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Preventing Preterm Births: Do Any Screening Tests Help? Joseph R. Biggio, M.D.

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Presentation on theme: "Preventing Preterm Births: Do Any Screening Tests Help? Joseph R. Biggio, M.D."— Presentation transcript:

1 Preventing Preterm Births: Do Any Screening Tests Help? Joseph R. Biggio, M.D.

2 Learning Objectives To understand the availability and performance of screening tests for the prediction of subsequent preterm birth To understand how to utilize screening tests to identify women most likely to benefit from interventions to reduce PTB To understand the limitations and challenges of using screening tests for preterm birth in different patient populations

3 Scope of the problem: Preterm Birth 30% Increase from 1980’s – 2006 ~450,000 – 500,000 infants/yr Peaked in 2006 PTB < 37 wk12.8 % PTB < 34 wk3.7 % PTB wk9.2 % Hamilton et al, NVSR, NCHS 2014

4 Scope of the problem: Preterm Birth Hamilton et al, NVSR 63(2), 2014

5 Scope of the problem: Preterm Birth % PTB < 34 wk3.4 % PTB wk7.99% Most significant declines in late preterm birth Hamilton et al, NVSR, NCHS 2014

6 March of Dimes 2014 Premature Birth Report Card Vermont 8.1%Mississippi 16.6%

7 Scope of the Problem: Preterm Birth PTL 40% PROM 35% Indicated 25%

8 Major cause of perinatal morbidity and mortality Cerebral Palsy Developmental Disability Neurologic impairment Chronic lung disease Minor Morbidities Scope of the Problem: Preterm Birth

9 Risks related to GA at birth Mortality 24 wk50% 28 wk10% Special education needs wk25% wk45% Scope of the Problem: Preterm Birth

10 History Serial digital examination Fetal fibronectin Salivary estriol Cervical length screening BV screening Home uterine activity monitoring Periodontal disease screening What Screening Tests Have Been Suggested?

11 Serial digital examination Salivary estriol BV treatment Periodontal disease treatment Home uterine activity monitoring +/- fFN in asymptomatic women What Screening Tests Do NOT Work?

12 Bedrest Pelvic rest Fish oil supplements Enhanced prenatal care What Interventions Do NOT Work?

13 Many other different biomarkers and measurements examined Many have reasonable + Likelihood ratios Positive predictive value or specificity too poor for clinical practice What Screening Tests Have Been Suggested?

14 So what does work to assess risk for subsequent PTB?

15 Major risk factor for subsequent preterm birth fold risk Number of prior PTB GA at prior delivery Sequence of deliveries McManemy et al, AJOG, 2007; Lemos et al, AJOG 2013 History of Prior Preterm Birth

16 Timing of prior PTB contributes to risk Earlier PTB  higher recurrence risk Spong et al, Am J Obstet Gynecol, 2005 History of Prior Preterm Birth

17 Correlates with timing of cervical shortening Wing et al, Am J Obstet Gynecol 2010 History of Prior Preterm Birth

18 Prior history of SPTB: Prevention of recurrence 17-hydroxy progesterone caproate Prior singleton PTB /7 wk Treatment started /7 wk 310 progesterone; 150 placebo PTB < 37 wk 36% vs 55% RR 0.66 (0.54 – 0.81) Meis et al, NEJM, 2003

19 Prior history of SPTB: Prevention of recurrence PTB <32 wk 11% vs 20% RR 0.58 (0.37 – 0.91) Significant reduction in Necrotizing enterocolitis Intraventricular hemorrhage Meis et al, NEJM, 2003

20 Utilizing the test to prevent PTB: History Vaginal progesterone High-risk for PTB 100 mg vaginal progesterone daily Reduction in uterine contractions 45-50% reduction in PTB <34 wk da Fonseca et al, AJOG, 2003

21 Cervical Length

22 Asymptomatic 24 wk Mean mm CL <26 mm PTB <37 wk RR 6.2 (3.8 – 10) ≥25 mm NPV >95% for PTB <32 wk <25 mm PPV 10% for PTB < 32 wk Iams et al, 1996

23 Cervical Length Iams et al, 1996

24 Cervical Length Transvaginal assessment Reproducible Not affected by obesity, position, fetal presentation like transabdominal Better able to assess for funneling and debris ACOG PB 130, 2012; Owen and Iams, Semin Perinatol 2003; Berghella et al Obstet Gynecol 2007

25 Utilizing the test to prevent PTB: Short Cervix Cervical length 15 mm or less Screened at wk Vaginal Progesterone 200 mg nightly PTB < 34 wk RR 0.56 (0.36 – 0.86) ~15% with prior PTB Non-significant reduction in adverse neonatal outcome RR 0.59 ( ) Fonseca et al, NEJM, 2007

26 Utilizing the test to prevent PTB: Short Cervix Cervical length mm Screened at /7 wk 16% with prior PTB 90 mg progesterone gel daily 45 % reduction in PTB < 33 wk and neonatal morbidity and mortality Hassan et al, US OG, 2011

27 Utilizing the test to prevent PTB: Short Cervix 17-OHP NOT effective in preventing PTB MFMU SCAN Trial Nulliparous CL ≤30 mm 17-OHP 250mg weekly No reduction in SPTB Grobman et al,

28 Utilizing the test to prevent PTB: Short Cervix Cerclage Trial Prior SPTB 17 – 33 6/7 wk CL 16 – 22 6/7 wk; <25 mm PTB < 35 wkOR 0.67 (0.42 – 1.07) < 15 mm OR 0.23 ( ) 16 – 24 mm OR 0.84 ( ) Perinatal death and pre-viable PTB significantly reduced Owen et al, AJOG, 2009

29 Short Cervix and Cerclage: Meta-analysis Individual patient data Singletons, Prior PTB, CL <25 mm PTB <35 wkRR 0.7 ( ) Neonatal mortality and morbidity RR 0.64 ( ) PTB <37, 32, 28, and 24 all reduced Berghella et al, Obstet Gynecol, 2011

30 Short Cervix, Cerclage & Progesterone No additional benefit with 17-OHP & cerclage Value of vaginal progesterone and cerclage unknown Berghella et al, XXXXXXXXX

31 Utilizing the test to prevent PTB: Short Cervix Pessary Mechanism of effect Change in angle of uterus-cervix junction Shift of weight to LUS Prevention of exposure of membranes

32 PECEP Trial 16,000 low-risk singletons CL surveillance ≤ 25mm randomized (n=385) Arabin pessary Expectant management Goya et al, Lancet 2012

33 Pessary and Short Cervix: PECEP PTB < 34 wk6% vs 27% OR 0.18 ( ) Composite neonatal outcome 3 % vs 16 % OR 0.14 ( )

34 What to do with a short cervix? No Prior PTB No role for cerclage unless acute cervical insufficiency Vaginal progesterone 200 mg capsule or 90 mg gel daily ? Role of pessary

35 Should we be doing universal cervical length screening in women without a history of prior PTB? Incidence of CL ≤ 20 mm ~2% Cost-effectiveness models suggest utility Assumptions on costs and behavior vary ACOG “consider” screening If detected treat with progesterone Can be incidental finding ACOG PB 130; Cahill et al, AJOG 2010; Werner et al, Obstet Gynecol 2011

36 Why hesitation on universal cervical length screening? NNS and NNT is high Quality assurance issues Skill set availability Potential for overtreatment or overscreening How often and how many screens needed?

37 What to do with a short cervix? Prior PTB “What is short?” Consider cerclage, especially if <15 mm Should already be on 17-OHP ? Role of vaginal progesterone CL 15 mm? Switch forms?

38 What to do with a short cervix? ACOG PB 130

39 What to do with a short cervix? Meta-analysis of data from 3 cohorts with prior PTB, short cervix Comparison of Rx No difference <37 wk <34 wk Perinatal death Alfirevic et al, US OG, 2013

40 Fetal Fibronectin

41 Fetal Fibronectin (fFN) Decidual-Chorionic interface glue Any disruption results in release Inflammation Hemorrhage Overdistension HPA axis activation Lockwood CJ et al. N Engl J Med. 1991;325:

42 Fetal Fibronectin detection Fetal Fibronectin (ng/mL) Gestational Age (Weeks) ng/mL Cutoff Level Adapted from Garite TJ et al. Contemp Obstet Gynecol. 1996;41: Normal pregnancy not detectable after 18 wk

43 Fetal Fibronectin (fFN) 725 singletons at 24 – 34 6/7 Sx of PTL; <3 cm dilated In 20% positive—Delivery in 7 dRR 38.8; sensitivity 90.5%; PPV 13.4% 14 dRR 31.3; sensitivity 88.5%; PPV 16.2% <37 wk RR 2.9; sensitivity 43.9%; PPV 43% Negative predictive value for delivery 7 d99.7 % 14 d99.5 % <37 wk 86.6 % Peaceman et al. Am J Obstet Gynecol. 1997

44 Utility of fFN in PTL triage Negative Less intervention and hospitalization Reassurance Positive Transfer to appropriate facility Corticosteroids, magnesium sulfate

45 Adequacy of neonatal care Preterm infants transferred to tertiary center rather than inborn 2X risk of death, Grade 3 or 4 IVH 5X risk of RDS 2-3X risk of nosocomial infection Chien et al, Obstet Gynecol, 2001

46 Fetal Fibronectin (fFN) Asymptomatic Women wk 3-4% positive PTB <28 wk: Sensitivity 63% Specificity 96% RR 59 PPV 13% ; 36% < 37 wk Goldenberg et al, Obstet Gynecol, 1996

47 Screening with fFN in asymptomatic women No interventional studies improve perinatal outcomes Screening therefore not recommended ACOG PB 130, 2012

48 Fetal Fibronectin (fFN) & CL in combination Asymptomatic Women at 24 & 28 wk Both negative—low risk of PTB Either positive—intermediate risk Both positive—highest level of risk Goldenberg et al, Am J Obstet Gynecol, 2000

49 Prematurity and Multiples

50 Preterm Birth Mean GA at delivery Twins 35 weeks Triplets 32 weeks Quads29 weeks

51 Cervical Shortening in Twins MFMU Preterm Prediction 24 wk scan: Singletons: 25 mm 10 th percentile Twins: 18% CL ≤25 mm PTB <32 wkOR 7.7 PTB <35 wkOR 3.4 Iams et al, NEJM 1996; Goldenberg et al, AJOG 1996

52 Cervical Shortening in Twins More common Greater risk even with longer cervix 50% PTB <32 wk Singleton ≤15 mm Twins ≤25 mm Hassan et al, 2000; Souka et al, 1999

53 Screening Tests Utility: Twins vs Singletons No significant difference in performance Delivery in 7 dRR dRR 20.4 <37 wk RR 2.9 Negative predictive value for delivery 7 d99.5 % 14 d99.2 % <37 wk 84.5 % Peaceman et al. Am J Obstet Gynecol. 1997

54 Cerclage Twins Elective placement Limited prospective studies; several retrospective No prolongation of pregnancy Roman et al, Am J Perinatol 30, 2013; Dor J et al, Gyn Obstet Invest 13, 1982; Strauss A et al, Twin Res 5, 2002

55 Cerclage Indicated for CL <25mm Meta-analysis 4 studies 49 twins CerclageNo CerclageRR (95% CI) PTB <35 wk18/24 (75%)9/25 (36%)2.2 ( ) PNM11/48 (23%)3/50 (6%)2.7 ( ) Berghella et al, Obstet Gynecol 106, 2005

56 17-OHPC—Twins with short cervix 2° analysis MFMU 221 of 661 had CL measured at wk 25 th percentile 36mm Increased risk of PTB—56 vs 37% 17OHPC did not reduce risk—64 vs 46% Durnwald et al, J Mat Fetal Neonatal Med 23, 2010

57 Vaginal progesterone—Twins Empiric use 3 randomized trials—16-24 wk Approximately 1200 women 90 mg P4 gel or 200 mg P4 capsules No significant difference in PTB, GA at delivery, neonatal outcomes Rode L et al, USOG 38, 2011; Norman JE et al, Lancet 373, 2009; Wood S et al, J Perinat Med 40, 2012

58 Meta-analysis: Vaginal P, short cervix, twins Individual patient data from 5 trials PTB < 33wk RR 0.7, CI 0.3 – 1.4 Neonatal morbidity and mortality RR 0.52, CI 0.3 – 0.9 Romero R et al, AJOG 206, 2012

59 Pessary and Multiples ProTWIN Subgroup Analysis 25 th percentile  38 mm utilized Poor perinatal outcome RR 0.4 (0.19 – 0.83) GA at delivery36.4 vs 35.0 wk PTB <28 wkRR 0.23 (0.06 – 0.87) PTB <32 wkRR 0.49 (0.24 – 0.97) Liem S et al, Lancet 382, 2013

60 Summary While a number of screening tests have been proposed, history and cervical length screening are the only methods that offer an intervention capable of reducing subsequent PTB Women with a history of prior SPTB should be strongly encouraged to take 17-OHP and cervical length screening should be performed between weeks

61 Summary Women with a history of prior SPTB in whom a short cervix is identified should be offered cerclage, especially for CL <15 mm, or at least vaginal progesterone Women without a prior history of PTB should be offered vaginal progesterone for a short cervical length


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