Managing Preterm Birth to Lower the Risk of Cerebral Palsy

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Mehmet R. Genc, MD, PhD Dr. Genc is Attending Physician Managing preterm birth to in the Department of Obstetrics, Gynecology, and Reproductive Biology at Brigham and Women’s lower the risk of cerebral palsy Hospital and Clinical Instructor at Harvard Medical School in Boston. Think past hypoxia to the interactions of infection, The author reports no fi nancial relationships relevant to this article. infl ammation, pPROM, and white matter disease

❚ Intrapartum hypoxia, once considered an The principal risk factor important cause of cerebral palsy (CP), is re- is prematurity sponsible for only 8% to 10% of cases. A precise cause for CP has not been identifi ed in more than 75% of cases. The lead- ❚ Increasingly, evidence® Dowden suggests that Healththe ing identifi Media able risk factor is prematurity. primary cause of CP lies in the relationship The prevalence of CP at 3 years of age among intrauterine infection and infl amma- is 4.4% among infants born earlier than tion,Copyright preterm labor,For preterm personal premature rupture use 27only weeks of gestation, compared with of membranes (pPROM), and neonatal white 0.06% among babies born at term.1 matter disease.

IN THIS ARTICLE ❚ This review focuses on that relationship and How inﬂ ammation leads ❙ 12 principles its implications for managing preterm birth to premature birth with intact membranes or pPROM. Any condition that increases the inci- and practices dence of prematurity can be expected when discussing erebral palsy is a complex dis- to increase the incidence of CP. More prevention ease characterized by aberrant than 80% of premature births follow Page 37 Ccontrol of movement or posture preterm labor or pPROM. Clinical and that results from an insult to the devel- experimental evidence suggests that most ❙ Use antenatal oping central nervous system (CNS). of these births refl ect one or more of steroids to reduce In addition to motor abnormalities, four major pathogenic processes, which some patients have seizures, cognitive lead to uterine contractions and cervical neonatal death and impairment, and extrapyramidal abnor- changes, with or without premature rup- disability malities. ture of membranes2: Page 41 Clinical and epidemiologic evidence • local or systemic infl ammatory im- points to white matter lesions and severe mune response intraventricular hemorrhage (IVH)—de- • activation of the maternal or fetal hy- tected by neonatal neurosonography—as pothalamic–pituitary–adrenal axis the key determinants of CP. The lesions • decidual hemorrhage (abruption) are the sonographic antecedent or coun- • pathologic distention of the uterus. terpart of periventricular leukomalacia Two or more of these processes of- (PVL), a cerebral lesion characterized by ten occur simultaneously, ultimately con- foci of necrosis in the white matter near verging on a fi nal common biochemical the ventricles (FIGURE, page 34). pathway that leads to degradation of the

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FIGURE are often those colonizing the vagina— Periventricular leukomalacia most commonly anaerobes, gram-negative rods, Gardnerella vaginalis, group B streptococci, Mycoplasma hominis, and Ureaplasma urealyticum.

Infection doesn’t always lead to infl ammation Bacterial products—particularly endotoxin, a major constituent of gram- negative bacteria—bind to a specifi c pattern-recognition receptor, known as a toll-like receptor, on cell surfaces. This activates innate immunity and stimulates a proinfl ammatory immune response. Endotoxin is a potent stimu- lant for proinfl ammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which promote the release of chemoattractant cytokines such as IL-6 and IL-8. Different white blood cells migrate into the infl amed tissue and Four axial magnetic resonance images of the brain of an infant show the usual appearance of become activated at the same time. this cerebral lesion, characterized by foci of necrosis of white matter near the ventricles. The uterine cavity is thought to be sterile, and microorganisms there are uni- extracellular matrix in the cervix and fe- versally associated with infl ammation. tal membranes and activation of the uter- Recent studies challenge this assumption. FAST TRACK ine myometrium. This process leads in One found bacteria in as many as 90% Prompt diagnosis turn to cervical dilation, rupture of mem- of endometrial samples from nonpreg- branes, and uterine contractions. nant women, but histologic endometritis and treatment The “infl ammatory pathway” is acti- in only 40%.5 Another noted bacteria in of intrauterine vated in most cases of spontaneous pre- as many as 80% of gestational tissues infl ammation may term labor and pPROM. As many as 50% delivered electively by cesarean section lower the risk of of women with preterm labor and intact at term or before 32 weeks because of cerebral palsy membranes have histologic chorioamnio- preeclampsia, but histologic assessment nitis; the rate is even higher in pPROM. showed no or minimal infl ammation.6 The incidence of chorioamnionitis increases with decreasing gestational age. Why don’t all women Invading microorganisms in gesta- develop infl ammation? tional tissues often cause intrauterine A critical question is why some pregnant infl ammation and preterm birth. Highly women with microbial invasion of ges- sensitive molecular techniques detect bac- tational tissues develop infl ammation, teria in the amniotic fl uid of as many as whereas others do not. Susceptibility half of patients with preterm labor with depends, in part, on the pathogenicity intact membranes3 and even more women and amount of invading bacteria. Endo- with pPROM. As with chorioamnionitis, toxin-containing gram-negative bacteria the lower the gestational age, the higher elicit an especially potent infl ammatory the bacterial isolation rates—45% at 23 response. The strength of the response to 26 weeks compared with 17% at 27 to correlates with the amount of endotoxin- 30 weeks.4 The microorganisms isolated containing bacteria in the environment.7 CONTINUED

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The isolation rate of bacteria from the intrauterine cavity is higher in women Cerebral palsy: Key preventive with bacterial vaginosis (BV), a condition characterized by malodorous vaginal dis- measures refl ect disease origins charge, vaginal pH higher than 4.5, and • Prematurity is the leading risk factor for cerebral palsy (CP) a shift from a Lactobacilli-dominant • Subacute intrauterine infection and infl ammation are vaginal fl ora toward predominance of common causes of preterm delivery G vaginalis, anaerobic bacteria, and M hominis. The greater number of bacteria • Intrauterine infl ammation may lower the threshold at which hypoxia becomes neurotoxic in the fetus may account, in part, for a twofold greater risk of preterm delivery among women • No single sign, symptom, or test accurately predicts diagnosed with BV during pregnancy.8 intrauterine infection and infl ammation in the pregnant patient Genetics may also play a role. Intra- • A biophysical profi le (BPP) score of 7 or lower predicts uterine infl ammation and morbidity are infection-related neonatal outcomes better than any single partly infl uenced by common variations component of the BPP (polymorphisms) in immunoregulatory • In a pregnancy complicated by pPROM, adjunctive genes. Preliminary evidence suggests that antibiotics prolong pregnancy for as long as 10 days, some women who carry a variant of the but do not affect neonatal neurologic outcome TNF-α gene can mount an exaggerated • Adjunctive antibiotics have no proven benefi t immune response to BV-related organ- in managing preterm labor with intact membranes isms (hyper-responders),9 increasing their • Screening for and treating bacterial vaginosis during risk of preterm delivery.10 pregnancy are not useful • Prophylactic antibiotic treatment during the periconceptional period has no proven benefi t Infl ammation alone • A single course of antenatal steroids in preterm labor is a risk factor for CP with intact membranes or pPROM signifi cantly decreases Growing evidence suggests that intra- neonatal mortality and neurologic morbidity without uterine infl ammation increases the risk of raising the risk of neonatal sepsis—even in the presence neonatal white matter disease and sub- of intrauterine infection sequent development of CP beyond the • Tocolysis with magnesium sulfate or a calcium-channel risk conferred by gestational age at birth. blocker to stop preterm labor with intact membranes may The relative risk (RR) for CP in preterm decrease neurologic morbidity in neonates infants born after intrauterine infection • Consider delivery after 32 weeks if fetal lung maturity is con- and infl ammation or infl ammation alone fi rmed because 1) expectant management of pPROM beyond is 1.9 and 1.6, respectively.11 32 completed weeks of gestation does not have a clear The association between infl amma- benefi t and 2) intrauterine infl ammation associated with white tion, neonatal white matter disease, and matter disease is common in pPROM CP is strongest in fetuses with funisitis and a plasma IL-6 level greater than 11 ng/mL12—a condition known as fetal in- risk of CP. No single sign, symptom, or fl ammatory response syndrome (FIRS). test accurately predicts intrauterine infec- FIRS is also associated with other sequel- tion and infl ammation in the pregnant ae of prematurity, including bronchopul- patient. Maternal signs and symptoms monary dysplasia, respiratory distress such as fundal tenderness, tachycardia, syndrome, and myocardial dysfunction. and fever, along with laboratory fi ndings such as an elevated C-reactive protein level and an elevated white blood cell Can we diagnose subacute (WBC) count in peripheral blood, indi- infl ammation and infection? cate overt chorioamnionitis and systemic Diagnosing and treating intrauterine in- maternal infection. However, these tests fl ammation promptly may decrease the are not especially useful for diagnosing

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subacute intrauterine infection and in- study found that women who were fl ammation in patients with preterm la- followed with daily BPP and delivered bor and intact membranes or pPROM. within 24 hours after a BPP score of 7 Some authorities advocate amniocentesis or lower on two examinations 2 hours for these patients. apart had a lower rate of neonatal sep- A positive bacterial culture or gram- sis than women who were managed ex- stained slide of amniotic fl uid confi rms pectantly or had a single amniocentesis intra-amniotic infection but detects few- on admission to the hospital.17 er than 50% of cases. Other diagnostic criteria, such as an elevated WBC count, high level of lactate dehydrogenase activ- How management tactics ity, high protein level, and low glucose affect neurologic outcome concentration in amniotic fl uid, are more Options for women in preterm labor with sensitive, but nonspecifi c, for amniotic in- intact membranes or pPROM include an- fection and infl ammation. tibiotics, antenatal steroids, tocolytics, or Elevated infl ammatory cytokinesearly delivery. such as IL-6 in amniotic fl uid and fetal blood have been associated with intra- Antibiotics in cases of pPROM only uterine infl ammation and neonatal white The fi ndings of two large clinical trials matter disease in women with preterm powerful enough to evaluate adjunctive labor and intact membranes or pPROM, antibiotics in women with pPROM are but they are not signifi cantly more ac- in agreement: Such treatment prolongs curate than the previously mentioned the pregnancy briefl y (as long as 10 biomarkers.13,14 An amniotic fl uid pocket days).18,19 may not be accessible by the abdominal NICHD-MFMU study. In a trial conducted approach in most patients with pPROM by the National Institute of Child Health because of signifi cant oligohydramnios. and Human Development Maternal–Fe- Testing amniotic fl uid from the vagina tal Medicine Units (NICHD-MFMU) Re- FAST TRACK is an alternative. Low glucose in vaginal search Network, 48 hours of intravenous Neither adjunctive samples is a specifi c, but not a sensitive, therapy with ampicillin and erythromy- marker for intra-amniotic infection.15 cin followed by 5 days of oral amoxicillin nor prophylactic Using the BPP. The biophysical profi le and enteric-coated erythromycin given to antibiotics are has been used to identify fetuses at risk of 614 women between 24 and 32 weeks’ meaningfully helpful FIRS in the presence of pPROM. Oligo- gestation decreased the number of infants in preventing hydramnios—especially when the largest who died or suffered a major morbidity, preterm birth vertical amniotic fl uid pocket is smaller including respiratory distress syndrome, than 1 cm—and diminished fetal breath- early sepsis, severe IVH, or severe necro- ing and body movement are associated tizing enterocolitis.18 with chorioamnionitis and suspected or ORACLE I. The results of the larger ORA- proven neonatal sepsis. A nonreactive CLE I trial, which included 4,826 women, nonstress test is specifi c but not sensitive. were less impressive.19 Patients who de- Although each component of the veloped pPROM before 37 weeks’ gesta- BPP provides useful information, a BPP tion received erythromycin, amoxicillin- score of 7 or lower predicts infection- clavulanic acid, or both, or placebo for related outcome much better than any up to 10 days. Although antibiotic thera- single fi nding. In a population with an py prolonged pregnancy briefl y, it did not infection-related outcome of 30%, a BPP have a major impact on neonatal mor- score of 7 or lower within 24 hours of tality or any major morbidity, including delivery had a positive predictive value cerebral abnormality on ultrasonography of 95% and a negative predictive value (US). In contrast to the NICHD-MFMU of 97%.16 A retrospective case-control Research Network study, treatment with

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oral amoxicillin-clavulanic acid increased the risk of necrotizing enterocolitis. How inﬂ ammation is ORACLE II. The ORACLE II trial evalu- implicated in neonatal ated the benefi t of adjunctive antibiotics for 6,295 women in spontaneous pre- white matter disease term labor before 37 weeks’ gestation who had intact membranes and no evi- everal mechanisms have been proposed to explain the role of infl ammation in neonatal white matter disease. dence of clinical infection.20 The women SMicroorganisms and microbial products can gain access received erythromycin, amoxicillin-cla- to the fetus and activate infl ammatory cytokines, increasing the vulanic acid, or both, or placebo for as permeability of the blood–brain barrier and facilitating passage long as 10 days. Compared with place- of the cytokines into the brain. bo, none of the antibiotics was associ- Microbial products stimulate human fetal microglia (the cen- ated with a lower rate of the composite tral nervous system [CNS] equivalent of macrophages) to pro- primary outcome, which included major duce interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which, cerebral abnormality on US before dis- in turn, stimulate proliferation of astrocytes (the CNS equivalent charge from the hospital. of fi broblasts) and production of TNF. Leviton proposed that Prophylaxis. It has been suggested that TNF-α can damage white matter by four mechanisms:33 antibiotics are more likely to prevent pre- • inducing hypotension and brain ischemia term birth if they are given long before • stimulating the production of a tissue factor, which can contractions start or membranes rupture. activate the hemostatic system and contribute to coagulation Studies of antibiotic prophylaxis to pre- necrosis of white matter vent preterm birth and related sequelae • inducing the release of platelet-activating factor, which can don’t support this notion. A Cochrane act as a membrane detergent, causing direct brain damage meta-analysis of six randomized clinical trials involving 2,184 asymptomatic • producing a direct cytotoxic effect on oligodendrocytes. women who received prophylactic anti- Polymorphisms in immunomodulatory genes, such as the biotics in the second or third trimester gene encoding TNF-α, modify the immune response and the 34 found no reduction in the risk of subse- risk for white matter disease in preterm infants. quent preterm birth.21 In fact, interven- tion increased the risk of neonatal sepsis (odds ratio [OR] = 8.07, 95% confi dence until conception.23 The 124 women who interval [CI], 1.36 to 47.77). Another conceived and were available for fol- meta-analysis of the effect of antibiotics low-up showed no difference in the rate on BV during pregnancy drew similar of preterm birth between the treatment conclusions.22 This analysis of 15 ran- and placebo groups. In fact, women who domized clinical trials with a total of received an antibiotic tended to have a 5,888 patients showed that treating BV shorter pregnancy and a lower-birth- did not reduce the risk of preterm birth. weight baby than those given placebo. The trials reported very few perinatal Based on available data, treatment deaths, and none reported substantive with a short course of antibiotics such neonatal morbidity. as erythromycin or ampicillin, or both, is Another hypothesis argues that the recommended only in cases of pPROM. events leading to preterm birth begin in very early stages of pregnancy, including Antenatal steroids improve outcome conception and implantation of the em- Antenatal steroids reduce neonatal mor- bryo. To test this hypothesis, 241 women tality and morbidity, including IVH and with a history of spontaneous preterm PVL, in infants born between 24 and birth or pPROM between 16 and 34 34 weeks’ gestation. One concern raised weeks’ gestation were randomized to re- about antenatal steroid use is whether ceive an oral course of azithromycin and it increases the risk of neonatal infec- metronidazole or placebo every 4 months tion and morbidity when intrauterine

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infection and infl ammation are present. countries. Eleven randomized controlled A retrospective analysis of infants who trials, involving 1,332 women, compared weighed 1,750 g or more at birth con- betamimetics with placebo.28 Although cluded that antenatal steroids signifi cant- betamimetics decreased the number of ly decreased neonatal mortality and mor- women in preterm labor who gave birth bidity—including IVH, PVL, and major within 48 hours, they didn’t reduce peri- brain lesions—without increasing neonatal or neonatal death. Data on CP were natal sepsis in babies delivered following too sparse to allow comment. Because preterm labor or pPROM.24 these drugs cause many maternal side ef- In another retrospective analysis of fects, they aren’t considered fi rst-line to- 457 consecutive 23- to 32-week live-born colytics. singletons, antenatal steroids weren’t as- Calcium-channel blockers are attract- sociated with signifi cant worsening of any ing growing interest as potentially effec- neonatal outcome. Steroids were associat- tive and well-tolerated tocolytic agents. ed with signifi cant reductions in respira- A meta-analysis of 12 randomized con- tory distress syndrome and neonatal sys- trolled trials involving 1,029 women sug- temic infl ammatory response syndrome gests that calcium-channel blockers re- in infants with positive placental cultures duce the number of women giving birth and elevated cord blood IL-6 levels.25 within 7 days of receiving treatment, These data suggest that antenatal ste- compared with other tocolytic agents roids may not be contraindicated in the (mainly betamimetics).29 They also de- face of infl ammation and infection; they crease the frequency of neonatal morbid- may, in fact, be benefi cial. In women with ity, including IVH (RR, 0.59; 95% CI, pPROM, weekly administration of ante- 0.36 to 0.98). natal steroids doesn’t seem to improve Cyclooxygenase (COX) inhibitors are easy neonatal outcomes more than single- to administer and cause fewer maternal course therapy and may increase the risk side effects than conventional tocolytics. of chorioamnionitis.26 A 2005 Cochrane meta-analysis includes FAST TRACK outcome data from 13 trials with a total Starting tocolysis Some tocolytics may help of 713 women.30 Indomethacin, a non- Tocolytic agents are often given to wom- selective COX inhibitor, was used in 10 before onset of en with preterm contractions to delay de- trials. COX inhibition reduced birth be- contractions in livery long enough to administer a course fore 37 weeks’ gestation more effectively women with pPROM of antenatal corticosteroids. than other tocolytic agents, but data prolongs latency; Magnesium sulfate is commonly used were insuffi cient to comment on neona- the jury is still out in the United States. A 2007 Cochrane tal outcomes. meta-analysis of four trials (3,701 ba- In women with pPROM, starting on the value of bies) found that antenatal magnesium tocolysis before onset of contractions tocolysis after sulfate had no statistically signifi cant ef- prolongs latency. However, the utility of pPROM fect on any major pediatric outcome, in- tocolytic therapy after pPROM remains cluding death and neurologic problems controversial pending more powerful such as CP in the fi rst few years of life.27 randomized trials. Nor did antenatal magnesium therapy signifi cantly affect combined rates of Early delivery is an option mortality and neurologic outcomes. Two It has been suggested that exposure to trials involving 2,848 infants found a infection, especially proinfl ammatory cy- signifi cant reduction in substantial gross tokines, reduces the threshold at which motor dysfunction (RR = 0.56; 95% CI, hypoxia becomes neurotoxic, making the 0.33 to 0.97). brain much more vulnerable to even mild Betamimetics are also widely used for hypoxic insults. A recent study found tocolysis, especially in resource-poor that infants with encephalopathy were

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more than 90 times more likely to have 4. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The experienced both neonatal intrapartum association of occult amniotic fl uid infection with gestational age and neonatal outcome among women in acidosis and maternal intrapartum fever preterm labor. Obstet Gynecol. 1992;79:351–357. than infants with no encephalopathy; ma- 5. Andrews WW, Hauth JC, Cliver SP, Conner MG, Gold- ternal fever or neonatal acidosis increased enberg RL, Goepfert AR. Association of asymptomatic bacterial vaginosis with endometrial microbial coloni- 31 the risk six- and 12-fold, respectively. zation and plasma cell endometritis in nonpregnant Lack of interaction between maternal women. Am J Obstet Gynecol. 2006;195:1611–1616. fever and acidosis suggests that these are 6. Steele JH, Malatos S, Kennea N, et al. Bacteria and infl ammatory cells in fetal membranes do not always separate causal pathways to adverse neo- cause preterm labor. Pediatr Res. 2005;57:404–411. natal outcomes. Although intrapartum 7. Genc MR, Witkin SS, Delaney ML, et al. A dispropor- fever doesn’t always correlate with intra- tionate increase in IL-1beta over IL-1ra in cervico- vaginal secretions of pregnant women with vaginal uterine infl ammation, the fi ndings of this microfl ora correlates with preterm birth. Am J Obstet study suggest that fetal acidosis should be Gynecol. 2004;190:1191–1197. avoided when intrauterine infection and 8. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk fac- infl ammation are suspected. tor for preterm delivery: a meta-analysis. Am J Obstet Conservative management of Gynecol. 2003;189:139–147. pPROM remote from term has been 9. Genc MR, Vardhana S, Delaney ML, Witkin SS, On- derdonk AB; MAP Study Group. TNFA-308G>A poly- shown to prolong pregnancy signifi cant- morphism infl uences the TNF-alpha response to al- ly and reduce complications in the infant tered vaginal fl ora. Eur J Obstet Gynecol Reprod Biol. when prophylactic antibiotics and ante- 2007;134:188–191. 10. Macones GA, Parry S, Elkousy M, et al. A polymor- natal steroids are given concurrently. The phism in the promoter region of TNF and bacterial benefi t of this strategy is less clear after vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm 32 weeks of gestation because: birth. Am J Obstet Gynecol. 2004;190:1504–1508. • The effi cacy of antenatal steroids af- 11. Wu YW, Colford JM. Chorioamnionitis as a risk fac- ter 32 weeks is unclear tor for cerebral palsy: a meta-analysis. JAMA. • Beyond 32 weeks, the risk of severe 2000;284:1417–1424. 12. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, complications of prematurity, includ- Berry SM. The fetal infl ammatory response syndrome. ing CP, is low if fetal lung maturity Am J Obstet Gynecol. 1998;179:194–202. FAST TRACK has been established by amniotic fl uid 13. Romero R, Yoon BH, Mazor M, et al. A comparative samples collected vaginally or by am- study of the diagnostic performance of amniotic fl uid Delivery can be glucose, white blood cell count, interleukin-6, and niocentesis. gram stain in the detection of microbial invasion in pa- considered after For these reasons and because sub- tients with preterm premature rupture of membranes. Am J Obstet Gynecol. 1993;169:839–851. 32 completed weeks acute intrauterine infl ammation may 14. Romero R, Yoon BH, Mazor M, et al. The diagnostic if fetal lung maturity harm the fetus, delivery can be consid- and prognostic value of amniotic fl uid white blood cell ered after 32 completed weeks of gesta- count, glucose, interleukin-6, and gram stain in pa- is conﬁ rmed tients with preterm labor and intact membranes. Am tion if fetal lung maturity is confi rmed. J Obstet Gynecol. 1993;169:805–816. A meta-analysis of four randomized con- 15. Buhimschi CS, Sfakianaki AK, Hamar BG, et al. A low trolled trials that compared intentional vaginal “pool” amniotic fl uid glucose measurement is a predictive but not a sensitive marker for infection delivery with expectant management af- in women with preterm premature rupture of mem- ter pPROM between 30 and 36 weeks of branes. Am J Obstet Gynecol. 2006;194:309–316. gestation found no difference in neonatal 16. Vintzileos AM, Campbell WA, Nochimson DJ, Con- 32 nolly ME, Fuenfer MM, Hoehn GJ. The fetal biophysi- outcomes. ■ cal profi le in patients with premature rupture of the membranes—an early predictor of fetal infection. Am References J Obstet Gynecol. 1985;152:510–516. 1. Cummins SK, Nelson KB, Grether JK, Velie EM. Ce- 17. Vintzileos AM, Bors-Koefoed R, Pelegano JF, et al. rebral palsy in four northern California counties, births The use of fetal biophysical profi le improves pregnan- 1983 through 1985. J Pediatr. 1993;123:230–237. cy outcome in premature rupture of the membranes. 2. Lockwood CJ, Kuczynski E. Risk stratifi cation and Am J Obstet Gynecol. 1987;157:236–240. pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol. 2001;15 Suppl 2:78–89. 18. Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic 3. Gardella C, Riley DE, Hitti J, Agnew K, Krieger JN, therapy for reduction of infant morbidity after preterm Eschenbach D. Identifi cation and sequencing of premature rupture of the membranes. A randomized bacterial rDNAs in culture-negative amniotic fl uid controlled trial. National Institute of Child Health and from women in premature labor. Am J Perinatol. Human Development Maternal–Fetal Medicine Units 2004;21:319–323. Network. JAMA. 1997;278:989–995. CONTINUED

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19. Kenyon SL, Taylor DJ, Tarnow-Mordi W; ORACLE Col- 27. Doyle LW, Crowther CA, Middleton P, Marret S. Mag- laborative Group. Broad-spectrum antibiotics for pre- nesium sulphate for women at risk of preterm birth for term, prelabour rupture of fetal membranes: the ORA- neuroprotection of the fetus. Cochrane Database Syst CLE I randomised trial. Lancet. 2001;357:979–988. Rev. 2007;(3):CD004661. 20. Kenyon SL, Taylor DJ, Tarnow-Mordi W; ORACLE 28. Anotayanonth S, Subhedar NV, Garner P, Neilson Collaborative Group. Broad-spectrum antibiotics JP, Harigopal S. Betamimetics for inhibiting pre- for spontaneous preterm labour: the ORACLE II ran- term labour. Cochrane Database Syst Rev. 2004;(8): domised trial. Lancet. 2001;357:989–994. CD004352. 21. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon 29. King JF, Flenady VJ, Papatsonis DN, Carbonne B. Cal- P. Prophylactic antibiotic administration in pregnancy cium channel blockers for inhibiting preterm labour. to prevent infectious morbidity and mortality. Co- Cochrane Database Syst Rev. 2002;(2):CD002255. chrane Database Syst Rev. 2002;(4):CD002250. 30. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygen- 22. McDonald H, Brocklehurst P, Parsons J. Antibiotics for ase (COX) inhibitors for treating preterm labour. Co- treating bacterial vaginosis in pregnancy. Cochrane chrane Database Syst Rev. 2005;(2):CD001992. Database Syst Rev. 2005;(1):CD000262. 31. Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil 23. Andrews WW, Goldenberg RL, Hauth JC, Cliver SP, O, Doyle P. The relationship between intrapartum Copper R, Conner M. Interconceptional antibiotics to maternal fever and neonatal acidosis as risk factors prevent spontaneous preterm birth: a randomized clin- for neonatal encephalopathy. Am J Obstet Gynecol. ical trial. Am J Obstet Gynecol. 2006;194:617–623. 2008;198:49–51. 24. Elimian A, Verma U, Canterino J, Shah J, Visintainer P, 32. Hartling L, Chari R, Friesen C, Vandermeer B, Tejani N. Effectiveness of antenatal steroids in obstet- Lacaze-Masmonteil T. A systematic review of inten- ric subgroups. Obstet Gynecol. 1999;93:174–179. tional delivery in women with preterm prelabor rup- 25. Goldenberg RL, Andrews WW, Faye-Petersen OM, ture of membranes. J Matern Fetal Neonatal Med. Cliver SP, Goepfert AR, Hauth JC. The Alabama 2006;19:177–187. preterm birth study: corticosteroids and neonatal 33. Leviton A. Preterm birth and cerebral palsy: is tumor outcomes in 23- to 32-week newborns with various necrosis factor the missing link? Dev Med Child Neu- markers of intrauterine infection. Am J Obstet Gyne- rol. 1993;35:553–558. col. 2006;195:1020–1024. 34. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, 26. Ghidini A, Salafi a CM, Minior VK. Repeated courses of Priest K, Dekker GA; South Australian Cerebral Palsy steroids in preterm membrane rupture do not increase Research Group. The association between inherited the risk of histologic chorioamnionitis. Am J Perinatol. cytokine polymorphisms and cerebral palsy. Am J Ob- 1997;14:309–313. stet Gynecol. 2006;194:674.e1–11.

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