Strategies for the Prevention of Prematurity Progesterone. Cervical Screening, Cerclage, and Pessaries

Transcription

1 Strategies for the Prevention of Prematurity Progesterone. Cervical Screening, Cerclage, and Pessaries Thomas J. Garite, M.D. Professor Emeritus, University of CA Irvine Editor Emeritus, American Journal of Obstetrics and Gynecology Director of Research and Education for Obstetrics, Pediatrix Medical Group

2 Causes of Preterm Birth: A Complex, Multi-factorial Syndrome 70% spontaneous Preterm premature rupture of the membranes (PPROM) Preterm labor Infection Idiopathic contractions Cervical dysfunction Uterine causes myomata, duplication abnormalities Polyhydramnios Multiple Preganancies Incompetent cervix Bleeding previa and abruption 30% medical decision to initiate delivery Obstetric Indication Maternal indication Hypertension Diabetes

3 Risk Factors Obstetric history Prior spontaneous preterm birth Prior low birth weight infant Prior high risk pregnancy Obstetric complications Premature cervical shortening Cervical cerclage Vaginal bleeding Cervical/uterine anomalies Medical complications Hypertension Gestational diabetes Renal or cardiac disease Maternal or intra-amniotic infection Fetal intrauterine growth restriction Twins/Multiples Demo graphic Factors Race African American Maternal age < 18 or > 40 years Low BMI Genetic factors Lifestyle factors Smoking Alcohol or drug use Lack of prenatal care Lack of prenatal care Nevertheless the majority of women delivering preterm are without any risk factors

4 What does not work to prevent prematurity in at risk patients Singletons Bed rest Prophylactic tocolytics Home uterine activity monitoring Baby ASA Antibiotics Risk Scoring and intensive antenatal surveillance Twins Bed rest Cervical cerclage (routine) Multifetal reduction

5 Two High Risk Groups, Two Proven Interventions 1 st risk screening: comprehensive obstetric history at first prenatal visit Relative risk = 2x Recurrent preterm birth accounts for 15% of all preterm birth 17-OHCP injections cut risk by 1/3 2 nd risk screening: mid-pregnancy cervical length measurement Relative risk = 10x At least 40% of pregnancies will deliver before 32 weeks if the cervix shortens to 20 mm or less before 24 weeks Vaginal progesterone cuts risk by 1/2 Combined, these two risk screening strategies identify more than 50% of pregnancies destined to deliver 34 weeks Identifying and treating these two high risk groups is our best hope for significant reductions in preterm birth and infant mortality.

6 Progesterone as an option for the prevention of prematurity

7 Endocrine Control of Parturition PROGESTERONE Maintains Pregnancy ESTROGENS Promotes Parturition Progesterone Withdrawal Estrogen Activation - Uterine contractions - Cervical ripening - Rupture of membranes PARTURITION

8 Physiologic Effects of Progesterone that Inhibit Labor Inhibits oxytocin activation of myometrium Directly inhibits prostaglandin production Decreases myometrial excitation Inhibition of gap junction formation Anti-inflammatory

9 Progesterone to Prevent Preterm Birth? Decline in progesterone is one etiology of spontaneous preterm birth Progesterone receptor antagonists (e.g., RU-486) anytime during pregnancy leads to cervical ripening, including cervical shortening Safety is well established First trimester use for pregnancy maintenance has been standard clinical practice for decades Premature cervical shortening might detect an effective progesterone deficiency Progesterone supplementation might slow or stop further shortening Studies demonstrate the efficacy of vaginal progesterone intervention for mid-pregnancy short cervix Reduce preterm birth risk Improve outcomes Reduce costs

10 Progesterone for Mothers with a Prior Preterm Birth due to PPROM or Preterm Labor

11 Prevention of Preterm Birth with 17Pc, Meta-Analysis Keirse, Br J Obstet Gynecol 97:149-54, 1990

12 The NEW ENGLAND JOURNAL of MEDICINE June 24, 2003 Prevention of Recurrent Preterm Delivery by alpha 17 hydroxy Progesterone Caproate Paul J. Meis, Mark Klebanoff, Elizabeth Thom, Mitchell Dombrowski, Baha Sabai, Atef Moawad, Catherine Spong, John Hauth, Menachem Miodovnik, Michael Warner, Kenneth Leveno, Steve Caritis, Jay Iams, Ronald Wapner, Deborah Conway, Mary J. O Sullivan, Marshall Carpenter, Brian Mercer, Susan Ramin, John Thorp, Alan Peaceman for The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

13 Multi-center RCT of Progesterone Randomized 463 women (310 Prog., 153 Plac.) Preterm Delivery: 36% Progesterone 55% Placebo (P < 0.001) Delivery before 35 weeks 21% Progesterone 31% Placebo ((P= 0.02) Delivery before 32 weeks 11% Progesterone 20% Placebo (P= 0.02) Borderline statistically significant reduction in neonatal death, ventilatory support, IVH, any O2 requirement

14 Fonseca et al: Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebocontrolled double-blind trial: Am J Obstet Gynecol 2003;18: Randomized patients with previous spont. preterm delivery, cerclage, uterine anomaly 100 mg progesterone suppositories or placebo every night from 24 to 34 weeks 142 patients randomize (70 Prog vs. 72 Plac.)

15 Fonseca et al: Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled doubleblind trial: Am J Obstet Gynecol 2003;18: Results Preterm Delivery Progesterone 14% Placebo 29% (p= 0.03) Delivery < 34 weeks Progesterone 3% Placebo 19% 9p= 0.002) Admitted for Preterm Labor Progesterone 19% Placebo 31%

16 Progestins for History of PTB Recent Trials, PTB < 32 or <34 wks

17 CERVICAL LENGTH The most powerful predictor of preterm birth risk

18 The Cervix During Pregnancy Credit: NIH 2011 Cervical shortening is one of the final common pathways to parturition Premature cervical shortening can be silent for weeks before onset of preterm labor or PPROM Long subclinical phase allows prediction and preventive treatment

19 Iams et al, NEJM 1996 NICHD, Maternal-Fetal Medicine Unit Network Landmark study Validated by hundreds of studies worldwide 2915 singleton patients TVU cervical 24 and 28 weeks Relative risk of spontaneous preterm delivery before 35 weeks Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996; 334:

20 Results: Iams et al Percentile Cervical Length Relative 24 weeks 25 th 30 mm th 26 mm th 22 mm st 13 mm Inverse relationship: the shorter the cervix the higher the risk Small percentage of pregnancies but very high risk Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996; 334:

21 VAGINAL PROGESTERONE Evidence based intervention for prematurely short cervix

22 Fonseca et al, NEJM 2007 Fetal Medicine Foundation of the UK 24,620 asymptomatic patients 90% singletons 85% no prior preterm birth TVU screening for short cervix 20 to 25 weeks 1.7% prevalence CL 15 mm 250 patients with CL 15 mm randomized to vaginal progesterone (200 mg) or placebo 44% reduction in PTB < 34 weeks 41% reduction in neonatal morbidity No serious adverse events Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:

23 Hassan et al, Ultrasound Ob Gyn 2011 Perinatal Research Branch, NICHD 32,091 asymptomatic patients Singletons 84% no prior preterm birth TVU screening for short cervix 19 0/7 to 23 6/7 weeks 2.3% prevalence CL mm 465 patients with CL mm randomized to vaginal progesterone (90 mg gel) or placebo 45% reduction in PTB < 33 weeks 50% reduction in PTB < 28 weeks 43% reduction in any neonatal morbidity or mortality event 61% reduction in respiratory distress syndrome No fetal or neonatal safety signal Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multi-center, randomized, double-blind, placebo-controlled study. Ultrasound Obstet Gynecol 2011; 38:

24 Romero et al, AJOG 2012 Individual Patient Data Meta-analysis 5 trials, 775 women, 827 infants Vaginal progesterone treatment for TVU CL 25 mm (asymptomatic) 42% reduction in PTB < 33 weeks 43% reduction in composite neonatal morbidity and mortality 25% significant reduction in NICU admissions No significant differences between treatment and placebo groups in rates of adverse maternal events or congenital anomalies Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data., Am J Obstet Gynecol 2012;206:124.e1-19.

25 Results: Romero et al Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data., Am J Obstet Gynecol 2012;206:124.e1-19.

26 Progestins for Twins & Triplets RCTs, Outcome = PTB <32 or <34 wks Twins: 7 Trials (Lim 2011 not shown), Total N = 2830 Triplets: 2 Trials, Total N = 215

27 Need to Treat for Benefit Vaginal progesterone for short cervix Treat 11 patients to prevent 1 PTB < 33 weeks Treat 14 patients to prevent 1 case of RDS Magnesium sulfate for pre-ecclampsia Treat 100 patients to prevent 1 case of eclampsia Antenatal corticosteroids during preterm labor Treat 13 patients to prevent 1 case of RDS

28 One Other Solution Am J Obstet Gynecol

29 Cerclage for Short Cervix Metaanalysis of 4 Randomized Trials Singleton, Short Cvx, No Other Risk Factor Singleton, Short Cvx, Prior PTB Total N PTB < 35w Cerclage PTB <35w No Cerclage RR % 33% % 39% 0.61* Twins, Short Cvx 49 75% 36% 2.15* * P < 0.05 Berghella et al, Obstet Gynecol 106:181-9, 2005

30 The Arabin Pessary for the Prevention of PTB with a Short Cervix

31 Two Large RCT s of Pessary for a Short Cervix PECEP Study (Goya et al:lancet 2012;379, women with CL < 25mm Delivery < 34 wks (primary outcome) 6% pessary, 27% control (RR 0.24, ) Delivery < 28 wks 2% pessary, 8% control (RR 0.24, ) Hui (Am J Perinat 2013 Apr;30(4): women with CL <25 Delivery < 34 wks 9% pessary, 6% control

32 One RCT of Pessary in Twins Liem et al: Lancet, :1341 RCT of all women with multiple pregnancy 40 Hospitals in the Netherlands 403 pessary, 410 control No overall difference in preterm birth or composite overall outcome In women with cervical length < 25 th %tile Composite nn morbidity - 12% pessary, 29% control(rr 0.42, ( ) PTD < 32 weeks 12% pessary, 28% control (RR 0.43,

33 Evidence Based Use of Progesterone Singletons Multiples 17-OHCP: history of spontaneous preterm birth 2003 Vaginal progesterone: prematurely short cervix 2011 Progesterone NOT effective in preventing preterm birth

34 IDENTIFYING PATIENTS FOR VAGINAL PROGESTERONE TREATMENT Screening for mid-pregnancy short cervix

35 Identifying the Short Cervix Current practice Treat only incidentally found short cervix Change in practice Universal cervical length screening Adds cervical length measurement at weeks gestation Per ACOG/SMFM Reasonable clinical practice to enable treatment Cannot mandate given limited access to TVU

36 Screening and Treatment is Cost Saving For every 100,000 women screened $19.5 million saved 735 Quality Adjusted Life Years gained $ million potential annual net savings in U.S. given widespread adoption This strategy is not only beneficial in terms of improvement in health in a condition of utmost importance to society, but also cost-effective, and in fact cost-saving.

37 Methods to Measure the Cervix Transabdominal ultrasound (TAU) Transvaginal ultrasound (TVU) Cervicometer: single use, disposable device

38 Transabdominal Ultrasound Designed to image the baby Routine fetal anatomy scan at weeks Protocol includes looking at the cervix Full bladder often elongates and distorts cervix Per ACOG/SMFM Not reliable nor reproducible as a screening method Not sufficient evidence to suggest benefit of TAU screening for progesterone or other intervention

39 Friedman et al: Can transabdominal ultrasound be used as a screening test for short cervical length? AJOG (3):190 Screened 1217 Patients at wks with both TA and TV US 76 had a TV CL <= 25 mm To have a 96% confidence of identifying these 76 women they needed to have a TA CL of <= 36 mm 6.2% could not be screened due to technical difficulty 54% (657/1217) had a TA CL <36 mm So with screening with TA US you will still need to do TV on 60% of women to identify almost all women who will have a TV CL of <25mm

40 Transvaginal Ultrasound Contemp Obstet Gynecol

41 Transvaginal Ultrasound Designed to image the reproductive organs Identify anomalies Diagnose complications (e.g., cervical shortening, funneling, amniotic sludge or debris) Used in clinical trials of vaginal progesterone Per ACOG/SMFM Diagnostic exam for intervention Proper technique, quality control, monitoring essential Certification recommended Perinatal Quality Foundation 3 lectures Exam Image review CME credit Cervical Length Education and Review

42 TVU Screening? TVU serves as both screening and diagnostic test in one step Feasible in most settings with high ultrasound capacity Maternal-Fetal Medicine practices Ultrasound centers: sonographers Generalists offices with full time sonographers Add TVU cervical length at the fetal anatomy scan Standard protocol for the facility Standing order from referring physician

43 Screening in Other Settings? Limited TVU capacity in many settings Limited number of TVU probes Limited scheduling of certified examiners Part-time sonographers Obstetricians perform in-office ultrasound MFM at clinic only once or twice a week No TVU availability in some settings Conclusion: there is not universal access to TVU for screening Another screening modality is needed

44 Cervicometer Single use, disposable Multiple peer-reviewed studies Identify patients for indicated TVU Classic two step screening-diagnostic approach Allows equitable access to screening where TVU screening is not feasible

45 Cervicometer Vaginal cervical length measurement during speculum exam Procedure performed by physicians, midwives, or nurses Simple screen for indicated TVU as diagnostic for intervention High negative predictive value to rule out short cervix by TVU and associated risk of preterm birth High sensitivity to identify patients likely to have a short cervix by TVU Ideal to perform at prenatal visit before the anatomy scan Add order for TVU cervical length when necessary

46 Studies Evaluating Cervicometer to Predict a Short Cervix by Transvaginal US Study/yr N Sensitivity Specificity PPV NPV Cutoff Harbor % 92% 93% 99% <30mm W. Australia % 73% 25% 98% <24mm Perugia, It % 100% <30mm Th.Jefferson % 100% <30

47 UNIVERSAL CERVICAL LENGTH SCREENING AND VAGINAL PROGESTERONE The next vital step for preterm birth prevention

48 Society Guidelines: Progesterone to Prevent Preterm Birth SMFM ACOG ACNM

49 Recommendations for Routine Cervical Length Screening SMFM The issue of universal TVU CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners ACOG Although this document does not mandate universal cervical length screening in women without a prior preterm birth, this screening strategy may be considered. Practitioners who decide to implement universal cervical length screening should follow one of the protocols for transvaginal measurement of cervical length from the clinical trials on this subject ACNM Application of evidence based strategies to effectively screen women at potential risk for preterm birth should be accessible and available to every woman including strategies to assess cervical length in order to implement timely prevention strategies

50 Prematurely Short Cervix ACOG/SMFM Recommendations RISK Relative risk = 10x At least 40% of pregnancies will deliver before 32 weeks if the cervix shortens to 20 mm or less before 24 weeks INDICATION Singleton without history of spontaneous preterm birth Asymptomatic Transvaginal ultrasound (TVU) diagnosis of premature cervical shortening Cervical length weeks TREATMENT Vaginal progesterone: 90 mg gel or 200 mg suppository daily Crinone 8% Prometrium (generic) Compounded From diagnosis to 36 weeks

51 The Time is Now Vaginal progesterone is a proven intervention for prematurely short cervix 45% reduction in early preterm births 25% fewer NICU admissions Cervical length screening to identify patients for treatment can be implemented universally TVU where feasible Cervicometer elsewhere Supported by professional society guidelines Save money: short- and long-term Improve population health Our best hope to reduce infant mortality