Panelists Dr.Manasi Wadekar Dr.Amisha Dumaswala Dr.Shalaka Ghogale Dr.Garima Goel

1. Infections & obstetrics Moderator : Dr Mona Shroff Panelists Dr.ManasiWadekar Dr.AmishaDumaswala Dr.ShalakaGhogale Dr.GarimaGoel

2. Case 1 : Mrs. A. G1P0, 27 wks pregnancy, comes to LxR with preterm labour pains. No h/o leaking p/v No fever(>100.4), No maternal /fetal tachycardia, No uterine tenderness O/E : mild contractions Cx :2 cms dilated ,membranes intact

3. What is the probability of this patient in preterm labour with intact membranes having intrauterine infection?

4. Russel P.Am.J.Diagn Gynaecol Obstet 1989;1:127-37Hitti J,Riley D,Krohn M.Clin Infect Dis 1997;24:1228-32Oyarzun E,Kato S,etal.Am J Obstet Gynaecol 1998;179:1115-9Markenson G,Martin R,et al. S,etal.Am J Obstet Gynaecol 1997;177:1471-7 • Intraamniotic infection - 10 % using PCR - 30-55% • Histological chorioamnionitis 5% overall 94%(21-24wks) most subclinical, only 13% had fever • V. high probability of infection if: • Clinical S/S of chorioamnionitis • Early gestational age (<28 wks) • Failure of tocolysis (before 2nd agent started)

5. Considering that most of us would want to prolong this pregnancy , what are the maternal & fetal risks associated with presumed intrauterine infection…?

6. Maternal consequencies Initiation of labor, postpartum endometritis septic shock, ARDS, DIC, and acute renal failure Fetal consequencies Infected fetuses can rapidly decompensate during labor. Fulminant sepsis, neonatal death, developmental delay & Infants exposed to intrauterine infection can present with - neonatal encephalopathy , - periventricular leucomalacia and - an increased risk of cerebral palsy (Hagberg 2002).

7. Considering the chance of subclinical infection,being the cause of PTL… …would you start antibiotics routinely in all cases of preterm labour being managed conservatively as an adjunct to tocolysis…..? • If no ; ; why not? • If yes ; which antibiotic & what dose…?

8. Meta-analysis of the 11 trials (7428 women enrolled; ’ORACLE II 2001’ trial largest) shows a reduction in maternal infection with the use of prophylactic antibiotics (relative risk 0.74) but fails to demonstrate a benefit or harm for any of the prespecified neonatal outcomes. In fact itraisesconcerns about increased neonatal mortality for those who received antibiotics !!! • Antibiotics should not be given routinely to patients with preterm labour with intact membranes for the purpose of prolonging pregnancy. King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database of SystematicReviews 2002, Issue 4

10. The finding of a reduction in maternal infection in women receiving prophylactic antibiotics, needs to be seen in the light of an incidence in the control group of 11.2%. Given that maternal infection is clinically relatively easy to diagnose and treat, this would argue against prophylactic antibiotics to prevent it, as 88.9% of women would be receiving antibiotics unnecessarily.

11. Would you like to confirm the intrauterine infection in all cases of established preterm labour, by amniocentesis & C/S of amniotic fluid while trying to arrest the preterm labour , keeping in mind the adverse consequencies of fetal infection?

12. amniocentesis….. • Not advisable for all pts in preterm labour (itself may predispose to infection) • But strongly recommended for patients with v. high probability of infection : • Clinical S/S of chorioamnionitis • Early gestational age (<28 wks) • Failure of tocolysis (before 2nd agent started)

13. Amniotic Fluid Glucose < 16-20 mg/dl Grams stain positive leucocyte esterase Culture : Gold Standard

14. If infection is confirmed clinically or amniocentesis , what would be your line of management…? Conservative Vs Delivery !!! Antibiotics before vs after baby delivery !!! Choice of antibiotic & why !!!

15. Conservative Vs Delivery !!! • Delivery is indicated once a diagnosis of intraamniotic infection is established. From the available evidence, a diagnosis to delivery interval of upto twelve hours is not associated with increased neonatal morbidity. (Gibbs 1980; Hauth 1985)

16. Immediate Vs Postpartum Ab Whether to begin parenteral antibiotic administration immediately after making the diagnosis or after delivery has been controversial. While immediate administration of antibiotics may limit maternal sepsis, intrapartum antibiotic therapy could obscure the diagnosis of neonatal sepsis and affect the management of the infant.

17. Intrapartum treatmentwith antibiotics for intraamniotic infection was associated with a reduction in • neonatal sepsis (relative risk 0.08) • pneumonia (RR 0.15) compared with treatment given immediately postpartum, although these results did not reach statistical significance (number of women studied = 45). Hopkins L, Smaill F. Antibiotic regimens for management of intraamniotic infection. Cochrane Database of Systematic Reviews 2002,

18. Choice of Antibiotic • There was no evidence to support the use of a more broad-spectrum regimen than ampicillin(2 gms IV 6hrly) and gentamicin for the treatment of intraamniotic infection. (both cross placenta well) There was no difference in the outcomes of neonatal sepsis (RR 2.16) or neonatal death (RR 0.72) between a regimen with and without anaerobic activity Hopkins L, Smaill F. Antibiotic regimens for management of intraamniotic infection. Cochrane Database of Systematic Reviews 2002,

20. Those ’macrolide’ antibiotics (such as clindamycin and erythromycin) which shut down bacterial virulence have theoretical advantages over the beta-lactam antibiotics (penicillins, cephalosporins), which by destroying bacteria release endotoxins which may worsen the outcomes for infants born preterm (McGregor 1997).

21. Implications for practice • Antibiotics should not be given routinely to patients with preterm labour with intact membranes for the purpose of prolonging pregnancy. • Amniocentesis for culture & antibiotics should be strongly considered if: Clinical S/S of chorioamnionitis Early gestational age (<28 wks) Failure of tocolysis (before 2nd agent started) • Delivery & antibiotcs indicated once a diagnosis of intraamniotic infection is established (clinical/culture).. Antibiotic preferable are macrolidegroup (erythromycin/clindamycin) • Current evidence favours immediate intrapartum Ab.

22. Implications for research Further research may be justified (when sensitive serological/biochemical markers for subclinical infection become available)…In order to determine..if there is a subgroup of women who could experience benefit from antibiotic treatment for preterm labour prior to membrane rupture, and to identify which antibiotic or combination of antibiotics is most effective. • Oral Erythromycin + Amoxicillin currently studied

23. Implications for research Although the trend was towards improved neonatal outcomes when antibiotics were administered intrapartum, adverse neonatal events associated with antibiotic administration were not specically sought. Further trials should be designed to look at longer term outcomes, including the consequences of neonatal cerebral damage, provide a thorough understanding of the pharmcokinetic profile of the drugs administered intrapartum and evaluate more comprehensively the effectiveness of different regimens.

24. Mark Twain Albert Einstein Winston Churchill Charles Darwin Napoleon Bonaparte Issac Newton

25. If Mrs.A. had come to you for ANC at 8 wks pregnancy, would you screen her for... - Bacterial vaginosis - Asymptomatic bacteriuria - Trichomonas vaginitis - Chlamydia trachomatis, - N. gonorrhoea - GBS carriage • Infections during pregnancy for which there is good evidence of an increased risk of preterm birth and preterm prelabour rupture of the membranes

26. Some factsB.V. • Bacterial vaginosis is present in up to 20% of women during pregnancy (Lamont 1993). • The majority of these cases will be asymptomatic. • BV ass. with 2 fold increase risk of PTB; Greatest risk being when BV before 16 wks.

27. Bacterial vaginosis • The results of trials that treat bacterial vaginosis in pregnancy, however, are not encouraging. • Treatment before 20 weeks‘ gestation may reduce the risk of preterm birth less than 37 weeks (Peto OR 0.63) • In women with a previous preterm birth, the use of antibiotics was associated with a statistically significant decreased risk of preterm PROM (Peto OR 0.14),and low birthweight , without significant reduction in PTB. • Vaginal antibiotics appear to have no effect on any measure of preterm birth (Peto OR 0.88) • No evidence of a reduction in neonatal sepsis with Rx. McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database of Systematic Reviews 2007, Issue 1. (fifteen trials of good quality, involving 5888 women.)

28. Implications for practice • The evidence to date does not suggest any benefit in screening and treating all pregnant women for asymptomatic bacterial vaginosis to prevent preterm birth. • Symptomatic/ previous preterm birth, - screening & treatment before 20 weeks • Oral metronidazole/clindamycin x 7 days

29. Some factsAsymptomatic Bacteriuria • Asymptomatic bacteriuria(detection of more than 100,000 bacterial/ml in a single voided midstream urine) occurs in 2%to10% of pregnancies and, if not treated, upto 30%of them will develop acute pyelonephritis. • Asymptomatic bacteriuria has been associated with low birthweight and preterm delivery. • Because the performance of rapid urine screening tests in pregnancy is poor, quantitative culture remains the gold standard for diagnosis... • E. coli is the most common pathogen associated with asymptomatic bacteriuria, representing at least 80% of isolates. Other organisms include other gram negative bacteria and group B streptococci.

30. Asymptomatic Bacteriuria • Screening & Rx– Standard recommendation in most ANC guidelines. • Antibiotic treatmentwas effective in reducing the incidence of pyelonephritis in women with asymptomatic bacteriuria (RR 0.23) & reduction in the incidence of LBW (RR 0.66). • There was no evidence of a reduction in preterm delivery Smaill F, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database of Systematic Reviews 2007, Issue 2.

31. The choice Rx: • Sulfonamide /a penicillin/ cephalosporin / nitrofurantoin, based on the results of susceptibility testing. • The optimal duration of treatment is unknown and standard treatment regimens are currently recommended • Sulfonamides : avoided during the late stage of pregnancy ,and breast feeding should be discontinued if sulfonamides are taken because of potential kernicterus or hemolysis ,due to G6PD deficiency in the infant

32. Implications for practice • Routine screening & Rx of asymptomatic bacteriuria at first prenatal visit is recommended (if local incidence > 2% -cost effective) • Antibiotic dep. on sensitivity testing & fetomaternal S/E. : Standard dose : optimal duration unknown(3-10d)

33. Implications for research None of these studies adequately addressed • the most appropriate time is to perform the initial screening culture, • how often to repeat a negative culture and • how best to monitor women initially treated for asymptomatic bacteriuria. There is a need to define the appropriate frequency of follow-up cultures and re-treatment strategies.

34. Trichomonas vaginitis • Ass. with small but significant increased risk of PTB (OR 1.3). • A couple of large RCTs of screening & Rx of asymptomatic TV in preg ,found no benefit ,but actually increased risk of PTB(RR 1.8),LBW(RR 2.49) & childhood mortality within 2yrs. • Mech. Unclear but possibly dying trichomonads release inflammatory mediators & viruses that trigger PTL. • Treatment of symptomatic TV however is recommended. • Oral metronidazole safe even in first trimester. Klebanoff M,Carey J,et al.N Engl J Med 2001;345:487-93 Kigozi G,Brahmbhatt H,et al.Am J Obstet Gynecol 2003;189:1398-400

35. Chlamydia : Screen with cervical swab & treat not to reduce PTB but to reduce vertical transmission & STD. • N.Gonorrhoea: Screen only high risk women & Rx to reduce vertical transmission & STD.

36. GBS carrier • Not ass. with PTB ,but intrapartum fetal exposure leads to early/late neonatal sepsis. • CDC guidelines recommend screening of all pts at 35-37 wks pregnancy (vaginal & anorectal swab) & intrapartum Px to carriers.(Ampi 2gms IV 6hrly) • Indian data (10 yr study CMC Vellore) carrier rate : 10-15% (special broth used) neonatal GBS sepsis rate : 0.17/1000 • Screening may not be cost effective in our setup

37. If same Mrs.A ,28 wks G1P0, has come with PPROM, & you have decided for conservative Mx ,(if not long at least till steroid cover),obviously you would want to start antibotics…. • Whichantibiotics are recommended based on evidence & why? • What other precautions would you take?

38. Preterm rupture of membranes PTB: substantial neonatal morbidity and mortality. One cause, associated with pROM, is often subclinical infection & pROM can in turn predispose to infection. • Maternal antibiotic therapy might lessen infectious morbidity and delay labour, but could suppress labour without treating underlying infection. Such prolongation of intrauterine infection may have adverse consequences for the health of the baby. Two observational studies (Murphy 1995; Spinillo 1995) showed a positive correlation between the duration of rupture of membranes and the risk of cerebral palsy or other neurodevelopmental impairment.

39. Routine antibiotic administration to women with pROM reduces maternal and neonatal morbidity. • Statistically significant reduction in - chorioamnionitis , - numbers of babies born within 48 hours - neonatal infection (RR 0.68), - use of surfactant (RR 0.83) & oxygen therapy (RR0.88) - abnormal cerebral ultrasound scan prior to discharge from hospital (RR 0.82). • Co-amoxiclav was associated with an increased risk of neonatalnecrotising enterocolitis (RR 4.60). • From the available evidence, erythromycin would seem a better choice. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. Cochrane Database of Systematic Reviews 2003, Issue2. (Twenty-two trials - over 6000 women and their babies)

40. Other precautions • No vaginal examination , unless cervix appears grossly dilated on P/S or patient appears in advanced labour or clear signs of infection precluding conservative management. • Close W/F S/O infection. • Consider amniocentesis for culture.

41. Would you like to get done a routine WBC count? • How helpful is count in Mx decision?

42. Elevated WBC count may support suspicious clinical findings but may be artificially elevated by recent STEROID administration.(within 5-7 days, as early as two hours after the first injection),( 35-65% rise) • But total count remain less than 20000 cells/cc in steroid induced leucocytosis J Perinat Med. 2002;30(4):287-91 Aust N Z J Obstet Gynaecol. 1998 Nov;38(4):396-8. Med Wieku Rozwoj. 2003 Jul-Sep;7(3 Suppl 1):261-70 Deibel N,Parsons M,et al,J Perinat Med. 1998;26(3):204-7 Denison F,et al,Br J Obstet Gynaecol. 1997 Jul;104(7):851-3.

43. Implications for practice • Antibiotic treatment following pPROM is associated with a statistically signicant delay in women giving birth and reductions in major markers of neonatal morbidity allow sufficient time for prophylactic prenatal corticosteroids to take effect . • On the basis of the available evidence erythromycin appears the antibiotic of choice. • Co-amoxiclav avoided

44. Further evaluation of the long-term outcome on health and development of children following this intervention is important.

45. Near term PROM • If Mrs.A comes at 36 weeks with PROM of 2 hrs, what would be your line of management based on evidence? - Immediate induction of labour – Y/N? - Antibiotics – Y/N? - Why? - When antibiotics?

46. PROM at or near term • The use of antibiotics resulted in a statistically signicant reduction in maternal infectious morbidity (chorioamnionitis or endometritis): RR 0.43 (3% vs 7%) • No statistically significant differences were shown for outcomes of neonatal morbidity. Given the low rate of maternal infection in the control population (7%), increasing bacterial resistance and S/E with antibiotic use, it does not seem justiable to expose all women with term PROM to antibiotics when treatment can be restricted to those who develop clinical indications for antibiotic treatment.(fever,maternal/fetal tachycardia, leaking > 12 hrs ,foul smelling liquor,,ut tenderness) Flenady V, King J. Antibiotics for prelabour rupture of membranes at or near term. Cochrane Database of Systematic Reviews 2002, Issue3. (two trials, involving a total of 838 women)

47. Implications for practice • Until more reliable evidence is available indicating overall benefit from prelabour prophylactic antibiotics for term PROM it would seem prudent that their routine use in PROM <12 hrs be avoided. • Immediate induction of labour recommended.

48. Implications for research Further well designed randomised controlled trials (adequately sized to address clinically important maternal and neonatal outcomes and include a cost analysis) are needed.

49. Thank You