Preterm birth risk assessment

Preterm Birth Risk Assessment Jill G. Mauldin and Roger B. Newman

Preterm birth is a leading cause of peripheral morbidity and mortality. The national rate of prematurity approaches 11%. In spite of widespread tocolytic use, the preterm birth rate has actually increased over the past 30 years in the United States. Preterm birth appears to have a multifactorial etiology. Leading theories include infectious, inflammatory or ischemic insult to the uteroplacental barrier, activation of the fetal hypothalamlc-pitnitary pathway, decreased cervical competence, and pathologic uterine distention. Multiple biochemical and biophysical markers have been studied for their potential to correctly identify women at risk of preterm delivery. Of these, fetal fibronecfin and endovaginal ultrasound examination of the cervix have proven effective in predicting which symptomatic women are actually at low risk of preterm birth. Salivary estriol is being studied as a marker for preterm labor and delivery and it too will likely be found to be a reliable risk identifier in a high risk population. However, home uterine activity monitoring has not been shown to decrease the frequency of preterm birth or its neonatal complications. Copyright 9 2001 by W.B. Saunders Company

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reterm birth is one of the leading causes o f perinatal morbidity and mortality, ranking second only to birth defects as a cause o f infant mortality. 1 It is responsible for 70% o f neonatal and infant deaths. Approximately 80% of these p r e t e r m births occur after preterm labor or preterm premature rupture of the membranes. T h e remaining 20% o f births before 37 weeks' gestation represent deliveries necessitated by an unreasonable risk to the m o t h e r or fetus with continuadon o f pregnancy. 1,2 As a result, the national rate of prematurity approximates 11%.1 In spite of the introduction and widespread use o f tocolytics, the rate of p r e t e r m birth has not decreased over the past 30 years, z,4 In fact, the rate of preterm birth has actually increased in the United States. 1 This f i n d i n g can be explained in part by the increased prevalence o f the clinical factors believed to impact the rate o f p r e t e r m birth. For instance, women at the far extreme o f the reproductive age experience an increased rate o f preterm deliveries. In fact, births to women over the age o f 35 years have increased by 47%. 1 Additionally, since 1980, the twin birth rate has risen 49% (from 18.9 to 28.1 per 1,000 live births) and the high o r d e r birth rate has increased 423% (from 37.0 to 193.5 per 100,000 live births).1 At least 50% of twin gestations and 90% of high order multiples will deliver preterm. 5 T h e efficacy of interventions to prevent preterm birth has been disappointing. 6,7 Preterm

labor has been traditionally defined by the presence o f uterine contractions and cervical change. T r e a t m e n t has b e e n directed at the early detection of uterine contractility with h o m e uterine activity monitors and tocolytics to suppress that uterine activity. Opinion is mixed as to whether these interventions are actually successful at prolonging pregnancy. 7 T h e r e are n u m e r o u s social, medical, and obstetric risk factors associated with preterm birth, suggesting a multifactorial etiology. Included among these are both mod/fiab/e and nonmodifiable risk factors, which interact together, with selected risk factors playing a greater or lesser role in any given patient. Interventions directed toward any o f these risk factors as an individual variable have failed to favorably impact outcome. Most authors now concede that the factors n e e d to be assessed together. Variables associated with spontaneous preterm birth include uterine volume, uterine contractions frequency, microbial colonization o f the lower and u p p e r genital tract, hypoxic o r From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecolog3, Medical University of South Carolina, Charleston, SC. Address reprint requests toJill G. Mauldin, MD, Medical University of South Carolina, 96 Jonathon Lucas St, Suite 634, P 0 Box 250619, Chaffeston, SC 29425. Copyright 9 2001 by W.B. Saunders Company 0146-0005/01/2504-0003535. 00/0 doi:l O.l O53/sper.200 L 26419

Seminars in Perinatolog~, Vol 25, No 4 (August), 2001: pp 215-222

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hemorrhagic injury to the maternal-fetal interface, fetal paracrine signals for labor, cervical competence, and maternal resistance to infection. These risk factors interact synergistically to produce the increased contractions o f preterm labor, p r e t e r m p r e m a t u r e rupture of the membranes, amnionitis, or cervical incompetence, ie, spontaneous p r e t e r m birth. An evolving school o f thought views p r e t e r m labor as an indolent disorder, whose onset is identifiable in the seco n d trimester and whose origin is even earlier, possibly predating the pregnancy. 3,8 T h e r e is a theory that occult infection o f the u p p e r genital tract and resultant intrauterine inflammation may cause the cervical changes of p r e t e r m labor, as opposed to abnormalities of uterine contractility. 9-11 O t h e r investigators feel that the cause of preterm delivery and resultant neonatal morbidity are linked. Thus, the phrase "preterm labor syndrome" has b e e n coined. 12 This theory postulates that abnormalities o f the placenta and uteroplacental blood flow act, either directly through injury to the decidua a n d / o r membranes, or indirectly by inducing fetal stress and a paracrine response, to result in spontaneous preterm birth. T h e fetal membranes and decidua p r o d u c e cytokines in response to an inflammatory, infectious, or ischemic insult or in response to a paracrine signal. Depending on the intensity and duration o f the insult or signal, proteases, and subsequently prostaglandins, are released and result in cervical changes a n d / o r amniorrhexis. In most cases, it is likely that several factors interact until this threshold is reached. 12 The traditional notion o f either cervical competence or i n c o m p e t e n c e has also b e e n challenged by the r e c e n t studies involving transvaginal sonography of cervical length t h r o u g h o u t pregnancy, x3,14 It is now thought that the cervix functions along a c o n t i n u u m of competence, and that a decreasing degree of cervical competence contributes to the defeat o f the host defense mechanisms and diminishes resistance to mechanical, biochemical, or inflammatory stimuli or p r e t e r m birth. 8 Multiple biochemical and biophysical markers have b e e n studied for their potential to correctly identify women at risk of preterm delivery. O f these, fetal fibronectin and endovaginal

ultrasound examination o f the cervix have proven effective in predicting which symptomatic women are actually at low risk o f p r e t e r m birth. A n o t h e r h o r m o n e , salivary estriol is being studied as a marker for preterm birth because of the partuition-associated increase in estriol. H o m e uterine activity monitoring has b e e n evaluated in multiple trials as a technique to provide earlier detection of p r e t e r m labor. However, its use has not been consistently associated with a decrease in the incidence o f preterm birth. T h e following will summarize our current understanding o f the efficacy for each o f these markers for preterm birth risk assessment. Cervical Length T h e r e is a growing consensus that the cervix functions along a c o n t i n u u m of c o m p e t e n c e rather than as a dichotomous variable o f comp e t e n t or incompetent. Endovaginal cervical sonography has been useful in determining the risk of p r e t e r m delivery and effectively excluding the diagnosis of preterm labor in patients who present with p r e t e r m contractions. T h e literature suggests that the best time to screen patients with cervical ultrasound to estimate their p r e t e r m delivery risk would be between 18 and 28 weeks' gestation. Before 18 weeks, it is difficult to differentiate the lower uterine segment from the cervix; therefore, the cervical length may be artificially lengthened. By the third trimester, the presence o f some degree o f funneling at the internal cervical os is probably norm a l . 14

T h e basic concept of cervical sonography is that shortening of the cervix represents prelabor cervical effacement. Studies suggest that the cervix effaces from the inside out and that funneling with resultant cervical shortening is essentially effacement in progress, a Importantly, funneling appears to occur in the absence o f uterine contractions. As the cervix progressively shortens, the funnel begins to disappear. Zilianti et all5 effectively described the visual cervical changes according to the shape of the letters T, Y, V, and U. This effacement progresses over a period of weeks. The effacement process can be dynamic, in that the internal os appears to o p e n and close while being observed. A f u n n e l e d cervix that comprises approximately 40% to 50% or

Preterm Birth Risk Assessment

m o r e of the total cervical length or a persistently s h o r t e n e d cervix measuring between the 10th -25th percentiles (25 m m to 30 mm) has consistently been associated with an increased risk of preterm birth, is,14 In a prospective investigation o f p r e t e r m birth prediction conducted by the Maternal Fetal Medicine Unit Network o f the National Institute o f Child Health and H u m a n Development, Iams and coworkers examined nearly 3,000 randomly selected women with singleton pregnancies. is Endovaginal cervical sonography was perf o r m e d at 24 weeks and again at 28 weeks o f pregnancy. Spontaneous preterm delivery was defined as one occurring before 35 weeks. This study estimated the relative risk o f p r e t e r m delivery for cervical length measurements at or below various percentiles c o m p a r e d to the refe r e n c e group of women whose cervical length was greater than the 75th percentile ( > 40 mm) (Table 1). T h e risk of a p r e t e r m delivery before 35 weeks was 6-fold higher for women with a cervical length measuring at or below the 10th percentile (26 mm) at 24 weeks o f gestation. T h e risk was 9-fold higher if the cervical length fell below the 5th percentile (22 mm) at 24 weeks gestationA ~ T h e negative predictive value of endovaginal cervical sonography as a screening test was impressive in this randomly selected population of singleton gestations. When a cervical length measured greater than 25 m m at 24 weeks' gestation (a "negative test"), the authors f o u n d the negative predictive value to be 97%, indicating a 97% probability o f the pregnancy delivering after 35 weeks. ~3 Imseis et alx6 at Ohio State reviewed data on cervical length gathered from their prematurity prevention clinic. The authors n o t e d that patients able to maintain long cervical lengths at 24 Table 1. The Relative Risk of Preterm Delivery Associated With a Shortened Cervical Length Cervical Length

-<40 mm, -<35 mm, --<30 mm, -<26 mm, --<22 mm,

7 5 th percentile 50 th percentile 25a~ percentile 10th percentile 5th percentile

Data from reference 13.

Relative Risk of Preterm Delivery

1.98 2.35 3.79 6.19 9.49

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to 26 weeks' gestation typically c a r d e d their pregnancies to term and required few, if any, interventions. This observation was confirmed by an analysis the authors presented at the Annual Meeting of the Society for Gynecologic Investigation in 1994. They established that it was not until 24 weeks' gestation that cervical sonography best identified women with a low or high risk of spontaneous p r e t e r m delivery. Their data also suggested that early cervical lengths between 16 to 18 weeks' gestation did not discriminate well between patients who ultimately delivered at term and those who delivered preterm. 17 When c o m p a r e d to singleton gestations, Kushnir et al TM f o u n d n o difference in the cervical lengths of twins u p to 19 weeks o f pregnancy. Thereafter, however, the cervix was significantly shorter in the twin gestations, even though all o f the multiples delivered at term. TMT h e MFM Unit Network investigation previously described also reported the cervical lengths a m o n g 147 twin gestations. 19 At both 24 and 28 weeks' gestation, women with twins were twice as likely to have a shortened cervix (<--25 mm) c o m p a r e d with the cervical sonography result o f a singleton pregnancy. As with singletons, a cervical length measurement in twin gestations p e r f o r m e d near 24 weeks o f p r e g n a n c y w a s an excellent predictor o f preterm delivery. A cervical length less than the 10th percentile (<-25 mm) at 24 weeks was the most significant predictor of spontaneous preterm birth before 32, 35, and 37 weeks. These patients experienced 27%, 54%, and 73% rates of spontaneous p r e t e r m birth, respectively. In contrast, a shortened cervix at 28 weeks was only able to significantly predict a p r e t e r m twin delivery before 35 weeks. 19

Fetal Fibronectin Fetal fibronectin is a glycoprotein p r o d u c e d by the trophoblast, which functions to maintain the chorionic-decidual extracellular matrix interface. Normally f o u n d in the cervical and vaginal secretions between 16 to 20 weeks o f pregnancy, the protein vanishes for nearly the remainder of pregnancy and reappears just days before labor. Therefore, its presence in the cervicovaginal secretions after 20 weeks has b e e n identified as a predictor of spontaneous p r e t e r m birth. 2~ T h e precise mechanism for the association of cervi-

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covaginal fetal fibronectin with spontaneous preterm birth is not known, but it has b e e n shown that a positive screen (>--50ng/ml) at 24 weeks' gestation is statistically associated with subsequent histologic and clinical chorioamnionitis and neonatal sepsis31 T h e finding o f fetal fibronectin protein in cervicovaginal secretions likely denotes a breakdown of the chorionicdecidual interface by either an inflammatory or infectious process. 8 Iams et al 2z have shown that preterm birth is unlikely in women with a negative fetal fibronectin level, regardless o f contraction frequency. In their analysis o f 192 patients with symptomatic preterm labor, intact membranes, and cervical dilation of less than 3 cm, 147 (76.5%) had a negative fetal fibronectin assay result. Only 1 o f these gestations delivered within 7 days o f testing, generating a negative predictive value of 99.3%. zz A large multicenter trim o f 725 women with g~/mptomatic p r e t e r m labor and singleton gestations also revealed a negative predictive value of 99.7% for delivery within 7 days of a negative fetal fibronectin screen (Table 2).2s Fetal fibi-onectin has also been investigated as a screening tool for p r e t e r m birth risk in asymptomatic women with multiple gestations. As with singletons, the detection o f the protein is associated with an increased risk of p r e t e r m birth among twins. In the MFM Unit Network investigation, 19 positive fetal fibronectin assay results at 28 weeks and 30 weeks' gestation were each associated with an increased risk of delivery prior to 32 weeks of pregnancy in the 147 twins studied. T h e positive assay result was not associated with an increased risk of delivery before 35 weeks.z 0 Although patients with positive fetal fibronectin assay results may be at an increased risk of preterm rupture o f membranes, preterm labor, and preterm delivery, the majority o f women with preterm contractions are assay negative and are not at higher risk for preterm delivery than Table 2. Reliability of Fetal Fibronectin Testing n

Sensitivity

Specificity

PPV

NPV

192

93%

82%

29%

99%

Abbreviations: PPV, positive predictive value; NPV, negative predictive value. Reprinted with permission. 22

the general population. With the negative predictive values described, this screening assay appears to suggest that treatment may be d e f e r r e d in those women with a negative test result. In fact, Joffe et alz4 analyzed the impact o f the fetal fibronectin assay use o n the admission rate for p r e t e r m labor. They d e t e r m i n e d that the test significantly reduced p r e t e r m labor admissions (28.1 to 17%), length o f stay (2.0 -+ 1.7 to 1.6 -+1.4 days), and prescriptions for tocolytic agents (10 to 7.9%). T h e r e was n o negative impact on neonatal outcome and the reduction in admissions resulted in a $416,120 savings over a 12-month period, z4

Salivary Estriol While infectious or inflammatory etiologies may account for a substantial percentage o f the deliveries before term, and especially the very early cases o f p r e m a t u r e delivery, other causes o f prematurity exist. A portion o f p r e m a t u r e delivery is felt to be explained by abnormalities o f the endocrine and paracrine pathways o f labor and possibly identifiable by the use o f h o r m o n a l markers. T h e r e are 2 well-established principles in the understanding o f mammalian parturition. First, the fetus participates in the timing o f its own birth through the hypothalamic-pituitary-adrenal-placental axis and second, the effective mechanism o f labor initiation involves estrogen dominance. O f the 3 major placental estrogens, estriol (E3) is the most a b u n d a n t during late pregnancy. It originates almost exclusively ( > 9 0 % ) from fetal DHEAS (dehydroepiandrosterone sulfate) and its production depends on an intact hypothalamic-pituitary-adrenal-placenhal axis in the fetus. In the mother, estriol levels serve as a specific marker of the activity o f the fetal adrenal gland. Serum E3 levels increase gradually during the first and second trimesters. The rise continues m o r e rapidly t h r o u g h o u t the third trimester, with a characteristic surge in the estriol level preceding the onset o f labor by approximately 3 to 4 weeks. This partuition-associated increase o f E3 occurs regardless o f the timing o f the labor event: preterm, at term, or postterm. Saliva has proven useful for measuring estriol levels because the free and biologically active form o f the h o r m o n e can be detected at

Preterm Birth Risk Assessment

levels which correlate with the level detected in the serum. 25 In 1999, Heine et a126 described a prospective comparative analysis o f salivary estriol testing and the well-established Creasy et a127 antenatal risk factor assessment for predicting the risk o f p r e t e r m labor and delivery before 37 weeks' gestation. A m o n g 601 patients evaluated, serial salivary estriol testing correctly predicted the timing o f delivery 91% o f the time while the Creasy scoring m e t h o d predicted the o u t c o m e only 75% of the time. They concluded that serial salivary estriol assessment was more accurate in predicting the timing o f delivery than the Creasy scoring method. 26 Subsequently, in a blinded, prospective multicenter trial of 956 singleton gestations, saliva was collected weekly, starting at 22 weeks o f pregnancy and tested for unconjugated estriol. ~s T h e authors d e t e r m i n e d that a single positive (-->2.1 n g / m L ) salivary E3 result predicted an increased risk of spontaneous p r e t e r m labor and delivery. T h e r e was a 4-fold increased risk o f p r e t e r m delivery a m o n g the patients considered low-risk and a 3.4-fold increased risk a m o n g patients considered high-risk, using the Creasy risk assessment system. With a single positive test, the negative predictive value for p r e t e r m birth was 98%, and it was therefore highly unlikely that p r e t e r m labor and delivery would occur in women with low salivary estriol values 28 (Table 3). Salivary estriol testing has several advantages as a risk-assessment marker for p r e t e r m labor. Testing for elevated levels o f E3 4s simple, convenient, and noninvasive. T h e samples can be collected at h o m e or in the office setting. Some investigators feel that serial determinations

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could be easily integrated into routine pregnancy m a n a g e m e n t protocols as a reliable risk identifier of p r e t e r m labor and delivery.

Home Uterine Activity M o n i t o r i n g H o m e uterine activity m o n i t o r i n g (HUAM) is a system o f care designed to provide early detection o f preterm labor. Based o n the premise that women will have an increase in subclinical uterine contractility before the onset of preterrn labor, it uses a combination o f outpatient uterine tocodynamometry and daily telephone calls from a health care provider to assess maternal status and offer patient support. The r e c o r d e d uterine activity data are transferred via telep h o n e to the care provider for review. Advocates of the system p r o p o s e that earlier detection o f u t e r i n e activity will allow for earlier and more timely administration o f tocolytic therapy a n d / o r other intervention. The possibility o f success with HUAM arose from the observation that only a minimum o f objectively r e c o r d e d prelabor uterine contractions are perceived by women. 29 On average, patients identify 15% o f their contractions. In fact, m o r e than 1 in 5 w o m e n are unable to identify any of their prelabor uterine activity. W o m e n carrying twins are even less effective in their self-perception o f uterine activity compared to women with singletonsY 9 This significandy worse perception o f uterine activity by patients with twins is i m p o r t a n t because multiple gestations exhibit an increased contraction frequency c o m p a r e d to the pattern seen in singletons. Since there is a further increase in contraction frequency within the 24 hours before the onset o f preterm labor for singletons, and to a

Table 3. Predictive Accuracy of Salivary Estriol

Low-risk population Single positive test Second positive test High-risk population Single positive test Second positive test

Sensitivity

Specificity

PPV

NPV

RR

50% 42%

81% 93%

7 14

98 98

4.0 8.5

64% 46%

68% 90%

14 26

96 96

3.4 5.8

Abbreviations: PPV, positive predictive value; NPV, negative predictive value; RR, relative risk. Adapted and reprinted with permission from the American College of Obstetricians and Gynecologists (Obstetrics and Gynecology,2000, 96:490-497).2a

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lesser extent for twins, s~ HUAM has been reco m m e n d e d in an attempt to augment maternal awareness o f uterine contractility. Controversy with this school o f thought, however, lies with the fact that the same results, ie, earlier detection o f p r e t e r m labor, can be achieved with intense patient education regarding the signs and symptoms o f p r e t e r m labor and with regularly scheduled nursing contact, al-ss Although initial trials o f HUAM suggested that earlier diagnosis of preterm labor and a resultant decrease in preterm births was possible a m o n g all enrolled patients, 31,34,sS,a6 subsequent investigations were not able to confirm these results. 32,s7,as T o date, the role o f HUAM for the prevention o f p r e t e r m birth has remained controversial in the m a n a g e m e n t of both singleton and multiple gestations. Despite n u m e r o u s studies, the expense o f HUAM and the inability to separate its effects from those o f frequent perinatal nursing contact has left the current status of HUAM as investigational and the selection o f patients for HUAM to be highly individualized. In 1995, Colton et ala9 p e r f o r m e d a metaanalysis o f 6 prospective randomized controlled trials o f HUAM. T h e goal o f this investigation was to review the use o f HUAM and its effect o n the primary prediction and prevention of preterm birth. When the results were stratified by singleton and twin gestations, singletons experienced a 24% reduction in preterm birth and an increase of 126 gms in m e a n infant birth weight associated with the use of HUAM. T h e r e was n o change in the n u m b e r o f neonatal intensive care unit admissions. In addition, twin pregnancies had a significant decrease in the occurrence o f preterm labor associated with advanced cervical dilation m o r e than 2 cm. T h e r e was a 56% reduction in risk of this adverse outcome. Nevertheless, despite the improved early prediction of preterm labor with twin pregnancies, there was no substantial decrease in the overall rate o f preterm delivery for twins, no increase in the mean infant birth weight, n o r a decrease in the n u m b e r o f neonatal intensive care unit admissions for twin pregnancies. The largest and most recent trial by Dyson et a s2 followed 2,422 padents at risk for preterm labor. This sample size included 844 patients with twins. T h e trial had 3 treatment arms: weekly contact with a nurse, daily contact with a

nurse, or daily contact with a nurse and a uterine contraction monitor. As a result, the nursing contact feature was more appropriately analyzed. T h e r e were no significant differences a m o n g the three groups in the rate o f p r e t e r m delivery before 35 weeks. T h e m e a n cervical dilation at the time o f preterm labor diagnosis was not different and there were n o differences in neonatal outcome a m o n g the 3 groups. These authors concluded that frequent monitoring o f uterine activity in high-risk women is o f n o benefit in decreasing the frequency o f p r e t e r m birth or its neonatal complications, s2 Regarding high o r d e r multiple gestations, the data in the literature indicates that progressive cervical change can occur without a significant increase in the pre-labor contraction frequency, s~ Thus, if prelabor uterine activity is not associated with cervical change, then the value o f HUAM in these pregnancies would be questioned.

Conclusion In summary, the majority o f women with prcterm uterine contractions arc not at increased risk o f a preterm delivery. This is based o n the finding that contractions arc really a secondary sign o f prcterm partuition and it is therefore not logical to primarily attempt suppression o f the uterine activity as a means o f preventing p r e t e r m birth. An important goal o f obstetrical care is to d e t e r m i n e which patients actually are at a significandy increased risk for an early delivery. While likely not efficacious for low-risk population screening at the present time, the markers and tools described here - endovaginal ultrasound, fetal fibronectin, salivary estriol and HUAM rI appear to be useful for at least excluding preterm labor in a population previously determined to be at high risk o f a preterm delivery. Each o f the c o m m o n etiologies o f p r e t e r m labor, such as infection/inflammation, decidual interface disruption, activation o f the fetal hypothalamic-pituitary pathway, cervical c o m p e t e n c e or pathologic uterine distention have differing biochemical a n d / o r h o r m o n a l patterns. Therefore, each o f the various biochemical markers or diagnostic tools may be m o r e predictive for different clinical situations. Future investigations will help us determine whether a single m a r k e r

Preterm Birth Risk Assessment

performs better at predicting p r e t e r m birth for a given etiology or whether multiple marker screening may be m o r e sensitive overall in identifying a woman at risk for p r e t e r m delivery.

References 1. Monthly Vital Statistics Report: Advance report of final natality statistics, 1998. National Center for Health Statistics 48(12) 2000 2. Cooper RL, Goldenberg RL, Creasy RK, et al: A multicenter study of preterm birth weight and gestational age-specific neonatal mortality. Am J Obstet Gynecol 168:78-83, 1993 3. IamsJD: Preterm labor, in, Gabbe SG, NeibylJR, SimpsonJL, (eds): Obstetrics: Normal and Problem Pregnancies. Churchill Livingstone, New York, 1996 4. Revah A, Hannah ME, Sue-A-Quan AK: Fetal fibronectin as a predictor of preterm birth: An overview. A m J Perinatol 15:613-621, 1998 5. Luke B: Perinatal significance of multiple gestations, in Newman RB and Luke B, (eds): Multifetal Pregnancy: A handbook for care of the pregnancy patient. Lippincott Williams and Wilkins, Philadelphia, PA, 2000 6. Macones GA, Sehdev HM, Berlin M, et al: Evidence for magnesium sulfate as a tocolytic agent. Obstet Gynecol Surv 52:652-654, 1997 7. King JF, Grant A, Keirse MJNC, et al: Beta-mimetics in preterm labor: An overview of the randomized clinical trials. B r J Obstet Gynaecol 95: 211-222, 1988 8. Association of Professors of Gynecology and Obstetrics Educational Series on Women's Health Issues. Prevention and Management of Preterm Birth. 1998 9. Hillier SL, Nugent RP, Eschenbach DA, et al: Association between bacterial vaginosis and preterm delivery of a low-birth weight infant: The Vaginal Infections and Prematurity Study Group. N Engl J Med. 333:173%1742, 1995 10. Gibbs RS, Romero MD, Hillier SL, et al: A review of premature birth and subclinical infection. Am J Obstet Gynecol 166:1515-1528, 1992 11. Goldenberg RL, Andrews WW, Yuan AC, et al: Sexually transmitted diseases and adverse outcomes of pregnancy. Clin Perinatol 24:23-41, 1997 12. Romero R, Avila C, Brekus CA, et al: The role of systemic and intrauterine infection in preterm parturition. Ann NY Acad Sci 622:355-375, 1991 13. Iams JD, Goldenberg RL, Meis PJ, et al: The length of the cervix and the risk of spontaneous premature delivery. N E n g l J Med 334:567-572, 1996 14. Berghella V, Kuhlman K, Weiner S, et al: Cervical funneling: Sonographic criteria predictive of preterm delivery. Ultrasound Obstet Gynecol 10:161-166, 1997 15. Zilianti M, Azuaga A, Calderon F, et al: Monitoring the effacement of the uterine cervix by transperineal sonography. J Ultrasound Med 14:719-724, 1995 16. Imseis HM, Albert TA, Iams JD: Identifying twin gestations at low risk for preterm birth with a transvaginal

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ultrasonographic cervical measurement at 24-26 weeks' gestation. Am J Obstet Gynecol 177:1149-1155, 1997 17. Albert T, Samuels P, Gebauer C, et al: Transvaginal cervical sonography as a predictor of preterm birth in twin pregnancies, in Proceedings of the Forty-first Annual Meeting of the Society for Gynecologic Investigation; 1994 Mar 15-18; Chicago, Illinois. Chicago: The Society; 1994 18. Kushnir O, Izquierdo LA, Smith JF, et al: Transvaginal sonographic measurement of cervical length: evaluation of twin pregnancies. J Reprod Med 40:380-382, 1995 19. Goldenberg RL, Iams JD, Miodovnik M, et al: The pre~ term prediction study: Risk factors in twin gestations. Am J Obstet Gynecol 175:104%1053, 1996 20. Goldenberg RL, Mercer BM, IamsJD, et al: The preterm prediction Study: patterns of cervicovaginal fetal fibronectin as predictors of spontaneous preterm delivery. A m J Obstet Gynecol 177:8-12, 1997 21. Goldenberg RL, Thom E, Moawad Ah, et al: The Preterm Prediction Study: fetal fibronectin, bacterial vaginosis, and peripartum infection. Obstet Gynecol 87:656660, 1996 22. Iams JD, Casal D, McGregor JA, et al: Fetal fibronectin improves the accuracy of diagnosis of preterm labor. A m J Obstet Gynecol 173:141-145, 1995 23. Peaceman AM, Andrews WW, Thorp JM, et al: Fetal fibronectin as a predictor of preterm birth in patients with symptoms: A multicenter trial. AmJ Obstet Gynecol 177:13-18, 1997 24. Joffe GM, Jacques D, Bemis-Heys R, et al: Impact of the fetal fibronectin assay on admissions for preterm labor. Am J Obstet Gynecol 180:581-586, 1999 25. Goodwin TM: A role for estriol in human labor, term and preterm. Am J Obstet Gynecol 180:$208-213, 1999 26. Heine PR, McGregorJA, DullienVK:Accuracyofsalivary estriol testing compared to traditional risk factor assessment in prediction preterm birth. A m J Obstet Gynecol 180:$214-218, 1999 27. Creasy RK, Gummer BA, Liggins GC: System for prediction spontaneous preterm birth. Am J Obste Gynecol 55:692-695, 1980 28. Heine PR, McGregor JA, Goodwin TM, et al: Serial Salivary Estriol to Detect an Increased Risk of Preterm Birth. Ohstet Gynecol 96:490-497, 2000 29. Newman RB, Gill PJ, Wittreich P, et al: Maternal perception of prelabor uterine activity. Obstet Gynecol 68:765769, 1986 30. Newman RB, Gill PJ, Campion S, et al: The influence of fetal number on antepartum uterine activity. Obstet Gynecol 73(5 Pt 1):695-699, 1989 31. Dyson DC, Crites YM, Ray DA, et al: Prevention of preterm birth in high-risk patients: The role of education and provider contact versus home uterine monitoring. A m J Obstet Gynecol 164:756-762, 1991 32. Dyson DC, Danbe KH, Bamer JA, et al: Monitoring women at risk for preterm labor. N EnglJ Med 338:1519, 1998 33. Newman RB: Preterm Birth Prediction and Prevention, in Newman RB, Luke B, (eds): Multifetal Pregnancy: A Handbook for Care of the Pregnancy Patient. Philadelphia, PA, Lippincott Williams and Wilkins, 2000

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