Idiopathic Preterm Labor Case File

Idiopathic Preterm Labor Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 40

A 32-year-old G3P0202 married African American woman at 31 weeks’ gestation arrives in the labor and delivery suite complaining of recurrent intermittent abdominal pain. She describes an increase in back pain yesterday and some mucous-like discharge today. She has noted no bleeding or leaking of fluid, but says she feels as if she is “starting her period.” In reviewing her prenatal record, you note that her first pregnancy resulted in a 28-week vaginal delivery of a 1200 g female, who is currently 7 years old and doing well. Her second baby, a male, is a healthy 3 years old, although he was delivered at 33 weeks’ gestation. 

On examination, she is afebrile, her BP is 120/80 mm Hg, pulse is 80 bpm and regular, and RR is 16 breaths/min. She appears to be in mild distress and holds her abdomen and moans every 3 to 5 minutes. Her abdomen is gravid with a fundal height of 32 cm, and soft, although you note two contractions by palpation during your 10-minute examination with her. Sterile speculum examination is negative for nitrazine and ferning, and no blood is noted. Membranes are visualized through the cervix. On digital examination, her cervix is dilated 3 cm, effacement is 80%, and station of the fetal vertex is at −1. The electronic fetal monitor shows a reassuring fetal heart rate of 140 bpm with mild contractions every 3 to 4 minutes.

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 40:

Idiopathic Preterm Labor

Summary: This is a 32-year-old G3P0202 woman with two prior preterm deliveries who is in preterm labor at 31 weeks. Because of the risk of imminent preterm birth, she should receive tocolytics in an attempt to delay delivery for at least 48 hours in order to administer antibiotics to reduce the risk of group B Streptococcus and corticosteroids to reduce the risk of respiratory distress syndrome.

➤ Most likely diagnosis: Idiopathic preterm labor.

➤ Next step: Begin hydration, administer tocolytics, corticosteroids, and antibiotics.

➤ Potential complications: Preterm birth with neonatal complications of respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), patent ductus arteriosus (PDA), and neonatal death.

ANALYSIS

Objectives

1. Understand the epidemiology of preterm birth.
2. Recognize risk factors that predispose to preterm delivery.
3. Understand methods of preventing or delaying preterm delivery.

Considerations

This is a 32-year-old G3P0202 patient with two prior preterm births presenting at 31 weeks with contractions and cervical dilation. She is at high risk for recurrent preterm birth because of the prior pregnancies. If there are no signs of infection, placental separation, or fetal stress, she is a candidate for tocolytics in an attempt to delay delivery for at least 48 hours in order to administer corticosteroids to obtain maximum effect to the fetus. Antibiotics effective against group B Streptococcus are customarily administered until her GBS status is known. Although in most circumstances, the etiology of preterm labor is unknown, a diligent search should be undertaken for a possible cause. Her clinical situation and the potential for neonatal damage underscore the importance of preterm birth in the United States today.

APPROACH TO

Idiopathic Preterm Labor

Epidemiology of Preterm Birth

Preterm birth, or delivery at less than 37 weeks’ gestational age, is a leading health problem in the United States, with annual costs exceeding $20 billion. Since 1999, prematurity exceeded congenital anomalies as the leading cause of neonatal mortality in this country for all racial and ethnic groups. The preterm birth rate has risen in most industrialized countries, with the US rate increasing from 9.5% in 1981 to 12.7% in 2005. A dramatic recent epidemiologic change is the shift in just one decade (1992-2002) from 40 to 39 weeks as the most common length of gestation for singleton births in the United States. The obstetric precursors leading to preterm birth are: (1) delivery for maternal or fetal indications (30%-35%); (2) spontaneous preterm labor with intact membranes (40%-45%); and (3) preterm premature rupture of the membranes (PPROM, 25%-30%). Spontaneous preterm birth is most commonly caused by preterm labor in white women, but by PPROM in black women. Preterm births can also be grouped according to gestational age, since about 5% of preterm births occur at less than 28 weeks, about 15% at 28 to 31 weeks, about 20% at 32 to 33 weeks, and 60% to 70% at 34 to 36 weeks. Rather than having a specific etiology in most cases, preterm labor is now thought to be a syndrome initiated by multiple mechanisms, including infection or inflammation, uteroplacental ischemia or hemorrhage, uterine overdistension, stress, and other immunologically mediated processes.

Risk Factors for Preterm Birth

The lowest gestational age for which an increased risk of preterm birth is seen in subsequent pregnancies is 18 weeks’ gestation. Previous births before 17 weeks’ gestation do not appear to confer an increased risk of recurrent preterm delivery. In the United States and the United Kingdom, women classified as black, African American, and Afro-Caribbean are consistently reported to be at higher risk of preterm delivery: preterm birth rates are in the range of 16% to 18% for black women compared with 5% to 9% for white women. Some investigators have speculated on mechanisms. Black women in both the United States and the United Kingdom are three times more likely to have bacterial vaginosis than are white women, and this difference could explain half of the excess preterm births in black women. East Asian and Hispanic women typically have low preterm birth rates. In many immigrant groups, the greater the length of time spent living in the United States, the higher the rate of preterm birth. A low prepregnancy BMI is associated with an increased risk of spontaneous preterm birth, whereas obesity can be protective. Women with low serum concentrations of iron, folate, or zinc have more preterm births than those with measurements within the normal range.

Microbiologic studies suggest that intrauterine infection might account for 25% to 40% of preterm births. By studying microbial “footprints” in the amniotic cavity (such as PCR detection of Ureaplasma urealyticum) in addition to traditional culture methods, this number may be an underestimate. At 21 to 24 weeks’ gestation, most spontaneous births are associated with histological chorioamnionitis compared to about 10% at 35 to 36 weeks. Trichomoniasis seems to be associated with preterm birth with a relative risk (RR) of about 1.3. Chlamydia does not appear to be associated with preterm birth. Syphilis and gonorrhea are probably associated with preterm birth with a RR of about 2.0. Vaginal group B Streptococcus, U urealyticum, and Mycoplasma hominis colonizations are not associated with an increased risk of preterm birth. Several nongenital tract infections, such as pyelonephritis and asymptomatic bacteriuria, pneumonia, and appendicitis, are associated with, and probably predispose to, preterm birth. Periodontal disease may also be a risk factor. On the other hand, viral DNA material in amniotic fluid has not been linked to preterm birth. 

Both digital and ultrasound examinations of the cervix have shown that cervical shortening is a risk factor for preterm delivery. Ultrasound has been shown to be useful in identifying women at increased risk for preterm birth in asymptomatic low-risk women with cervical length of less than 25 mm at 24 weeks’ gestation. Women with preterm contractions, on the other hand, with a cervical length of over 30 mm, have about a 1% chance of delivering within the next week. Fetal fibronectin, a marker of chorio-decidual disruption, is typically absent from cervico-vaginal secretions from 24 weeks’ gestation until near term; however, 3% to 4% of women undergoing routine screening at 24 to 26 weeks are positive, and are at substantially increased risk of preterm delivery. In questionable cases of preterm labor, only about 1% of women with a negative test deliver in the next week. Genetic association studies have been used to identify single-nucleotide polymorphisms in several genes associated with preterm labor and PPROM. While maternal carriage of a polymorphism in the IL6 gene did not result in an increased risk of spontaneous preterm birth for white or black women, black women who were carriers of the IL6 allele and who had bacterial vaginosis had a twofold greater risk of preterm birth than did those who carried the variant but did not have such infection.

Methods to Reduce PTB

Work in a standing position compared with that in a sitting position and work at night compared to work during the day have been associated with an increased rate of preterm birth (PTB). A Cochrane review reported that smoking cessation programs in pregnancy successfully reduce the incidence of preterm birth. Although genital-tract infection and colonization are consistently associated with an increased risk of preterm birth, antibiotic treatment does not reliably reduce this risk. Screening for and treatment of U urealyticum, group B Streptococcus, bacterial vaginosis (BV), and Trichomonas vaginalis does not reduce the rate of preterm birth, and, in the case of trichomonas and metronidazole, can actually increase the risk of prematurity.

Dietary supplementation with omega-3 polyunsaturated fatty acids has been associated with reduced production of inflammatory mediators, and a randomized trial of omega-3 supplements undertaken in women at risk of preterm birth showed a reduction in the preterm birth rate as did a randomized trial of supplemental fish oil. The risk of preterm birth was reduced by about a third in two trials of progesterone supplementation, given as intramuscular injections of 250 mg per week of 17α-hydroxyprogesterone caproate and as daily vaginal progesterone, although two systematic reviews noted that studies of progesterone have not been sufficiently powered to detect an effect on neonatal or infant outcomes. Progesterone has not been uniformly beneficial in all populations at risk, including patients with twins. 

In a meta-analysis of data from four trials, the risk of birth before 35 weeks’ gestation was reduced with cerclage in women with previous preterm birth and a short cervix (defined as less than 25 mm) in the present pregnancy. Cerclage in women with short cervices who did not have previous preterm births showed no advantage. In women with twins, cerclage for short cervix was associated with an increased risk of preterm birth.

Pharmacologic Therapy for Women in Preterm Labor

Treatment to arrest preterm labor established by progressive cervical dilation and effacement or membrane rupture does not prolong pregnancy sufficiently to allow further intrauterine growth and maturation. Treatment can, however, defer preterm birth long enough to allow for interventions that reduce neonatal morbidity and mortality. Antibiotic treatment of all women with threatened preterm labor to prevent neonatal infection with group B Streptococcus is recommended because preterm infants have an increased risk of this infection. Antenatal administration of corticosteroids to the mother reduces neonatal morbidity and mortality from respiratory distress, intraventricular hemorrhage, necrotizing enterocolitis, and patent ductus arteriosus. A single course consists either of two doses of 12 mg betamethasone given intramuscularly, 24 hours apart, or four doses of 6 mg dexamethasone given intramuscularly every 12 hours. The duration of fetal benefit after a course of glucocorticoids is uncertain. Data suggest that a repeat course might confer modest additional neonatal benefit, whereas multiple courses can reduce fetal growth. The earliest gestational age at which corticosteroids are administered is either 23 or 24 weeks.

Tocolytic drugs are used to prolong pregnancy in women with acute risk of preterm birth caused mainly by active preterm labor and, less commonly, by ruptured membranes. The main rationale for use of these drugs is a 48-hour delayed delivery that allows transfer to a specialist unit and the administration of corticosteroids. No studies have shown that any tocolytic drug can reduce the rate of preterm birth. The Cochrane database meta-analyses suggest that calciumchannel blockers and an oxytocin antagonist (atosiban) can delay delivery by 2 to 7 days with an optimum risk-benefit ratio. The Cochrane analysts concluded that β2-agonist drugs, such as ritodrine and terbutaline, can delay delivery by 48 hours, but carry greater side-effects than other agents, and that magnesium sulfate is ineffective. Magnesium, however, is currently the subject of intense review after studies have shown that intrapartum administration may reduce the risk of cerebral palsy. Although the cyclooxygenase inhibitor indomethacin reduced the occurrence of preterm birth when compared with placebo and other tocolytic agents in some controlled trials, the Cochrane analysts reported that the volume of evidence did not allow firm conclusions about efficacy. In light of this information, it is interesting that a recent survey noted that almost all maternal–fetal medicine specialists in this country recommend tocolysis in the setting of acute preterm labor. Magnesium and nifedipine are the most commonly prescribed first-line tocolytics, according to the survey. 

Continued suppression of contractions after acute tocolysis does not reduce the rate of preterm birth. Posthospitalization surveillance with outpatient monitoring of uterine contractions also has no effect on the rate of preterm birth or low birth weight, or gestational age at delivery.

Summary

It is clear that spontaneous preterm birth causes a tremendous health care burden for the individual patient as well as society overall. Our current understanding of the etiologies, detection, and intervention is insufficient to make a dramatic impact of this important disease. Associated conditions and risk factors have not uniformly led to successful intervention in randomized controlled trials. More research is critically important for gains to be made in unlocking the mechanisms and making meaningful strides in preterm birth.

Comprehension Questions

40.1 The most common length of gestation for singleton births in the United States is which of the following?

A. 37 weeks

B. 38 weeks

C. 39 weeks

D. 40 weeks

40.2 The lowest gestational age at delivery associated with an increased risk of preterm birth in subsequent pregnancy is which of the following?

A. 16 weeks

B. 18 weeks

C. 20 weeks

D. 22 weeks

40.3 At 24 weeks’ gestation, the threshold cervical length below which the risk of preterm birth increases is which of the following?

A. 2.0 cm

B. 2.5 cm

C. 3.0 cm

D. 3.5 cm

40.4 Cerclage has been shown to reduce preterm birth when a patient has a history of prior preterm delivery in which of the following circumstances?

A. Positive fetal fibronectin (fFN)

B. Cervical length less than 2.5 cm

C. Positive fern test

D. Twin gestation

ANSWERS

40.1 C. Due to the increased number of preterm births in this country, the most common gestational age at delivery since 2002 is 39 weeks.

40.2 B. Women with a previous delivery prior to 37 weeks’ gestation remain at increased risk for subsequent preterm birth unless the delivery occurred before 18 weeks gestation. No increase in subsequent preterm birth has been seen when a pregnancy ends prior to 18 weeks.

40.3 B. Cervical length at 24 weeks should be over 2.5 cm. When it is noted by ultrasound to be less than 2.5 cm, the patient should be considered to be at increased risk for preterm birth.

40.4 B. Cerclage has been shown to reduce the rate of PTB if placed in a patient with a history of a prior preterm birth and cervical length of less than 2.5 cm. Patients with either of those risk factors alone, or with the risk factor of twins, have not been shown to benefit by placement of a cerclage.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ The obstetric precursors leading to preterm birth are indicated preterm birth (30%-35%), spontaneous preterm labor (40%-45%), and preterm premature rupture of the membranes (25%-30%) (Level II-2).

➤ Rather than having one specific etiology, preterm labor is now thought to be a syndrome initiated by multiple mechanisms, including infection or inflammation, uteroplacental ischemia or hemorrhage, uterine overdistension, stress, and other immunologically mediated processes (Level III).

➤ Microbiologic studies suggest that intrauterine infection might account for 25% to 40% of preterm births, although with sophisticated measurement of microbial “footprints” in amniotic fluid, the number is likely higher (Level II-3).

➤ Women with cervical length less than 2.5 cm who are over 20 weeks gestation are at increased risk for preterm birth, while those with uterine contractions and cervical length greater than 3.0 cm have around a 1% chance of delivering within the next week (Level II-2).

➤ No studies have shown that any tocolytic drug can reduce the rate of preterm birth (Level I).

REFERENCES

1. Damus K. Prevention of preterm birth: a renewed national priority. Curr Opin Obstet Gynecol. 2008;20:590-596. 

2. Fox NS, Gelber SE, Kalish RB, Chasen SE. Contemporary practice patterns and beliefs regarding tocolysis among U.S. maternal–fetal medicine specialists. Obstet Gynecol. 2008;112:42-47. 

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

4. Huddleston JF, Sanchez-Ramox L, Huddleston KW. Acute management of preterm labor. Clin Perinatol. 2003;30:803-824. This review outlines our understanding of the mechanism of labor and how tocolytics may intervene to delay or prevent preterm birth. 

5. Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet. 2008;371:164-175. 

6. Smith V, Devane D, Begley CM, Clarke M, Higgins S. A systematic review and quality assessment of systematic reviews of randomised trials of interventions for preventing and treating preterm birth. Eur J Obstet Gynecol. 2008;doi:10.1016/ j.ejogrb.2008.09.008. This paper reports on the quality of reviews of techniques for preventing and treating preterm birth.

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