Prepared by: Sheena Gallardo, Julie Lauron, Justine Quieta, Monece Solis, and Cyrus Tejam

A Clinical Vignette: Premature Rupture of Membrane

A 22-year-old woman presents at 32 weeks' gestation in her first pregnancy with regular painful contractions for 6 hours. She has a BMI of 17, smokes 10 cigarettes per day, and has a history of a large loop excision of her cervix following a diagnosis of cervical intraepithelial neoplasia grade II. She has had recurrent UTIs, including 2 positive cultures during pregnancy, but no episodes of vaginal bleeding. She has no history of recreational drug use or domestic violence. There is no family history of early birth. Previous ultrasound showed normal fetal and uterine anatomy. Dipstick urinalysis demonstrates leukocytes and nitrites. A speculum exam reveals a closed cervix, <2 cm long, and a positive bedside fetal fibronectin swab. Definition: PROM represents a rupture of the amniotic membranes prior to 37 weeks of gestation without the onset of uterine contractions. Ruptured membranes can fall into two different categories. When labor starts, the process of getting ready for labor has three parts. Preparation of the cervix (at 32 to 36 weeks) usually happens first, followed by a signal from the baby through the membranes to the uterine muscle to start the third part, uterine contractions. Or in some cases, the cervix may not be ripened at all and the membranes just break. In a small percentage of those cases, there is some sort of history of earlier bleeding in the pregnancy or trauma such as a fall or amniocentesis procedure. Depending on the severity and size of the tear, there is a chance the opening in the sac can close back up on its own until the start of labor closer to term. Epidemiology: Globally, the incidence rate of premature rupture of membranes is approximately 8% to 10% in pregnant women. More than 500,000 babies are born preterm in the US each year, accounting for 12.5% of all births, and this incidence is increasing. In the UK in 2005, 7.6% of live births were preterm. In the last decade there has been more than a 50% increase in preterm births to low-risk European women aged between 20 and 40 years. A higher proportion of preterm deliveries occur in women of black ethnicity, and this may in part be related to social disadvantage. Only 1% of all births occur below 32 weeks' gestation. Review of the maternal conditions giving rise to a 25% or more rate of neonatal morbidity in the Philippines shows that premature rupture of membranes accounts for an incidence rate of 38%. Etiology: Premature labor has a multifactorial etiology, and it is now viewed as a syndrome. Its causal factors can be generally categorized into maternal or fetal. A. Maternal factors Spontaneous premature labor is often associated with infection and inflammation, particularly at early gestations. Once intrauterine infection occurs, it may not be desirable to prolong pregnancy, as infection can cause neurologic damage to the fetus. UTIs, including asymptomatic bacteriuria, have a strong association with preterm birth, and treatment results in a significant reduction in the incidence of pyelonephritis and low birth weight, although a fall in preterm birth rates has not been shown. Abnormal vaginal flora, particularly bacterial vaginosis found early in pregnancy, is associated with higher risk of spontaneous premature labor. However, antimicrobial treatment does not have a significant impact on likelihood of preterm delivery. Furthermore, screening for bacterial vaginosis is not currently recommended as no interventions have been shown to improve outcome. Systemic infections, such as malaria or listeria, may also cause preterm labor.

Prepared by: Sheena Gallardo, Julie Lauron, Justine Quieta, Monece Solis, and Cyrus Tejam
Risks of premature labor are greater in women who have had a previous preterm

delivery. One previous preterm delivery increases the risk 4-fold, rising to 6.5-fold with 2 previous preterm deliveries. Gestational age at delivery also affects risk; the earlier the delivery the higher the risk of recurrence. Several factors associated with social disadvantage and with lifestyle have been related to spontaneous premature labor, including poor nutrition, cigarette smoking, single marital status, coffee consumption, and alcohol and recreational drug abuse. Mechanism and causation are difficult to elucidate, as many of these factors are commonly associated. There is some evidence that smoking-cessation programs may reduce preterm birth rates, but tackling other social factors has not proved to be effective. Domestic violence is associated with premature labor, and this association is prevalent across all social groups. Cervical trauma such as iatrogenic dilatation of the cervix or previous treatment for cervical intraepithelial neoplasia results in increased risk. Laser conization, radical diathermy, and large loop excisions may all be associated with higher risks of adverse events including perinatal mortality. Cervical preparation or less-invasive techniques (e.g., avoiding cone biopsies) could reduce future risks. Women with hx of induced abortion also have an increased risk of premature labor and delivery, particularly for deliveries before 28 weeks' gestation. A short cervical length (<2 cm) and a positive fetal fibronectin test place a woman at higher risk of preterm delivery. Between one third and one half of women who have a positive fibronectin test at 23 weeks' gestation deliver before 30 weeks. These tests have been identified as the best predictors of preterm birth. Low maternal weight is associated with increased risk of early delivery. Higher rates of spontaneous premature labor are associated with low BMI. However, iatrogenic causes of preterm birth are increased with obesity, possibly owing to the associated oxidative stress, particularly as a result of preeclampsia. Preterm prelabor rupture of membranes (PPROM): in more than one third of preterm women, rupture will occur prior to the onset of symptomatic contractions. This is associated with a higher risk of maternal and fetal infection (both as a cause and a consequence of PPROM). Pooling of the amniotic fluid may be seen on speculum examination. Dental caries, poor dentition, and peridontal disease may be associated with an increased risk for preterm birth. B. Fetal factors Multiple pregnancies are associated with premature labor due to uterine stretch. Limiting the number of embryo transfers to avoid higher-order multiple pregnancies could contribute substantially to reducing the rate of early preterm birth. Fetal abnormalities and polyhydramnios can also result in spontaneous premature birth. Common fetal indications for premature labor include fetal growth restriction, fetal stress, and congenital abnormalities. Fetal abnormalities are associated with 30% of preterm deliveries (including iatrogenic preterm delivery.) Pathophysiology: For preterm delivery to occur, the cervix undergoes considerable change, related to collagen breakdown and altered proteoglycan and water content, allowing effacement and dilatation. The hypertrophied upper uterine segment switches to fundally dominant contractions, which coordinate to expel the fetus. This is a gradual process, often over a number of weeks, allowing both biophysical (e.g., cervical ultrasound) and biochemical (e.g., fetal fibronectin) tests to predict delivery. Clinically identified factors such as contractions or cervical dilatation occur late in the process, partly explaining the poor performance of tocolysis in

Prepared by: Sheena Gallardo, Julie Lauron, Justine Quieta, Monece Solis, and Cyrus Tejam improving outcome. The lower segment also stretches, and there is an increase in inflammatory mediators and prostaglandins. Cervical change is mediated by the influx of inflammatory cells releasing matrix metalloproteinases. Increased contractility of the upper segment is associated with expression of prostaglandin and oxytocin receptors and gap junction proteins and other signaling pathways. Progesterone withdrawal is not seen in humans prior to labor, but progesterone therapy may be anti-inflammatory, and thus has a plausible mechanism as a prophylactic treatment. Infection also causes inflammation, and ascending micro-organisms through a deficient cervix can stimulate an inflammatory response through the innate immune system. Other routes include hematogenous spread, iatrogenic introduction, and retrograde spread through the fallopian tubes. These activate prostaglandins, inflammatory cytokines, and phospholipase A2 and can result in ruptured membranes or contractions. This could also explain the increased risk of premature labor with genital tract infection. Diagnosis: The most commonly reported symptom is a 'gush' or intermittent to continuous flow of clear or 'red-tinged' fluid from the vagina. There are tests that the doctor can perform to help ensure the membranes have actually ruptured, such as the Nitrazine Paper Confirmation, a "Fern" Test, Amnisure and a clinical ultrasound. Treatment: Prevention: Complications: