PERINATAL GBS PROPHYLAXIS

GBS prophylaxis is unnecessary for women with potential preterm delivery who have been screened and are GBS negative.⁴⁶ For those at less than 37 weeks' gestation who have not yet been screened, a rectovaginal culture or rapid streptococcal test should be obtained, and prophylaxis should be started.⁴⁷ Full antibiotic prophylaxis is indicated in patients who are culture-positive for GBS, who had GBS bacteriuria prenatally, or who had a prior newborn infected with GBS (Table 4).⁴⁶ Antibiotics do not affect the outcome of preterm labor in patients with intact membranes, except when given for treatment of suspected infection (e.g., chorioamnionitis) or for GBS prophylaxis.⁴⁸

Regimen	Medication
Recommended prophylaxis	Penicillin G: initial dose of 5 million units IV, then 2.5 million units IV every four hours until delivery
Alternative prophylaxis	Ampicillin: initial dose of 2 g IV, then 1 g IV every four hours until delivery
For patients who are allergic to penicillin
Not at high risk of anaphylaxis	Cefazolin: initial dose of 2 g IV, then 1 g IV every eight hours until delivery
At high risk of anaphylaxis and GBS susceptible to clindamycin (Cleocin) and erythromycin	Clindamycin: 900 mg IV every eight hours until delivery
	or
	Erythromycin: 500 mg IV every six hours until delivery
At high risk of anaphylaxis and GBS resistant to clindamycin or erythromycin, or GBS susceptibility unknown	Vancomycin: 1 g every 12 hours until delivery

TOCOLYSIS

In contrast with antenatal steroid administration, tocolysis lacks robust outcome-based research support. The use of tocolytics decreases the odds of delivery within 48 hours, but has not consistently been shown to improve neonatal and perinatal outcomes.⁴⁹ A delay of delivery for 48 hours allows for corticosteroid administration or maternal transfer.⁵⁰ Table 5 summarizes individual tocolytic dosages, contraindications, and adverse effect information.^{34,49,51–58} General contraindications to tocolysis include fetal distress, chorioamnionitis, and maternal instability.³⁵

Medication (class)	Dosage	Comment	Contraindications and adverse effects	References
Indomethacin (Indocin; class: NSAIDs)	Loading dose: 50 mg rectally or 50 to 100 mg orally Maintenance dosage: 25 to 50 mg orally every four hours for 48 hours Total 24-hour dose should not be greater than 200 mg	NSAIDs theoretically intervene more proximally in the labor cascade than other agents; effectiveness similar to other agents Maternal adverse effect profile is favorable Other NSAIDs (sulindac [Clinoril], ketorolac [formerly Toradol]) may be used May be optimal choice for tocolysis before 32 weeks' gestation	Contraindications: maternal renal or hepatic impairment, active peptic ulcer disease, oligohydramnios Maternal adverse effects: nausea, heartburn Fetal adverse effects: constriction of the ductus arteriosus (not recommended after 32 weeks' gestation), pulmonary hypertension, reversible decrease in renal function with oligohydramnios, intraventricular hemorrhage, hyperbilirubinemia, necrotizing enterocolitis	³⁴, ⁴⁹, ^51–54
Magnesium sulfate	4- to 6-g bolus intravenously over 20 minutes, then 1 to 2 g per hour (3 g per hour maximum)	In widespread use in the United States, although meta-analysis fails to demonstrate improvement in outcomes; comparison studies demonstrate similar effectiveness to other agents in delay of delivery	Contraindication: myasthenia gravis Maternal adverse effects: flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest Newborn adverse effects: lethargy, hypotonia, respiratory depression, demineralization with prolonged use	³⁴, ⁵², ⁵³, ⁵⁵, ⁵⁶
Nifedipine (Procardia; class: calcium channel blockers)	30-mg loading dose orally, then 10 to 20 mg every four to six hours	May offer the best outcomes of the tocolytic agents May prolong pregnancy for seven days; delivery after 34 weeks' gestation is also increased Decreased incidence of neonatal respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, and jaundice Neonatal mortality not affected	Contraindication: maternal hypotension Maternal adverse effects: flushing, headache, dizziness, nausea, transient hypotension No fetal adverse effects noted	³⁴, ⁴⁹, ⁵⁷
Terbutaline (formerly Brethine; class: beta mimetics)	0.25 mg subcutaneously every 20 to 30 minutes for four to six doses	Appropriate as the first-line agent Beta mimetics may delay delivery for 48 hours, but neonatal outcomes are variable and maternal adverse effects common	Maternal contraindications: heart disease, poorly controlled diabetes mellitus, thyrotoxicosis Maternal adverse effects: cardiac arrhythmias, pulmonary edema, myocardial ischemia, hypotension, tachycardia, hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, altered thyroid function, physiologic tremor, palpitations, nervousness, nausea, vomiting, fever, hallucinations Fetal and newborn adverse effects: tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, intraventricular hemorrhage	³⁴, ⁴⁹, ⁵², ⁵⁸

Delivery of the Preterm Infant

The odds of neonatal death in infants weighing less than 1,500 g (3 lb, 5 oz) decrease as the level of NICU care at the birth hospital increases.⁵⁹ Maternal transfer to a facility with a level III NICU is indicated if delivery is not imminent and if level III NICU services are unavailable at the current facility.^50,59 The preterm fetus is more susceptible to injury from acidosis and anoxia, and therefore should have continuous electronic fetal monitoring.³⁴ The immaturity of the fetus and adverse effects of tocolytic medications complicate fetal surveillance.

Malpresentations are more common at earlier gestations and should be anticipated. There is no evidence that prophylactic episiotomy, forceps delivery, or cesarean delivery (other than for nonvertex presentation) improve neonatal outcomes in preterm delivery.⁶⁰ Retained placenta is more common than with term pregnancies.⁶¹ Umbilical cord blood acid-base studies should be considered after delivery.⁶²

Martin JA, Hamilton BE, Sutton PD, et al.; for the Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System. Births: final data for 2005. Natl Vital Stat Rep. 2007;56(6):1-103.

Wright VC, Chang J, Jeng G, Macaluso M. Assisted reproductive technology surveillance—United States, 2003. MMWR Surveill Summ. 2006;55(4):1-22.

Alexander GR. Prematurity at birth: determinants, consequences, and geographic variation. In: Behrman RE, Butler AS, eds. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: National Academies Press; 2007:607–608.

Ananth CV, Vintzileos AM. Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth. Am J Obstet Gynecol. 2006;195(6):1557-1563.

Centers for Disease Control and Prevention. Table 46. Live births, infant deaths, and infant mortality rates by plurality, birthweight, race of mother, and gestational age: United States, 2001 period data. http://www.cdc.gov/nchs/data/dvs/LINK01WK46.pdf. Accessed May 31, 2007.

Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.

Smith GC, Pell JP, Dobbie R. Interpregnancy interval and risk of preterm birth and neonatal death: retrospective cohort study [published correction appears in BMJ. 2003;327(7419):851]. BMJ. 2003;327(7410):313-316.

Mercer BM, Goldenberg RL, Moawad AH, et al. The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol. 1999;181(5 pt 1):1216-1221.

Adams MM, Elam-Evans LD, Wilson HG, Gilbertz DA. Rates of and factors associated with recurrence of preterm delivery. JAMA. 2000;283(12):1591-1596.

Jakobsson M, Gissler M, Sainio S, Paavonen J, Tapper AM. Preterm delivery after surgical treatment for cervical intraepithelial neoplasia [published correction appears in Obstet Gynecol. 2008;112(4):945]. Obstet Gynecol. 2007;109(2 pt 1):309-313.

Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res. 2004(6 suppl 2):S125-140.

Andrews WW, Goldenberg RL, Mercer B, et al. The Preterm Prediction Study: association of second-trimester genitourinary chlamydia infection with subsequent spontaneous preterm birth. Am J Obstet Gynecol. 2000;183(3):662-668.

Offenbacher S, Boggess KA, Murtha AP, et al. Progressive periodontal disease and risk of very preterm delivery [published correction appears in Obstet Gynecol. 2006;107(5):1171]. Obstet Gynecol. 2006;107(1):29-36.

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):567-572.

Owen J. Evaluation of the cervix by ultrasound for the prediction of preterm birth. Clin Perinatol. 2003;30(4):735-755.

Iams JD, Romero R, Creasy RK. Preterm labor and birth. In: Creasy RK, Resnik R, Iams JD, eds. Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 6th ed. Philadelphia, Pa.: Saunders/Elsevier; 2009:559.

Lumley J, Oliver SS, Chamberlain C, Oakley L. Interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev. 2004;4:CD001055.

Smaill F, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev. 2007;2:CD000490.

Michalowicz BS, Hodges JS, DiAngelis AJ, et al.; for the OPT Study. Treatment of periodontal disease and the risk of preterm birth. N Engl J Med. 2006;355(18):1885-1894.

McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2007;1:CD000262.

Lamont RF, Duncan SL, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol. 2003;101(3):516-522.

Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet. 2003;361(9362):983-988.

Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ. 2004;329(7462):371.

Swadpanich U, Lumbiganon P, Prasertcharoensook W, Laopaiboon M. Antenatal lower genital tract infection screening and treatment programs for preventing preterm delivery. Cochrane Database Syst Rev. 2008;2:CD006178.

U.S. Preventive Services Task Force. Screening for bacterial vaginosis in pregnancy to prevent preterm delivery: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;148(3):214-219.

Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D, Holmes KK. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med. 1983;74(1):14-22.

Workowski KA, Berman SM for the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006 [published correction appears in MMWR Recomm Rep. 2006;55(36):997]. MMWR Recomm Rep. 2006;55(RR11):1-94.

Mackenzie R, Walker M, Armson A, Hannah ME. 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. 2006;194(5):1234-1242.

Meis PJ, Klebanoff M, Thom E, et al.; for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxy-progesterone caproate [published correction appears in N Engl J Med. 2003;349(13):1299]. N Engl J Med. 2003;348(24):2379-2385.

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):419-424.

Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH for the Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357(5):462-469.

Rouse DJ, Caritis SN, Peaceman AM, et al.; for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med. 2007;357(5):454-461.

American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Use of progesterone to reduce preterm birth. Obstet Gynecol. 2003;102(5 pt 1):1115-1116.

ACOG Committee on Practice Bulletins; American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologist. Number 43, May 2003. Management of preterm labor. Obstet Gynecol. 2003;101(5 pt 1):1039-1047.

Iams JD. Prediction and early detection of preterm labor. Obstet Gynecol. 2003;101(2):402-412.

Lockwood CJ. Overview of preterm labor and delivery. UpToDate Online. http://www.utdol.com/patients/content/topic.do?topicKey=~IGteIB_WZFbd8_S (subscription required). Accessed February 23, 2009.

Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol. 2003;101(1):178-193.

Bennett SL, Cullen JB, Sherer DM, Woods JR. The ferning and nitrazine tests of amniotic fluid between 12 and 41 weeks gestation. Am J Perinatol. 1993;10(2):101-104.

Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol. 1997;177(1):13-18.

Lukes AS, Thorp JM, Eucker B, Pahel-Short L. Predictors of positivity for fetal fibronectin in patients with symptoms of preterm labor. Am J Obstet Gynecol. 1997;176(3):639-641.

Ramsey PS, Andrews WW. Biochemical predictors of preterm labor: fetal fibronectin and salivary estriol. Clin Perinatol. 2003;30(4):701-733.

Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes [published correction appears in Am J Obstet Gynecol. 2005; 193(1):308–309]. Am J Obstet Gynecol. 2005;192(2):350-359.

Tsoi E, Fuchs IB, Rane S, Geerts L, Nicolaides KH. Sonographic measurement of cervical length in threatened preterm labor in singleton pregnancies with intact membranes. Ultrasound Obstet Gynecol. 2005;25(4):353-356.

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454.

American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 402: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol. 2008;111(3):805-807.

Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002;51(RR-11):1-22.

Honest H, Sharma S, Khan KS. Rapid tests for group B streptococcus colonization in laboring women: a systematic review. Pediatrics. 2006;117(4):1055-1066.

King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database Syst Rev. 2002;4:CD000246.

Berkman ND, Thorp JM, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188(6):1648-1659.

Towers CV, Bonebrake R, Padilla G, Rumney P. The effect of transport on the rate of severe intraventricular hemorrhage in very low birth weight infants. Obstet Gynecol. 2000;95(2):291-295.

King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005;2:CD001992.

Goldenberg RL. The management of preterm labor. Obstet Gynecol. 2002;100(5 pt 1):1020-1037.

Di Renzo GC, Roura LC for the Europeaon Association of Perinatal Medicine-Study Group on Preterm Birth. Guidelines for the management of spontaneous preterm labor. J Perinat Med. 2006;34(5):359-366.

Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and deision analysis. Obstet Gynecol. 2009;113(3):585-594.

Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev. 2002;4:CD001060.

Lyell DJ, Pullen K, Campbell L, et al. Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial. Obstet Gynecol. 2007;110(1):61-67.

King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2003;1:CD002255.

Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004;4:CD004352.

Phibbs CS, Baker LC, Caughey AB, Danielsen B, Schmitt SK, Phibbs RH. Level and volume of neonatal intensive care and mortality in very-low-birth-weight infants. N Engl J Med. 2007;356(21):2165-2175.

Grant A, Glazener CM. Elective caesarean section versus expectant management for delivery of the small baby. Cochrane Database Syst Rev. 2001;2:CD000078.

Romero R, Hsu YC, Athanassiadis AP, et al. Preterm delivery: a risk factor for retained placenta. Am J Obstet Gynecol. 1990;163(3):823-825.

ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 348, November 2006: Umbilical cord blood gas and acid-base analysis. Obstet Gynecol. 2006;108(5):1319-1322.

Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev. 2006;1:CD004947.