preterm birth

Quality Improvement in Perinatal Care 2006

Preterm birth

Henrik Hagberg, MD, PhD,

Professor in Obstetrics and Gynaecology, especially Perinatology, Department for Women’s and Children’s Health, University of Gothenburg, Sweden.

Essential reading Chapters 24-25 in “A guide to effective care…” http://www.childbirthconnection.org/article.asp?ClickedLink=194&ck=10218&area=2 Pick the most interesting articles in the reference lists below and read the abstracts at Medline. Find your own references, e.g. guidelines and compare them with this material. Outline

• Preterm birth and perinatal morbidity and mortality • Incidence of preterm birth in different countries • Subgroups of preterm birth • Preterm birth – Pathophysiological mechanisms • Risk factors for preterm birth • Tests for prediction of preterm delivery • Prevention of preterm delivery • Treatment of symptomatic patients

Corticosteroids Tocolytics Antibiotics Preterm birth and perinatal mortality and morbidity Preterm birth (PTB) remains one of the main causes of perinatal mortality and long-term morbidity (1, 2). More than 70% of the total perinatal mortality can be attributed to preterm birth (1,2). The risk of sepsis, necrotizing enterocolitis, periventricular hemorrhage, periventricular white matter injury and cerebral palsy is high (3-5). In spite of that only 5% of infants are born <37 gestational weeks in Sweden (see below), they account for nearly half of all cases with CP (3). In addition, the risk of CP is inversely proportional to gestational high meaning that the risk of CP is 60 times higher at gestational age <28 compared to term (3). Long-term follow up studies indicate that a high proportion of infants born very preterm suffer from a high risk of neuropsychological impairment, school problems and behavioral abnormalities (4-8).

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http://www.childbirthconnection.org/article.asp?ClickedLink=194&ck=10218&area=2


Readings

EntrezPubMed: If you do not have the full text available to you, at least study the abstract, which can be obtained at PubMed (www.pubmed.org). Full text articles from this journal are available free to HINARI users in low-income countries.

1. Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med

1998;339(5):313-20. 2. Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360(9344):1489-97. 3. Hagberg B, Hagberg G, Olow I, van Wendt L. The changing panorama of cerebral

palsy in Sweden. VII. Prevalence and origin in the birth year period 1987-90. Acta Paediatr 1996;85:954-60.

4. Finnström O, Otterblad Olausson P, Sedin G, Serenius F, Svenningsen N, Thiringer K et al. Neurosensory outcome and growth at three years in extremely low birthweight infants: follow-up results from the Swedish national prospective study. Acta Paediatr 1998;87:1055-60.

5. Finnström O, Olausson Otterblad P, Sedin G, Serenius F, Svenningsen N, Thiringer K et al. The Swedish national prospective study on extremely low birthweight (ELBW) infants. Incidence, mortality and survival in relation to level of care. Acta Paediatr 1997;86:503-11.

6. Hack M, Taylor G, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. School-age outcomes in children with birth weights under 750 g. N Engl J Med 1994;331:753-9.

7. Bennett FC, Scott DT. Long-term perspective on premature infant outcome and contemporary intervention issues. Seminar Perinatol 1997;21:190-201.

8. Vohr BR, Msall ME. Neuropsychological and functional outcomes of very low birth weight infants. Seminar Perinatol 1997;21:202-20.

Incidence of preterm birth in different countries The US incidence of PTB in 2000 (11.6 %) (1), was much higher than in Sweden, (5.6%) (2). There has been a slight increase during the last decades in the USA and Canada (3). In the USA, the PTB rate has risen steadily from 9.4 % in 1981, to 10.6 % in 1990 and 11.6 % in 2000 (3). Among the non-Hispanic white population, the PTB rate has risen from 8.5 % in 1990 to 10.4 % in 2000, but there has been a slight reduction in PTBs in the black population from 18.9 % in 1991 to 17.3 % in 2000 (1). Three exceptions from the stable or increased PTB rate are France (4, 5), Finland (6) and more recently also Sweden (2) that have reported decreasing incidence of PTB. Although all births before 37 weeks of gestation are considered preterm according to the World Health Organization’s definition, births before 32 weeks of gestation account for most neonatal deaths and disorders (7). Sweden and the USA also differ when it comes to the rate of births occurring < 32 weeks of gestation, 0.85 % and 1.93 % respectively (1, 8).

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http://www.pubmed.org/


In the developed world, the most serious squeals of preterm birth and highest risk of death occur in those preterm neonates born at less than 32 weeks. In the developing world, the morbidity and mortality associated with preterm birth are devastating even up to 36 weeks’ gestation. Preterm birth is an epidemic characterized by disparity. Newborn health is one of the most striking examples of health inequality in the world. 98% of 3.9 million neonatal deaths each year occur in the poorest countries of the world (11). Of those deaths, 50% are due to being born underweight, because of preterm delivery and/or intrauterine growth restriction. Even in the developed world, the frequency and consequences of preterm birth are characterized by disparity. In the United States, African American women are nearly twice as likely to have a baby born preterm as Caucasian women. In fact, approximately 100,000 African American newborns in the U.S. are affected each year by this common, costly and serious problem (9, 10).

Readings


1. MacDorman MF, Minino AM, Strobino DM, Guyer B. Annual summary of vital statistics--2001. Pediatrics 2002;110(6):1037-52. 2. Morken NH, Källen K, Hagberg H, Jacobsson B. Preterm birth in Sweden 1973-2001: rate, subgroups and effect of changing patterns in multiple births, maternal age and smoking. Acta Obstet Gynecol Scand 2004:In Press. 3. Joseph KS, Kramer MS, Marcoux S, Ohlsson A, Wen SW, Allen A, Platt R. Determinants of preterm birth rates in Canada from 1981 through 1983 and from 1992 through 1994. N Engl J Med 1998;339(20):1434-9. 4. Papiernik E, Bouyer J, Dreyfus J, Collin D, Winisdorffer G, Guegen S, Lecomte M, Lazar P. Prevention of preterm births: a perinatal study in Haguenau, France. Pediatrics 1985;76(2):154-8. 5. Breart G, Blondel B, Tuppin P, Grandjean H, Kaminski M. Did preterm deliveries continue to decrease in France in the 1980s? Paediatr Perinat Epidemiol 1995;9(3):296-306. 6. Olsen P, Laara E, Rantakallio P, Jarvelin MR, Sarpola A, Hartikainen AL. Epidemiology of preterm delivery in two birth cohorts with an interval of 20 years. Am J Epidemiol 1995;142(11):1184-93. 7. Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360(9344):1489-97. 8. Medical birth registration in 2000: Swedish National Board of Health and Welfare; 2002. 9. Adams MM, Read JA, Rawlings JS, Harlass FB, Sarno AP, Rhodes PH. Preterm delivery among black and white enlisted women in the United States Army. Obstet Gynecol 1993;81(1):65-71. 10. Mattison DR, Damus K, Fiore E, Petrini J, Alter C. Preterm delivery: a public health perspective. Paediatr Perinat Epidemiol 2001;15 Suppl 2:7-16.

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Subgroups of preterm birth The possibility that the clinical consequences of preterm birth for the infant could vary according to causal mechanism has led to a subdivision of PTB into sub-groups (1). One classification of PTB is based on the manner in which the patients presents, i.e. spontaneous preterm labor (PTL), preterm prelabor rupture of membranes (pPROM) and elective induction or cesarean section (CS) (usually due to a complication of pregnancy), respectively (1). The first two groups are often combined and called spontaneous PTB, in contrast to indicated PTB. This subdivision has been questioned but is still the one in most common use (2). All studies related to this issue are hospital-based. The proportion of preterm deliveries resulting from PTL varies in different studies from 18 to 64 % (3-5), while that resulting from pPROM is reported at between 7 and 51% (6-8). The proportion of preterm deliveries classified as indicated varies between 18 and 38% (4, 6, 9). It seems like areas with low and high incidence of preterm birth has the same composition of preterm birth (1,10). Figure 1 shows the composition of preterm singleton births according to a Swedish national cohort study.

Preterm birth

Malformations and IUFDMultiple pregnancy 7.7% 12.3%

80%

Iatrogenic preterm birth

73.2%26.7% Spontaneous preterm birth

58.6%

21.4%

Figure 1 Morken NH, Källen K, Hagberg H, Jacobsson B. Preterm birth in Sweden 1973-2001: rate, subgroups and effect of changing patterns in multiple births, maternal age and smoking. Acta Obstet Gynecol Scand 2005; 84:558-565:

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Readings


1. Savitz DA, Blackmore CA, Thorp JM. Epidemiologic characteristics of preterm delivery: etiologic heterogeneity. Am J Obstet Gynecol 1991;164(2):467-71. 2. Klebanoff MA, Shiono PH. Top down, bottom up and inside out: reflections on preterm birth. Paediatr Perinat Epidemiol 1995;9(2):125-9. 3. Piekkala P, Kero P, Erkkola R, Sillanpaa M. Perinatal events and neonatal morbidity: an analysis of 5380 cases. Early Hum Dev 1986;13(3):249-68. 4. Wolf EJ, Vintzileos AM, Rosenkrantz TS, Rodis JF, Salafia CM, Pezzullo JG. Do survival and morbidity of very-low-birth-weight infants vary according to the primary pregnancy complication that results in preterm delivery? Am J Obstet Gynecol 1993;169(5):1233-9. 5. Hewitt BG, Newnham JP. A review of the obstetric and medical complications leading to the delivery of infants of very low birthweight. Med J Aust 1988;149(5):234, 236, 238 passim. 6. Meis PJ, Ernest JM, Moore ML. Causes of low birth weight births in public and private patients. Am J Obstet Gynecol 1987;156(5):1165-8. 7. Hagan R, Benninger H, Chiffings D, Evans S, French N. Very preterm birth--a regional study. Part 1: Maternal and obstetric factors. Br J Obstet Gynaecol 1996;103(3):230-8. 8. Hagan R, Benninger H, Chiffings D, Evans S, French N. Very preterm birth--a regional study. Part 2: The very preterm infant. Br J Obstet Gynaecol 1996;103(3):239-45. 9. Kimberlin DF, Hauth JC, Owen J, Bottoms SF, Iams JD, Mercer BM, Thom EA, Moawad AH, VanDorsten JP, Thurnau GR. Indicated versus spontaneous preterm delivery: An evaluation of neonatal morbidity among infants weighing </=1000 grams at birth. Am J Obstet Gynecol 1999;180(3 Pt 1):683-9. 10. Morken NH, Källen K, Hagberg H, Jacobsson B. Preterm birth in Sweden 1973-2001: rate, subgroups and effect of changing patterns in multiple births, maternal age and smoking. Acta Obstet Gynecol Scand 2004:In Press. Preterm birth – pathophysiological mechanisms There are several pathophysiological factors that may trigger the events leading to preterm birth.

• Maternal stress/release of corticotropin releasing hormone (CRH) (1), • uterine overdistension (multiple pregnancy, polyhydramniosis), lack of prostaglandin

dehydrogenase (2), • hemorrhage (3) • infections (4)

Infection seems to be the most important etiology in early gestation (4), whereas over distension and maternal stress play more important roles at later gestation.

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These factors can act individually or in various combinations to induce uterine contractions (through production of prostaglandins, endothelin, increase the estrogen/progesterone balance, increased density of oxytocin receptors or gap junctions) (5-8);

• by promoting cervical maturation (activation of proteolytic enzymes in the cervical tissue through interleukin-8 triggered neutrophil activation)

• by inducing proteolytic degradation of adhering proteins between the chorion and the decidua with subsequent release of fetal fibronectin);

• by rupture of the membranes (apoptosis of cells in the chorioamniotic membranes and breakdown of extracellular collagen and mucopolysacccharides).

During recent years infection-related preterm has been recognized as an important etiology. There is a strong correlation between intraamniotic cytokine-mediated inflammation and preterm delivery both in PTL and PPROM patients (4,9). Furthermore, the risk of neonatal neurologic morbidity seems to be higher in spontaneous preterm birth (often related to infections) compared to indicated delivery related to maternal or fetal complications. Verma et al. (10) demonstrated that the occurrence of periventricular/intraventricular hemorrhage or periventricular leukomalacia was much high subsequent to PTL (17%) or PPROM (14%) compared to after physician-initiated preterm delivery (0.5%) and the difference persisted after correction for differences in gestational age. According to some studies, there is also a strong correlation between the degree of cytokine elevation in the amniotic fluid in women with preterm labor and the subsequent occurrence of white matter injury and cerebral palsy in the offspring (11). Therefore, it seems particularly urgent to understand more about infection-related preterm birth to develop preventive and therapeutic strategies (12).

Readings


1. Korebrits C, Ramirez MM, Watson L, Brinkman E, Bocking AD, Challis JR. Maternal corticotropin-releasing hormone is increased with impending preterm birth. J Clin Endocrinol Metab 1998;83:1585-91.

2. van Meir CA, Matthews SG, Keirse MJ, Ramirez MM, Bocking A, Challis JR. 15-hydroxyprostaglandin dehydrogenase: implications in preterm labor with and without ascending infection. J Clin Endocrinol Metab 1997;82:969-76.

3. Williams M, Mittendorf R, Lieberman E, Monson R. Adverse infant outcomes associated with first-trimester vaginal bleeding. Obstet Gynecol 1991;78:14-8.

4. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery.N Engl J Med. 2000 May 18;342(20):1500-7.

5. Lockwood CJ. Recent advances in elucidating the pathogenesis of preterm delivery, the detection of patients at risk, and preventative therapies. Curr Opin Obstet Gynecol 1994;6:7-18.

6. Bocking AD. Preterm labour: recent advances in understanding of pathophysiology, diagnosis and management. Curr Opin Obstet Gynecol 1998;10:151-6.

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10816189


7. Dudley DJ, Trautman MS. Infection, inflammation, and contractions: the role of cytokines in the pathophysiology of preterm birth. Seminar Reprod Endocrinol 1994;12:263-72.

8. Keelan JA, Coleman M, Mitchell MD. The molecular mechanisms of term and preterm labor: recent progress and clinical implications. Clin Obstet Gynecol 1997;40:460-78.

9. Hillier S, Witkin S, Krohn M, Watts D, Kiviat N, Eschenbach D. The relationship of amniotic fluidcytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis and chorioamnion infection. Obstet Gynecol 1993;81:941-8.

10. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997;176:275-81.

11. Yoon B, Jun J, Romero R, Park K, Gomez R, Choi J et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1b, and tumor necrosis factor-a), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177:19-26.

12. Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997;42:1-8.

Risk factors of preterm birth Although the pathophysiology of preterm delivery is poorly understood there are many well-known contributing risk factors and a thorough history is an important part of the assessment of preterm labor. Factors found in association with preterm labor can be divided into three main groups,

• sociobiologic variables, past obstetric history and complications of the current pregnancy.

• Risk factors for preterm labor are listed in table 1. • Individual factors may not be independent so in a study it is necessary to do

both univariate and multivariate analysis. Three important and readily recognised conditions associated with preterm birth are

• Previous preterm birth • Multiple pregnancy • Medically assisted conception

A strong predictor of subsequent preterm birth is a history of previous preterm delivery. The relative risk of preterm birth increases with the number of previous preterm births: 2.2 for one, 3.7 for two and 4.9 for three or more. In addition the earlier the previous preterm birth, the earlier would be the gestation of the subsequent birth. This is most evident when the previous birth has been before 28 weeks of gestation (1). Multiple pregnancy is associated with a high risk preterm delivery. In twin gestations the proportion of preterm births is 40-60%, in triplets > 80% and in higher order multiple pregnancies > 95%. Not the entire increased rate of preterm birth in multiple pregnancy is due to spontaneous onset of labor as multiple pregnancy is also associated with a variety of conditions that may cause the clinicians to end pregnancy before term.

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Assisted reproductive technology (ART) results in a markedly increased risk of both preterm and very preterm birth mainly due to the high rate of multiple pregnancy which is an effect of the transfer of multiple embryos (2). In the Scandinavian countries major advances have been made in reduction of the multiple birth rate by reducing the number of embryos transferred (3). The high incidence of preterm birth after ART is not confined to multiple pregnancies but also occurs in singleton pregnancies. Several studies have shown at least a two fold increased risk of preterm birth in singleton pregnancies after ART (4).

Readings


1. Bakketeig, L. & Hoffman, H. (1981). Epidemiology of preterm birth. In Preterm labour, Elder, M. & Hendricks, C. (eds). Butterworth*s International Medical Reviews: London.

2. Bergh, T., Ericson, A., Hillensjo, T., Nygren, K.G. & Wennerholm, U.B. (1999). Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet, 354, 1579-85.

3. Thurin, A., Hausken, J., Hillensjo, T., Jablonowska, B., Pinborg, A., Strandell, A. & Bergh, C. (2004). Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med, 351, 2392-402.

4. Wennerholm, U. & Bergh, C. (2004). Outcome of IVF pregnancies. Fetal and Maternal Medicine Review, 15, 27-57.

Factors associated with preterm delivery Table 1 Sociobiologic variables

• Maternal age (adolescence, advanced maternal age) • Parity • Maternal size (short stature, low weight) • Low socioeconomic status • Race (African-American rates disproportionately high) • Smoking, drug abuse • Environmental stress

Past obstetric history • Prior preterm birth • Prior spontaneous abortion • Prior therapeutic abortion • Cervical incompetence • Maternal genital abnormality

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Complications of the current pregnancy

• Elective preterm birth (preeclampsia, eclampsia, isoimmunisation, placenta previa, abruption)

• Multiple gestation • Antepartum hemorrhage • Preterm prelabor rupture of the membranes (PPROM) • Medically assisted conception • Late or no antenatal care • Maternal infection

Asymptomatic bacteruria Pyelonephritis Genital infections Syphilis,gonorrhea, chlamydia Group B streptococcal infection Bacterial vaginosis

Ureaplasma urealyticum, mycoplasma hominis, trichomonas vaginalis- relationship to preterm labor or PPROM controversial

Other systemic infections (e.g. pneumonia, malaria, typhoid fever) • Abdominal surgery • Maternal trauma • Polyhydramniosis • Fetal malformation • Male sex

Tests for prediction of preterm delivery Early detection of preterm labor is difficult because initial symptoms and signs are often mild and may occur in normal pregnancies. Only half of the women who show signs of preterm labor actually deliver early. In others contractions die out on their own indicating that the patients have had “false” labor. Tests used for prediction of preterm delivery can be defined as screening tests e.g. tests that are used to detect asymptomatic disease or diagnostic tests that are used in patients with symptoms of preterm labor. A good screening test should have a high sensitivity, a high negative predictive value and a low cost. Furthermore an effective prophylactic intervention or treatment should be available for those individuals who test positive. The primary and ultimate goal in a screening programme for preterm birth should be an improvement in neonatal outcome; secondary outcomes should be reduction in preterm deliveries and shortened time – to- delivery.

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Diagnostic indices Sensitivity - proportion of persons with condition who test positive Specificity – proportion of persons without condition who test negative Positive predictive value (PPV) = proportion of persons with positive tests who have condition) Negative predictive value (NPV) = proportion of persons with negative tests who do not have condition) Likelihood ratio (LR’s)= probability of the test result in the presence of disease divided by the probability of the result in those without the disease LR’s express how many times more (or less) likely a test result is to be found in those with the disease compared to those without the disease. Different test that have been used to determine the risk of preterm labor, the most common of them being transvaginal sonography (TVS), the cervicovaginal fetal fibronectin test (FFN), salivary estriol test, home uterine activity monitoring (HUAM) and clinical risk predictors (risk scoring systems). Risk scoring systems A number of risk scoring systems have been developed with the aim of identifying women likely to deliver prematurely, the one developed by Creasy being the most commonly evaluated (1). In risk scoring systems various factors known to be associated with preterm birth are incorporated resulting in a total score that gives an estimation of the magnitude of the risk (formal risk scoring). In clinical practice, the implementation of these scoring systems has not shown to be useful. However, most systems rely heavily on past obstetric history and thus are inappropriate for nulliparae who constitute about 45% of pregnant women at their first antenatal visit. The positive predictive values using risk scoring systems are low, and the percentage of women who give birth preterm has never been higher than 30% of those considered being at high risk, including women with multiple pregnancy and /or a history of previous preterm birth (who can easily be identified without formal risk scoring). On the other hand and consistent among different scoring systems, between 20 and 50% of preterm births occur in women who were considered to be at low risk. Therefore, formal risk scoring offers no advantages over careful clinical assessment and cannot be recommended (2). Home uterine activity monitoring (HUAM) Use of home uterine monitoring has demonstrated no consistent benefit in reducing rates of preterm delivery in either low risk or high risk women. It increases the use of prophylactic tocolytics and unscheduled visits to obstetricians and hospitals without improvement in neonatal outcome (3).

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Salivary estriol Preterm deliveries might be associated with elevated maternal serum estriol levels. A surge has been noted approximately 3 weeks before the onset of labor in women who delivered prematurely or at term. It has been shown that maternal salivary estriol reflect maternal serum levels and salivary estriol has been used to assess risk for spontaneous preterm labor and delivery in symptomatic and asymptomatic women. Levels of salivary estriol can be accurately measured with a radioimmunoassay. Heine et al (4) showed that a single positive (at or above 2.1ng/mL) salivary estriol predicted a 3-4 fold increased risk of preterm birth in both low risk and high risk women. Two consecutively positive tests significantly increased the predictive accuracy but with only a modest decrease in sensitivity. Salivary estriol testing offers several advantages; it is a non-invasive test, salivary samples are easy to collect and a positive test may occur several weeks before onset of labor. However, further studies to evaluate potential interventions and treatments of women with elevated salivary estriol are needed before its use can be recommended in the general obstetric population.

Fetal fibronectin

Cervicovaginal fetal fibronectin test Fibronectin is:

• Glycoprotein in amniotic or placental tissue • Present in vagina before 20 wks, then absent

until labor • Released because of damage to membranes or

placenta • Measured from cervical or vaginal swabs • The test appears to be useful in ruling out

preterm delivery within the next 2 weeks Fetal fibronectin (FFN) is an extracellular glycoprotein produced by many cell types in the body and functions to bind cells together. It is a glue-like substance that also plays a part in the maintenance of the placental attachment to the decidua. It is concentrated in amniotic fluid, placental tissue and the extracellular substance of decidua basalis next to the placental intervillous space. It is thought to be released through mechanical and inflammatory mediated damage to the membranes or placenta before birth. It is expressed in cervicovaginal secretions during the first 20 weeks of gestation, disappears from the secretions after this period and does not normally reappear until term. Detecting fetal fibronectin in the vaginal secretions has been studied to see if this test can be predictive of preterm birth. A positive FFN result has generally been accepted at a value greater than or equal to 50ng/mL. False positive results can be cause by contamination of the sample with maternal blood or sampling within 24 hours after intercourse. A recent large meta-analysis included both studies on asymptomatic and symptomatic women (n= 26 876 women) and analysed the value of a positive or negative FFN test for predicting preterm birth before 34 and 37 weeks of gestation and for symptomatic women also for delivery within 7-10 days of testing (5). They found that the accuracy of the FFN test in predicting various spontaneous preterm birth outcomes varies. The test is most accurate in

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predicting spontaneous preterm birth within 7-10 days after testing among women with symptoms of threatened preterm birth before advanced cervical dilatation. FFN test in asymptomatic women (28 studies; 8 low risk studies, 9 high risk studies, 11 not risk categorised studies) showed that the best summary likelihood ratio for positive results was 4.01 (95% CI 2.93 to 5.49) for predicting birth before 34 weeks of gestation, with corresponding negative results of 0.78 (95% CI 0.72 to 0.84). Although statistically significant, it currently has little clinical value since there is still no intervention that has demonstrated any clear benefit in preventing preterm birth. FFN test in symptomatic women (40 studies; 5 low risk studies, 4 high risk studies, 31 not risk categorised studies) showed that the best summary likelihood ratio for positive results was 5.42 (95% CI 4.36 to 6.74) for predicting birth 7-10 days after testing. Despite the increased likelihood of preterm delivery most of the women remained pregnant 10 days after the test. Of more interest, the negative likelihood ratio of preterm delivery was 0.25 (95% CI 0.20 to 0.31) with negative results on the test. In the group with a negative result 99.5% were still pregnant seven days later and 99.2% were still pregnant 14 days later. The clinical implication of a positive test needs to be further evaluated (6,7). Exercise: What is the positive and negative likelihood ratio of FFN? What consequences does that have for the interpretation and use of the test? What are the primary benefits of the test? Cervical assessment Table 2 Technique for assessing the cervical length with transvaginal sonography. See Figure 1, 2, 3

1. Ask the patient to empty her bladder prior to the examination 2. Examine in the dorsal lithotomy position 3. Do a digital pelvic examination first unless there is a history of bleeding

Location of cervix – anterior, posterior 4. Insert probe under continuous sonographic vision

Look for familiar anatomy – bladder, amniotic fluid 5. Find the midline sagittal plane 6. Identify the internal cervical os 7. Rotate probe slightly to get best long axis of cervix with both internal and external os

seen 8. Pull back probe until lightest touch consistent with a good image of the cervical canal

is obtained. 9. Measure (x 3) shortest distance between “notches” made by interface of the canal

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Figure 1. Transvaginal ultrasound image of the cervix obtained from a woman with symptoms of preterm labor. The image excludes a diagnosis of preterm labor because of the length (38 mm) and the T-shaped appearance of the cervix (8).

Figure 2. Transvaginal ultrasound image of the cervix obtained from a woman with symptoms of preterm labor. The image supports a diagnosis of preterm labor because of the length (23 mm) and the Y-shaped appearance of the cervix (8). Ultrasonographic assessment of cervical length has been studied as a tool to predict preterm birth and appears to provide helpful diagnostic support in some situations. Transvaginal sonography provides advantages over transabdominal sonography, which may be unreliable

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due to maternal habitus, position of the cervix, degree of bladder filling and the obscuring effect of the fetus. The technique for transvaginal sonography is described in table 2, figure 1 and 2. Excessive pressure on the vaginal probe and failure to empty the maternal bladder are associated with falsely long measurements. Multiple dimensions of the cervix have been measured including the presence and size of a funnel at the internal os. The residual closed portion of the cervix has been shown to be the most reliable measurement and most consistently correlated with the duration of pregnancy (Figure 3). Funnelling must be associated with a residual length that is short (i.e. less than 25 mm) to be clinically significant.

Figure 3. Diagram of a sagittal view of the cervix by transvaginal ultrasonography indicating the appropriate measurement of the cervical length as the residual length (8). Studies have shown that cervical length is indirectly proportional to the relative risk of preterm delivery. Iams et al evaluated the cervical length of 2915 women at 22 to 24 weeks’ gestation. A cervical length at 22-24 weeks that was below 25 mm (the tenth percentile) was associated with a more than six-fold increase in preterm birth before 35 weeks relative to those women whose cervical length was above the 75th percentile (Figure 4). Unfortunately, there was no cervical length below which all women delivered prematurely and no cervical length above which none of the women delivered early (9).

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Figure 4. Distribution of subjects among percentiles for cervical length measured by transvaginal ultrasonography at 24 weeks' gestation (solid line) and relative risk of spontaneous preterm delivery before 35 weeks' gestation according to percentiles for cervical length (bars). The risks among women with values at or below the first, fifth, tenth, 25th, 50th, and 75th percentiles for cervical length are compared with the risk among women with values above the 75th percentile (9). A systematic review and meta-analysis of transvaginal ultrasonography in asymptomatic women (33 studies included) showed that there was a great variation amongst studies with respect to gestational age at testing, definition of threshold of abnormality and definition of reference standard (10). The most commonly reported sub-group was testing of asymptomatic women at <20 weeks’gestation with a singleton pregnancy using a threshold cervical length of 25 mm and with spontaneous preterm birth before 34 weeks’ gestation as outcome. The summary LRr for this group was 6.29 (95% CI 3.29-12.02) for predicting preterm birth before 34 weeks and 0.79 (95% CI 0.65-0.95) for a negative result. This translates the pre-test probability of 4.1% to a post-test probability of 15.8%. Ultrasound assessment of cervical length may be used in the assessment of a woman with presumed preterm labor. Leitich et al (10) as well as Iams et al (9) have noted that in symptomatic women the optimal threshold to exclude a diagnosis of preterm labor is 30 mm. If the cervical length is less than 20 mm, the patient is more likely to be in preterm labor. Because cervical effacement occurs slowly and often precedes clinically evident preterm labor a cervical length less than 20 mm does not always indicate the presence of preterm labor but a length of more than 30 mm reliably excludes preterm labor if the examination is done properly (10,11).

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In the future: There are other possible indicators of preterm labor and preterm birth i.e. cervical alpha-fetoprotein, cytokines, corticotropin-releasing hormone (CRH) and interleukin-6. Exercise TVS is often used in women with preterm labour for prediction of the risk of preterm birth. What is the greatest advantage of measuring the length of cervix? Are evidence supporting screening of symptomless pregnant women with TVS to avoid preterm birth? Readings


1. Holbrook, R.H., Jr., Laros, R.K., Jr. & Creasy, R.K. (1989). Evaluation of a risk-scoring system for prediction of preterm labor. Am J Perinatol, 6, 62-8.

2. Honest, H., Bachmann, L.M., Sundaram, R., Gupta, J.K., Kleijnen, J. & Khan, K.S. (2004). The accuracy of risk scores in predicting preterm birth--a systematic review. J Obstet Gynaecol, 24, 343-59.

3. Dyson, D.C., Danbe, K.H., Bamber, J.A., Crites, Y.M., Field, D.R., Maier, J.A., Newman, L.A., Ray, D.A., Walton, D.L. & Armstrong, M.A. (1998). Monitoring women at risk for preterm labor. N Engl J Med, 338, 15-9.

4. Heine RP, McGregor JA, Goodwin TM, Artal R, Hayashi RH, Robertson PA, Varner MW. Serial salivary estriol to detect an increased risk of preterm birth. Obstet Gynecol. 2000 96:490-7.

5. Leitich, H., Kaider, A., Goepfert, A.R., Goldenberg, R.L., Mercer, B., Iams, J., Meis, P., Moawad, A., Thom, E., VanDorsten, J.P., Caritis, S.N., Thurnau, G., Miodovnik, M., Dombrowski, M., Roberts, J.M., McNellis, D., Revah, A., Hannah, M.E., Sue, A.Q.A.K. & Creasy, R.K. (2003b). Fetal fibronectin--how useful is it in the prediction of preterm birth?

6. Giles, W., Bisits, A., Knox, M., Madsen, G. & Smith, R. (2000). The effect of fetal fibronectin testing on admissions to a tertiary maternal-fetal medicine unit and cost savings. Am J Obstet Gynecol, 182, 439-42.

7. Joffe, G.M., Jacques, D., Bemis-Heys, R., Burton, R., Skram, B. & Shelburne, P. (1999). Impact of the fetal fibronectin assay on admissions for preterm labor. Am J Obstet Gynecol, 180, 581-6.

8. Iams JD Prediction and early detection of preterm labor. Obstet Gynecol. 2003 101(2):402-12.

9. Iams, J.D., Goldenberg, R.L., Meis, P.J., Mercer, B.M., Moawad, A., Das, A., Thom, E., McNellis, D., Copper, R.L., Johnson, F. & Roberts, J.M. (1996). The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child

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Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med, 334, 567-72.

10. Leitich, H., Brunbauer, M., Kaider, A., Egarter, C. & Husslein, P. (1999). Cervical length and dilatation of the internal cervical os detected by vaginal ultrasonography as markers for preterm delivery: A systematic review. Am J Obstet Gynecol, 181, 1465-72.

11. Iams, J.D., Paraskos, J., Landon, M.B., Teteris, J.N. & Johnson, F.F. (1994). Cervical sonography in preterm labor. Obstet Gynecol, 84, 40-6.

Prevention of preterm delivery Prophylaxis for prematurity has been attempted with several interventions such as patient education, bed rest, antibiotics, tocolytics, nutrional supplements, cervical cerclage and social support, all with consistent evidence of benefit. Some interventions need some further discussion: Screening for bacterial vaginosis Bacterial vaginosis is a condition characterised by reduction of the normal lactobacilli and overgrowth of anaerobic bacteria in the vagina. Many clinical studies have consistently found that women with bacterial vaginosis in pregnancy have at least a two fold increased risk of preterm labor and preterm birth (1). The diagnosis of bacterial vaginosis is confirmed by fulfilling three of the following 4 criteria:

• vaginal pH > 4.7; • presence of “clue cells” on a gram stain or wet mount; • presence of a thin homogenous discharge, • release of a fishy odour when potassium hydroxide is added.

Current evidence does not support screening and treatment of all pregnant women for bacterial vaginosis. For high-risk women with a history of a previous preterm birth, screening and treatment of bacterial vaginosis may prevent a proportion of these women having another preterm birth (2). However, a recent meta-analysis showed considerable heterogenity between 6 studies including asymptomatic women with a history of previous preterm birth and a combined OR of 0.61 (95% CI 0.28-1.34) precludes a definitive conclusion. Subgroups of women who benefit, and possibly subgroups who are harmed by treatment during pregnancy (3). Screening for asymptomatic bacteriuria Asymptomatic bacteriuria in pregnant women is a risk factor for preterm birth and antibiotic therapy has been found to significantly reduce the risk (OR 0.52 95% CI 0.38- to 0.70) (4). Prophylactic use of progesterone treatment to prevent preterm birth Recently 2 large trials have been reported of the use of progestagens to prevent preterm birth (5). The importance of progesterone in maintaining pregnancy has long been recognized. In the study of Meis women with a previous preterm birth were randomized to weekly injections of 17-progesterone (P) or a placebo. Treatment begun between 16 to 20 weeks of gestation

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and continued until 37 weeks or delivery. Both treatment and placebo group had exceptionally high rates of preterm deliveries. Statistically significant reduction in delivery < 37, < 35 and 32 weeks of gestation was found in 17-P group compared with placebo group. Neonatal mortality and morbidity ( low birth weight, NEC, IVH) was lower in the 17-P group. In conclusion, progesterone treatment seems to be effective in reducing recurrent preterm delivery in women with singleton pregnancies, however this group of women accounts only for a fraction of all preterm births. Although it is the only proven effective prevention therapy for preterm birth it cannot yet be considered standard of care.

Readings


1. Leitich, H., Bodner-Adler, B., Brunbauer, M., Kaider, A., Egarter, C. & Husslein, P. (2003a). Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol, 189, 139-47.

2. Brocklehurst, P., Hannah, M. & McDonald, H. (2000). Interventions for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev, CD000262.

3. Riggs, M.A. & Klebanoff, M.A. (2004). Treatment of vaginal infections to prevent preterm birth: a meta-analysis. Clin Obstet Gynecol, 47, 796-807.

4. Smaill, F. (2000). Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev, CD000490.

5. Meis, P.J. & Connors, N. (2004). Progesterone treatment to prevent preterm birth. Clin Obstet Gynecol, 47, 784-95.

Treatment of symptomatic patients Antenatal glucocorticoids While investigating the effect of GC on the initiation of birth, Liggins observed that lambs exposed to prenatal corticosteroids appeared viable at an earlier gestational age than expected (1). This observation inspired others to perform randomized controlled trials. Today, GC are considered the most beneficial intervention in preterm labor. A meta-analysis of 18 randomised trials demonstrates that antenatal corticosteroids significantly reduce the occurrence of neonatal respiratory distress syndrome (Odds ratio 0.53, 95% confidence interval 0.44-0.63) and neonatal death (0.6, 0.48-0.75). Furthermore, there was a significant reduction of intraventricular hemorrhage (IVH) diagnosed both at autopsy (0.29, 0.14-0.61) and by ultrasound (0.48, 0.32-0.72) (2). One single course of antenatal GC may also reduce periventricular leukomalacia (PVL) and cerebral palsy. In a retrospective cohort study of 883 infants born at gestational age 24-31 weeks, betamethasone was associated with a reduced the risk for cystic PVL vs. patients that did not receive GC (0.5, 0.2-0.9) (3). In a regional cohort of 541 very preterm singletons born in Western Australia, antenatal GC was associated with a significantly reduced risk for IVH (grades III-IV) or PVL

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(0.4, 0.24-0.66) and CP (4). However, the numbers of infants with CP were rather small (16/281 infants that did not receive GC vs. 6/260 in the group that obtained 1,2 or >3 doses of betamethasone) (4). Betamethasone and dexamethasone are the two most widely used GC for antenatal prophylaxis, but there are no randomized controlled studies comparing these agents with respect to efficacy. Studies on potential adverse effects are also lacking. Even though betamethasone seems to affect fetal heart rate variation and fetal movements more than dexamethasone (5), it seems to offer several advantages. In a well performed study, betamethasone was found to reduce PVL (3) (above) whereas dexamethasone tended to increase the risk (1.5, 0.8-2.9). In a recently published prospective observational study of 201 preterm (24-34 weeks of gestation) singleton infants who received one or more antenatal doses of betamethasone or dexamethasone, multiple doses of dexamethasone were associated with an increased risk for PVL (3.21, 0.07-9.77) compared to betamethasone (6). Furthermore, only betamethasone was associated with reduced mortality (0.52; 0.39-0.70) whereas dexamethasone was not (0.89; 0.60-1.32) (2,6). Dexamethasone and betamethasone are both fluorinated compounds, the difference being that the methyl group at position 16 is in the alpha configuration in dexamethasone and in the beta configuration in betamethasone. Moreover, the preservatives used for the i.v. or i.m. preparations of dexamethasone contain sulfites absent from betamethasone (8). Indeed, experimental studies suggest that pure dexamethasone and betamethasone do not differ appreciably in their CNS effects and that sulfites in the dexamethasone preparation exert toxicity and prevent the expression of the protective effects exerted by pure dexamethasone (8). In summary, randomized controlled trials are warranted comparing dexamethasone and betamethasone, but until these studies have been performed we consider betamethasone to be the preferable agent. Even though there is ample support in favour of one single course of GC, the use of repeated doses is questionable. Animal studies performed in a number of species have shown that repeated doses of antenatal GC improve lung function but exert adverse effects on central nervous system structure and function, and fetal growth (9). One recent observational clinical study including 477 preterm (<33 weeks) singletons demonstrated a reduction in both birth weight and head circumference with increasing number of GC courses (10) without any additional benefits in respiratory outcome. In a recent follow-up, more than two doses of GC were associated with increased rates of aggressive/destructive, distractible and hyperkinetic behaviour both at 3 and 6 years of age (4). These worrisome data are to some extent offset by a lower incidence of cerebral palsy in the GC group but the limited number of cases makes it impossible to draw any firm conclusions with respect to single vs. repeated doses (4). Non-randomized studies have been performed (see ref 11) without demonstrating any clear benefit by repeated courses. These studies are biased by the fact that the patient groups receiving single courses (more often PTL and PPROM) are not the same groups of patients receiving multiple doses (multiples, preeclampsia, intrauterine growth restriction). This is likely to be very important as these groups seem to have very different outcome (12, 13). Only one randomized placebo-controlled trial (14), including 502 women between 24 and 32 completed weeks, compared single vs. repeated courses of corticosteroids. Repeated weekly doses were not associated with reduction of composite neonatal morbidity defined as in the total sample but there was some improvement among those delivered before 28 weeks (0.8, 0.65-0.98). Repeated doses reduced severe respiratory distress syndrome without improvement in neonatal survival, chronic lung disease, or duration of hospitalization (14).

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However, weekly courses increased the risk of severe IVH (3.8, 0.85-17.45). The study has been criticized for being underpowered considering that nearly half of the infants were delivered beyond 34 weeks and thereby having a lower risk of bad outcome. Several other studies on single vs. repeated doses are in progress (15), and hopefully these studies will resolve the efficacy and safety issues mentioned above. In the absence of conclusive evidence we suggest that multiple courses of corticosteroids should be avoided. In summary, administration of GC is likely to be the most important treatment to prevent brain injury and increase survival that can be provided by the obstetrician to patients in preterm labour or preterm rupture of the membranes. The current recommendation is to administer betamethasone, e.g. 12 + 12 mg over 24 h to women who are at risk for preterm delivery between 24 weeks and 34 weeks. There is no evidence to support multiple courses of corticosteroids and animal and clinical data even infer safety concerns especially with respect to CNS development. Readings


1. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515-23.

2. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173:322-35.

3. Baud O, Foix-L'Helias L, Kaminski M, Audibert F, Jarreau PH, Papiernik E, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999;341:1190-6.

4. French NP, Hagan R, Evans SF, Mullan A, Newnham JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190:588-95.

5. Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid therapy and fetal behaviour: a randomised study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 1997;104:1239-47.

6. Spinillo A, Viazzo F, Colleoni R, Chiara A, Maria Cerbo R, Fazzi E. Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol 2004;191:217-24.

7. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173:254-62.

8. Baud O, Laudenbach V, Evrard P, Gressens P. Neurotoxic effects of fluorinated glucocorticoid preparations on the developing mouse brain: role of preservatives. Pediatr Res 2001;50:706-11.

9. Aghajafari F, Murphy K, Matthews S, Ohlsson A, Amankwah K, Hannah M. Repeated doses of antenatal corticosteroids in animals: a systematic review. Am J Obstet Gynecol 2002;186:843-9.

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10. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114-21.

11. Leung TN, Lam PM, Ng PC, Lau TK. Repeated courses of antenatal corticosteroids: is it justified? Acta Obstet Gynecol Scand 2003;82:589-96.

12. Baud O, Zupan V, Lacaze-Masmonteil T, Audibert F, Shojaei T, Thebaud B, et al. The relationships between antenatal management, the cause of delivery and neonatal outcome in a large cohort of very preterm singleton infants. Br J Obstet Gynecol 2000;107:877-84.

13. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997;176:275-81.

14. Guinn DA, Atkinson MW, Sullivan L, Lee M, MacGregor S, Parilla BV, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial. Jama 2001;286:1581-7.

15. Murphy KE, Hannah M, Brocklehurst P. Are weekly courses of antenatal steroids beneficial or dangerous? JAMA 2002;287:188; author reply 189-90.

Antibiotics Several conditions during pregnancy, e.g. preterm labor syndrome, bacterial vaginosis, have been approached with prophylactic antibiotic treatment but with few or no clear-cut benefits on neonatal outcome. In the management of the PTL syndrome the benefit of antibiotic administration is uncertain. A meta-analysis failed to demonstrate a clear overall benefit from prophylactic antibiotic treatment on neonatal outcomes and raises even concerns about increased neonatal mortality for those who received antibiotics. This treatment cannot therefore be currently recommended for routine practice (1). The use of antibiotics following PPROM has also been reviewed recently in a Cochrane meta-analysis and the results have been under debate. Most outcome studied are related to maternal and neonatal infectious morbidity, but an intermediate marker for long term neurological impairment was also studied (2). The use of antibiotics to women with PPROM was associated with a statistically significant reduction of chorioamnionitis (RR 0.57, 95% CI 0.37-0.86). There was a reduction in the numbers of babies born within 48 hours (RR 0.71, 95% CI 0.58-0.87) and seven days of randomization (RR 0.80, 95% CI 0.71-0.90). The following markers of neonatal morbidity were reduced: neonatal infection (RR 0.68, 95% CI 0.53-0.87), use of surfactant (RR 0.83, 95% CI 0.72-0.96), oxygen therapy (RR 0.88, 95% CI 0.81-0.96), and abnormal cerebral ultrasound scan prior to discharge from the hospital (RR 0.82, 95% CI 0.68-0.98) (12 trials/6294 babies). The reduction of cerebral sonographic abnormalities indicates a cerebro-protective effect but it is important to emphasize that ultrasound findings do not always translate to an increased risk of neurological disability. A benefit was present both in trials where penicillins and erythromycin were used. Amoxicillin/clavulanate was associated with a highly significant increase in the risk of necrotizing enterocolitis (RR 4.60, 95% CI 1.98-10.72) (2).

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Readings


1. King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database Syst Rev 2002(4):CD000246. 2. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2003(2):CD001058. Exercise Study the Cochrane reviews and commentaries in WHO RHL. Does antibiotic treatment improve outcome in cases with risk for premature birth? What regimens should be applied? Tocolytics A recently published Cochrane meta-analysis compared betamimetics with placebo. Betamimetics decreased the number of women in preterm labor giving birth within 48 hours (RR 0.63; 95% CI 0.53-0.75) but there was no decrease in the number of births within seven days after carrying out a sensitivity analysis of studies with adequate allocation of concealment. No benefit was demonstrated for betamimetics on perinatal death (RR 0.84; 95% CI 0.46-1.55, 7 trials, n = 1332) or any other neonatal or long term child outcome. Betamimetics help to delay delivery to allow transferal to a tertiary care center or allow administration of a complete course of antenatal corticosteroids (1). This might be important as there are observations that the risk to develop cerebral palsy is greater if the infant is born in a non-tertiary clinic. Calcium channel blockers, mainly nifidipin, have also been evaluated in meta-analyses. Twelve randomized controlled trials involving 1029 women were included. When compared with any other tocolytics agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within seven days of receiving treatment (RR 0.76; 95% CI 0.60-0.97) and prior to 34 weeks' gestation (RR 0.83; 95% CI 0.69-0.99). Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.14; 95% CI 0.05-0.36), the frequency of neonatal respiratory distress syndrome (RR 0.63; 95% CI 0.46-0.88), necrotising enterocolitis (RR 0.21; 95% CI 0.05-0.96), intraventricular hemorrhage (RR 0.59 95% CI 0.36-0.98) and neonatal jaundice (RR 0.73; 95% CI 0.57-0.93). However, nifidipin is not licensed for use as a tocolytic (3), maternal cardiovascular side effects by nifidipin have recently been reported (4) and the quality of the present documentation with respect to drug safety has been questioned (3). Therefore we cannot presently recommend the use of nifidipin or other calcium antagonists. Atosiban (an oxytocin receptor modulator) has very few side effects and a similar efficacy as betamimetics but there are no data available on neonatal outcomes but it postpones delivery to the same extent as betamimetics, but it is an expensive drug. In the last ten years, the body of scientific knowledge concerning the use of antenatal pharmacologic magnesium sulfate (MgSO4) has become substantially larger. The recent Cochrane Systematic Review, as well as other studies, has shown that there is no evidence

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basis for the use of MgSO4 for tocolysis. Furthermore, when tocolytic doses of MgSO4 are employed, there is an excess risk for total pediatric mortality (5). It is conceivable, nonetheless, that low doses of MgSO4, when used as prophylaxis in some selected cases of preterm labor, may ultimately be shown to be neuroprotective for a relatively small number of children (5). Unfortunately, the indiscriminate use of high-dosage MgSO4 for attempted tocolysis in preterm labor is much more likely to cause harm than do good (6). In summery, there is no direct evidence in support of the use of tocolytics as a means improving neonatal neurological outcome. The main purpose is to postpone delivery to allow treatment with corticosteroids and patient transfer to a tertiary center, which indirectly may have beneficial effect on the immature CNS. Readings


1. Anotayanonth S, Subhedar N, Garner P, Neilson J, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2004(4):CD004352. 3. Beattie RB, Helmer H, Khan KS, Lamont RF, McNamara H, Svare J, Tsatsaris V, van Geijn HP. Emerging issues over the choice of nifedipine, beta-agonists and atosiban for tocolysis in spontaneous preterm labour--a proposed systematic review by the International Preterm Labour Council. J Obstet Gynaecol 2004;24(3):213-5. 4. Hodges R, Barkehall-Thomas A, Tippett C. Maternal hypoxia associated with nifedipine for threatened preterm labour. Bjog 2004;111(4):380-1. 5. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. Jama 2003;290(20):2669-76. 6. Mittendorf R, Pryde PG, Roizen N. Second overview of relationships between antenatal pharmacologic magnesium sulfate and neurologic outcomes in children. J Perinat Med 2004;32(3):201-10. Exercise What routines for diagnosing preterm labor and prevent/postpone birth in your own setting are evidence based according to the material and references you have studied?

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