a S - Children`s Memorial Hermann Hospital
Transcription
a S - Children`s Memorial Hermann Hospital
5TH ANNUAL TEXAS TWO-STEP CONFERENCE Navigating Changes in Ob/Gyn: Are You On Board? Texas Two-Step Conference, Januar 9 - 10, 2015 Texas Two-Step Conference 2015 THANK YOU, SPONSORS 4407610 Cord Blood Registry • Exact Sciences • GE Healthcare Houston Fertility Institute • Lumara Health Sequenom • Xpress Med Solutions 1 Texas Two-Step Conference, Januar 9 - 10, 2015 AGEN NDA |FRIDA AY, JAN NUARY Y 9, 20 015 7:55 a.m. WELCOME A W AND INTROD DUCTIONS ̶ Sean Blackwell, M.D., and Baha SSibai, M.D. 8 – 8:45 INTERACTIVE DEBATE: Shou uld We Try to Decrease or Inncrease the C Cesarean Delivery Rate?? ̶ Baha Sibai, M.D., a and Clara Warrd, M.D. 8:45 – 9:30 Patient Safetyy Stories: Lesso ons Learned from Tragedy ̶ Sean Blackwell, M.D. 9:30 – 9:45 9:45 – 10:30 BREAK B 10:30 0 – 11:15 a.m. INTERACTIVE DEBATE: Robo otic Surgery in n GYN – Fad o r the Future? ael Adler, M.D D., and Sara Ho olcombe, D.O.. ̶ Micha What Every O W B/GYN Needss to Know about In‐Utero Feetal Surgery ̶ Antho ony Johnson, D D.O. 11:15 5 – Noon Ramifications of Lapses in D Detail During EEndoscopic Suurgery Micha ael Baggish, M M.D. Noon n – 12:45 p.m. 12:45 5 – 1:30 LUNCH L Major Complications from IInappropriate Gynecologic Laparoscopic Procedures ̶ Micha ael Baggish, M M.D. 1:30 – 2:15 INTERACTIVE DEBATE: Whaat is the Best M Management oof Mode of Deelivery for Twin Pregnan T cies: Is Vaginaal Delivery Still a Safe Optio n? ̶ Roberrt Silver, M.D. and Suneet C Chauhan, M.D.. 2:15 – 2:30 2:30 – 3:15 BREAK B 3:15 – 4 Evidence‐Base ed Guidelines for Use of Pro ogestogens too Prevent PTB ̶ Adi Abramovici, M..D. 4 – 4:45 What Would Y W You Do? Comp plicated Case Presentationss ̶ Hecto or Mendez‐Fig gueroa, M.D. 4:45 – 5 CLOSING RE C EMARKS Obstetrical M O anagement off Women with h Recurrent Prregnancy Losss ̶ Roberrt Silver, M.D. 2 Texas Two-Step Conference, Januar 9 - 10, 2015 AGEND A DA |SA ATURD DAY JA ANUAR RY 10, 2015 7:55 a.m. WELCOME A W AND INTROD DUCTIONS ̶ Sean Blackwell, M.D., and Baha SSibai, M.D. 8 – 8:45 Management of Placenta A Accreta: How to Avoid Catasstrophes ̶ Baha Sibai, M.D. 8:45 – 9:30 INTERACTIVE DEBATE: Shou uld NIPT for Fe etal Aneuploiddy be Offered to All Patients? ̶ Georg ge Saade, M.D D. and Eleazarr Soto, M.D. 9:30 – 9:45 9:45 – 10:30 BREAK B 10:30 0 – 11:15 a.m. 11:15 5 – Noon Management of the Adnexaal Mass ̶ Adnan Munkarah, M.D. INTERACTIVE DEBATE: Shou uld We Increasse or Decreas e the Numberr of Cervical Cerclage Plac C ements to Pre event Preterm m Birth? ̶ Alfred do Gei, M.D. a and Suneet Chauhan, M.D. Texas Perinata T al Levels of Caare Designatio on: What Everyy OB/GYN Neeeds to Know ̶ Eugen ne Toy, M.D. Noon n – 12:45 p.m. 12:45 5 – 1:30 LUNCH L All Uterine Ca A ncers are Nott Born Equal! ̶ Adnan Munkarah, M.D. 1:30 – 2:15 What Every O W B/GYN Should d Know Aboutt Hospital Opeerations ̶ Susan n Distefano, M M.S.N., RN, NEA A‐BC 2:15 – 2:30 2:30 – 3:15 BREAK B 3:15 – 4 3:45 – 4 What Every O W B/GYN Needss to Know about Surgical Woound Compliccations ̶ Josep ph Lucci, III, M..D. What Would Y W You Do? Complicated Case Presentation s ̶ Micha ael Adler, M.D D. and Joseph Rodriguez, M..D., Ph.D. CLOSING RE C EMARKS 3 Texas Two-Step Conference, Januar 9 - 10, 2015 Cou urse Description The 5th Annual TTexas Two‐SStep Confere ence, Navigating Changees in OB/GYN N: Are You O On Board? brrings togetherr experts in obstetrrics and gyneccology to disccuss recent ch hanges in heaalthcare policyy and practice guidelines aand their impaact on patientts, physicians,, nurses and h hospital operrations. Conference attendees will learrn about ACOG and SMFM recommend ations for maanagement off high‐risk preegnancies o prevent nea r misses and medical erro ors to avoid un nnecessary and ggynecologicall conditions, aas well as tipss and tools to harm m. This year’s event will alsso include a se eries of interaactive debatees surroundin ng controversial topics in O OB/GYN. Highllights of this yyear’s conference include:: • Inteeractive debaate series • Acttive audience participation n • Com mplicated casse studies • Unparalleled on ne‐on‐one nettworking opportunities witth industry exxperts Con ntinuing Ed ducation Targget Audience e Physicians (OB/GYYN, maternal‐‐fetal medicin ne, family me edicine), geneetic counselorrs, nurses, midwives, sono ographers and d healtthcare administrators Conttinuing Educcation Hourss for Nurses Mem morial Herman nn‐Texas Med dical Center iss an approved d provider of f continuing n nursing educaation by th he Texas Nursses Associatio on, an accredited approverr by the Amerrican Nurses C Credentialingg Center’s Com mmission on Accreeditation. proved for 7.5 5 contact hou urs on Day 1 aand 6.5 contaact hours on D Day 2. This aactivity is app Conttinuing Educcation Hourss for Physicians This aactivity has been planned and impleme ented in accordance with tthe accreditation requirem ments and policies of the Texas Medical Asssociation (TM MA) through th he joint proviidership of M Memorial Herm mann Health System and U UTHealth Medical School. The Memorial Hermann He ealth System iis accredited by the TMA tto provide co ontinuing med dical morial Herman nn Health Sysstem designattes this live acctivity for a m maximum of 1 14 AMA PRA educcation for phyysicians. Mem Categ gory 1 Creditt(s)™. Particip pants should cclaim only the e credit comm mensurate wiith the extentt of their participation in the acttivity. The p presentationss, “Understan nding Hospital Operations in OB/GYN P ractice” and ““How Will thee Afforrdable Care A Act Change OB B/GYN Practicce?” have eacch been desiggnated by Meemorial Herm mann Health System for 1 crediit of educatio on in medical ethics and/orr professional responsibilitty. This conference is in collabo oration with h: 4 Texas Two-Step Conference, Januar 9 - 10, 2015 INTERACTTIVE DEB BATEE: Sh hould d We Tryy to Deccreasse or Inccreasse th he Cesarrean n Delliverry Raate?? Baha SSibai, M.D. Ward, M.D.. Clara W 5 Texas Two-Step Conference, Januar 9 - 10, 2015 Should we try to increase the cesarean delivery rate? Baha M. Sibai, MD Professor, MFM Division Principal Investigator, Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Network Director, Maternal-Fetal Medicine Fellowship Program PRESERVE‐1 Study Design Multicenter, randomized, placebo-controlled, double-blind, phase 3 trial • Patients treated with rhAT or placebo until delivery 120 pregnant women with PPE at 24‐28 weeks of gestation RANDOMIZE • IV rhAT 2000 mg 24-h CI (n=60) IV placebo (n=60) Primary objective: Prolong gestational age Secondary objective: Reduce neonatal morbidity and mortality Maternal, fetal, and neonatal assessments and complications Futility analysis after 50% of primary endpoint Sample size re‐estimation after 75% of secondary endpoint Having a healthy baby by C/S is unforgettable experience 6 Texas Two-Step Conference, Januar 9 - 10, 2015 Angelina Jolie : Elective C/S Saying, "It ended up being the greatest thing. I had a C-section and I found it fascinating I didn't find it a sacrifice I didn't find it a painful experience I found it a fascinating miracle of what a body can do." What is the appropriate cesarean rate ? “We are not interested in targets for c/s rates , we are interested in healthy mothers and babies.” The Lancet, 1997 “Chasing an elusive ideal C/S rate (whatever that rate may be) is not a useful exercise” ANZ J Obstet Gynaecol , 2014 Caesarean section was the last resort - 1666 7 Texas Two-Step Conference, Januar 9 - 10, 2015 Cesarean Section From 1950 Gradually getting safer Intubation Epidural Antibiotics Blood transfusion Lowers the threshold Increasing CS rates First in developing countries Rest of the world follows Fetal reasons and some maternal reasons C-Section is the way to go Cesarean section is good for mature women Cesarean section is safest for baby Cesarean Section • Elective is safe • Emergency is not Cesarean section is best for both Mother/fetus Past Cesarean section bad for mother Why do women request C- Section? Fear • Birth experience • Pain, use of oxytocic agents, multiple vaginal exams • Prolonged labor , hooked to monitors/ catheters • Chorio , bleeding, retained tissues , need for emergency delivery • Past Experience (terror) • Maternal pelvic floor damage : acute and long-term • Prolapse • Urinary/fecal Incontinence • Sexual dysfunction • Baby Damage • Death • Hypoxia, acidosis, trauma, neonatal infections • Long-term injury Planning 8 Texas Two-Step Conference, Januar 9 - 10, 2015 Britney Spears: planned C/S due to tocophobia Chose a C-section because she didn't want to go through the pain. My mom said giving birth was the most excruciating thing she's ever gone through in her life. Planned C-section : date and time Christina Aguilera : Elective C/S “I didn’t want surprises I didn’t want any tearing. I heard horror stories of women laboring for hrs. and having to have an emergency C-section. The hardest part was deciding on his birthday.” 9 Texas Two-Step Conference, Januar 9 - 10, 2015 Victoria 'Posh Spice' Beckham Victoria Spice Beckham inspired the phrase "too posh to push," reportedly delivering all four kids via C-section. She had no accreta. Women have changed and practice patterns have changed Why shouldn’t C/S rate change ? Reasons for increased C-Section rate AMA/Infertility • G1 > 40 years IVF • BMI > 40 kg/m2 • Multifetal gestation Medical problems • Cardiac, pulmonary renal , etc. Placental abnormalities: • previa, accreta • vasa previa , abruptio preeclampsia < 30 wk Severe FGR • Prior C/S or other uterine cavity surgery Maternal infections transmitted during labor • HIV , Herpes, Hepatitis C, B‐ strep Abnormal labor patterns: • Latent phase Active phase Second stage Abnormal fetal size /position/ presentation • Macrosomia, Breech, transverse lie, hydrocephalus Abnormal FHR patterns: • Category‐II Category –III Indeterminate 10 Texas Two-Step Conference, Januar 9 - 10, 2015 Obstetric complications continue to increase Change in obstetric demographics AMA during pregnancy • > 35 : 20% • ≥ 40 : 5% Increased obesity • BMI ≥ 30 :3035% • BMI ≥ 50 : 5 % • Larger fetal size Increased multifetal gestation • Twins : 5% Triplets : 1 % C/S rate by maternal age, 2009-2011 Source: CDC/NCHS, National Vital Statistics System C/S rate by BMI, 2002-2008 Source: Am J Obstet. Gynecol, 2010 11 Texas Two-Step Conference, Januar 9 - 10, 2015 By the numbers: Twin Birth in US 140,000 Twins 130,000 120,000 110,000 100,000 90,000 80,000 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2011 Reasons for increased induction or C/S Increased Obstetric / medical disorders • Obstetric complications – Abnormal placentation : Previa , abruptio – FGR / PROM : More interventions – GHTN- preeclampsia : 25-30% in nullipara • Increased prevalence of medical disorders – – – – – – CHTN / renal disease : 5-7% Type-2 DM : 3-5% Moderate to severe asthma Cardiac disease Seizure disorder Many others Obstetric complications continue to increase Change in obstetric practice ( Routine screening) Abnormal serum screening Serial U/S screening New screening guidelines for GDM • 1st-T: 5% • 2nd -T: 5% • • • • AC/ EFW <10th : 10% LGA : 10 % Oligo/ polyhydramnios: 10 % Markers of aneuploidy : 10% • First visit and at 24-26 wk. • Lower threshold and 1 step DX. (15-20%) 12 Texas Two-Step Conference, Januar 9 - 10, 2015 Cesarean Delivery rate in the US 1.3 Million Per Year Total 32% Primary 22% VBAC 9.2% CDC,NVSS Preventing the first Cesarean section Keep C/S rise to a minimum • Reduce elective CS • Improve information • Breech, twins, inductions Reduce emergency C/S • Fetal distress • Diagnosis & management • Failure to progress • Oxytocin/time after ROM • Full dilatation • Instrumental delivery • Duration of 2nd stage 13 Texas Two-Step Conference, Januar 9 - 10, 2015 Algorithm for induced labor. NICHD Workshop INDUCTION P!nk: c/s for breech "We tried everything to turn her around. Turns out this little girl had other plans -she is my daughter, after all." Reason for Kate Hudson having C/S Kate Hudson opted for a c/s when her labor wasn't progressing "The doctor said I could go home.. I was like, 'I am not going home, just don't want to do this again. Let's just have a C- section.' 14 Texas Two-Step Conference, Januar 9 - 10, 2015 Camila Alves : C/S in labor Labored for 40 hours .The vacuum didn't work, and the doctor said, “C-section" Ureter Uterine Vessels Transverse Laceration Vertical Laceration Uterine Lacerations B. Sibai Should the rising cesarean section rates be reversed ? 15 Texas Two-Step Conference, Januar 9 - 10, 2015 Leeds Institute of Dr. Ward’s Delivery Room Bioscience and Clinical Science Section of Obstetrics and Gynaecology “THERE ARE MANY WHO BELIEVE THAT THE DELIVERY OF WOMEN IS EASY… AND IN TRUTH THERE IS NO MYSTERY WHEN THINGS GO NORMALLY. BUT, WHEN AN ACCOUCHEMENT IS PRETERNATURAL IT BECOMES THE MOST DIFFICULT, LABORIOUS AND DANGEROUS OF ALL SURGICAL PROCEDURES.” FRANCOIS MAURICEAU, 1694 • French 17th century obstetrician • Established obstetrics as a science (book) • Breech delivery maneuver Request for c- section or vaginal delivery Objectives of counselling – Women who need/want a vaginal are able to get it • • • • • Discuss all risks of waiting for onset of labor Discuss all risks of induction of labor Discuss all complications of labor Discuss all complications of vaginal delivery Care is adequate to support vaginal birth for those who want attempted vaginal birth – Women who need /want a C/S can have one – Discuss all risks of C/S Discuss all complications: current and long-term 16 Texas Two-Step Conference, Januar 9 - 10, 2015 Risks Included in consent for Cesarean Delivery • Injury to bowel, bladder, or ureter • Brain damage, injury or death to the fetus during cesarean section • Neonatal respiratory complications • Uterine disease or injury requiring hysterectomy or resulting in sterility • Thromboembolism • Need for transfusions • Wound complications/ infection • Maternal death Potential Costs of Waiting from 38 wks. to Labor (meconium injury) cord accidents Increased macrosomia: shoulder dystocia Fetal deaths (1/1,000) Abruptio placentae GHpreeclampsia Increased meconium Decreased fluid: Emergent surgery HIE B. Sibai Neonatal Complication Rates by Week of Gestation GA (wk) N Meconium (%) ≥ 4500 g (%) ICU Adm (%) 38 4489 13.8 0.88 4.5 39 7626 18.3 1.15 3.1 40 9808 25.8 2.22 2.6 41 5717 31.9 3.58 3.4 ≥ 42 2986 36.4 6.92 4.8 B. Sibai 17 Texas Two-Step Conference, Januar 9 - 10, 2015 Risks of attempted vaginal delivery • Prolonged labor in latent phase – Pain and suffering – Medications , multiple pelvic exams – Contractions, FHR monitors, catheters • Prolonged ROM in active phase – – – – Intermittent hypoxia : oxytocin, cord compression Epidural monitoring Chorioamnionitis, fetal infection Prolapsed cord • Prolonged second stage: Same as above • Delivery: Same as above plus – – – – – Fetal / pelvic trauma: Instrumental delivery Need for emergency C/S Shoulder dystocia Uterine atony, inversion : hemorrhage Endometritis, retained placental tissue, infertility Risks from attempted vaginal delivery Uterine Atony: PPH Maternal Trauma: 3rd, 4th degree tears Retained Placenta ; bleeding , infection Chorioamnionitis : bad for both mom and infant Fetal Infections Uterine Inversion/Rupture Fetal Trauma: Forceps , vaccum, prolonged 2nd stage Cerebral Palsy, HIE, Hypoxia, acidosis Shoulder dystocia, fractures, nerve injury Fetal Death Need for emergency crash C‐section End result of successful vaginal delivery 18 Texas Two-Step Conference, Januar 9 - 10, 2015 Vaccum assisted vaginal delivery Fractured clavicle Shoulder dystoscia from vaginal delivery Scars of attempted vaginal delivery are ugly Vulvar hematoma Vulvar necrotizing fascitis Vulvar hematoma Third degree tear Leeds Institute of Bioscience and Clinical Science Section of Obstetrics and Gynaecology 19 Texas Two-Step Conference, Januar 9 - 10, 2015 Cesarean scars can be beautiful Ethical Principles Can a planned C-section for an uncomplicated pregnancy be ethically justified? Beneficence Nonmaleficence Voracity Decision making based on Justice Autonomy Ethical Principles Patients retain a “negative right”: right to decline care • But do not hold a “positive right”:the right to demand care that may be unnecessarily risky or medically unproven • Physicians recommend C/S at 23 wk despite poor outcome • But not at term with 100% survival and excellent outcome 20 Texas Two-Step Conference, Januar 9 - 10, 2015 Autonomy Obligates the physician to discuss reasonable alternatives and elicit a decision within the framework of informed consent What is the information to give? Risks / benefits of planned C/S Risks / benefits of attempted vaginal delivery Planned C/S v labor with C/S if not successful Non-maleficence • This principle refers to physician’s obligation to do no harm to the patient – “First do no harm” – This works both ways • Is C/S more dangerous? • Is vaginal birth more dangerous? – How about harm to providers ? • May be sued for doing “unnecessary” vaginal birth – – – – Delayed C/S for non-reassuring tracing Traumatic breech delivery Traumatic shoulder dystocia Traumatic instrumental delivery Conclusions Available data, though not robust, suggest that overall maternal /perinatal mortality, short- and long-term maternal and neonatal and infant morbidity favor a planned cesarean delivery at 39 0/7 wk in those who are not yet in labor 21 Texas Two-Step Conference, Januar 9 - 10, 2015 What would men prefer vaginal delivery or C-section? 22 Texas Two-Step Conference, Januar 9 - 10, 2015 Should We Try to Decrease or Increase the Cesarean Delivery Rate? Vaginal Birth is not a Failed Cesarean: Reducing the Rate of Cesarean Delivery Clara Ward, MD Division of Maternal Fetal Medicine University of Texas Health Science Center Disclosures • No disclosures 23 Texas Two-Step Conference, Januar 9 - 10, 2015 What this talk is NOT http://www.nytimes.com OBJECTIVES • Extent • Evidence – Perceptions of benefit vs. harm • Economics – Consumerism – Quality reporting – Health care metrics • Ethics – – – – Informed consent Autonomy vs. paternalism Nonmaleficience/beneficience Distributive justice EXTENT 24 Texas Two-Step Conference, Januar 9 - 10, 2015 Trends in Cesarean Delivery Overall CS Primary CS VBAC 25 Texas Two-Step Conference, Januar 9 - 10, 2015 Primary Cesarean Rates • Multiparous: 11.5% of total c‐sections • Primiparous: 30.8% of total c‐sections • Of these 45% were in low risk women Boyle et al, Obstet Gynecol 2013 Indications for Primary Cesarean Delivery Boyle et al, Obstet Gynecol, 2013 Variation in Cesarean Section Rate • AHRQ database • Variation in CS rates – Reflects underuse or overuse – Suggests modifiable factors • 10 fold variation in overall CS rate (7‐70%) • 15 fold variation (2‐37%) in low risk women Kozhimannil et al, Health Aff, 2013 26 Texas Two-Step Conference, Januar 9 - 10, 2015 EVIDENCE Benefits of Cesarean Delivery • • • • • • Matter of Perception vs. Evidence Reduction in maternal harm (incontinence) Reduction in fetal harm (demise and injury) Surgical control Pain control Scheduling convenience Risk of Adverse Maternal and Neonatal Outcomes by Mode of Delivery ACOG‐SMFM Obstetric Care Consensus, March 2014 27 Texas Two-Step Conference, Januar 9 - 10, 2015 Complications of Cesarean Delivery • • • • • • • • • TOLAC/uterine rupture Thromboembolism Abnormal placentation Maternal surgical morbidity Respiratory complications in the newborn Recovery Pain Cost Risk accumulates with each cesarean section Reducing the Cesarean Section Rate • Decreasing primary cesarean section rate – Low risk women • • • • Nulliparous Term Singleton Vertex – High risk women • Increasing rate of trial of labor after cesarean Linear Relationship between hospital VBAC rate and low risk primary cesarean section rate Rosenstein et al, Obstet Gynecol 2013. 28 Texas Two-Step Conference, Januar 9 - 10, 2015 Self Fulfilling Prophecy of Cesarean Safe Prevention of the Primary Cesarean Delivery • • • • • Revisit definition of labor dystocia Standardized fetal heart rate interpretation Improving access to nonmedical interventions External cephalic version Trial of labor for twins 29 Texas Two-Step Conference, Januar 9 - 10, 2015 Defining labor dystocia Cesarean Sections Prior to Active Labor Boyle et al, Obstet Gynecol, 2013 Cesarean Sections in the Second Stage of Labor Boyle et al, Obstet Gynecol, 2013 30 Texas Two-Step Conference, Januar 9 - 10, 2015 Cesarean Sections for Suspected Macrosomia • Actual birth weights for neonates delivered by cesarean section for suspected macrosomia – 97.3% <5000 grams – 80.3% <4500 grams – 41.9% <4000 grams Boyle et al, Obstet Gynecol, 2013 Cesarean Sections for Twin Gestation • Twins – VTX‐VTX: 25% – VTX‐nonVTX: 25% – nonVTX presenting: 27% – Not recorded: 23% Boyle et al, Obstet Gynecol, 2013 Fetal heart rate interpretation 31 Texas Two-Step Conference, Januar 9 - 10, 2015 Interobserver variability of intrapartum FHR Chauhan et al, AJOG 2008. Potentially Modifiable Indications for Cesarean Section Spong et al, Obstet Gynecol 2012 Potentially Modifiable Indications for Cesarean Section Spong et al, Obstet Gynecol 2012 32 Texas Two-Step Conference, Januar 9 - 10, 2015 Potentially Modifiable Indications for Cesarean Section Spong et al, Obstet Gynecol 2012 • Success of TOLAC high • Risk of uterine rupture low • VBAC begets VBAC 33 Texas Two-Step Conference, Januar 9 - 10, 2015 In Perspective National Institutes of Health Consensus Development Conference Statement Vaginal Birth After Cesarean: New Insights March 8–10, 2010 NNT in the setting of TOLAC • Number of c‐sections needed to prevent ONE – Symptomatic uterine rupture: 370 – Uterine rupture related hysterectomy: 2941 – Uterine rupture related perinatal death: 7142 • Furthermore the difference between groups is so small… – It would take only one misclassified case to negate any difference Guise et al, BMJ, 2004 ECONOMICS 34 Texas Two-Step Conference, Januar 9 - 10, 2015 35 Texas Two-Step Conference, Januar 9 - 10, 2015 Financial Costs Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Health Care Policy and Research (US); 2006-2014 May. TOLAC TOLAC 36 Texas Two-Step Conference, Januar 9 - 10, 2015 Unquantified losses and costs • Increased recovery time • Implications for bonding and breastfeeding • Costs of sitters/food/parking for extra 2 days (or more) 37 Texas Two-Step Conference, Januar 9 - 10, 2015 Precedents • SCIP – Surgical Care Improvement Process – Initiated in 2003 – Surgery and anesthesia colleagues – Antibiotics prior to surgery, SCDs – Determines hospital accreditation and medicare reimbursement • SART – Society for Assisted Reproductive Technology – Annual reporting to CDC – Underperformance provokes formal improvement process ETHICS Challenge of Informed Consent 38 Texas Two-Step Conference, Januar 9 - 10, 2015 Most profound knowledge deficits • The majority of patients in both groups did not know the chance of success • Over half of the patients did not know the risk of rupture rate • Half of patients undergoing ERCD did not know recovery was longer • Half of patients undergoing ERCD did not know that risk increases with each cesarean section Provider influence • When patients felt their provider had a preference – 86% chose ERCD – 78% chose TOLAC • When patients did not perceive a provider preference – 50% chose ERCD and 50% chose TOLAC What Do Women Want? • Healthy outcomes • Preferences studies o >90% of women expressed preference for vaginal delivery o A stronger preference correlated with higher success rate 39 Texas Two-Step Conference, Januar 9 - 10, 2015 How do we Proceed? • Parties involved – Physician – Patient – Payers – Hospitals – litigation • Resources/expertise available • Data Æ assessment 40 Texas Two-Step Conference, Januar 9 - 10, 2015 How can we reduce the rate of cesarean section? • Support the patients – Expectation management – Doula support • Support the providers – Midwives – Hospitalists – Culture change – Medicolegal reform http://www.inhabitots.com Dr. Sibai Dr. Ward 41 Texas Two-Step Conference, Januar 9 - 10, 2015 Paatien nt Saafetyy Sto oriess: Lessson ns Le earned ffrom m Traagedy Sean Blacckwell, M.D. 42 Texas Two-Step Conference, Januar 9 - 10, 2015 Perinatal Safety Stories: Lessons Learned From Tragedy Sean C. Blackwell M.D. Chair, Department of Obstetrics, Gynecology and Reproductive Sciences Director, Larry C. Gilstrap M.D. Center for Perinatal and Women’s Health Research Assistant Dean for Healthcare Quality in Perinatal Medicine and Women's Health UT Health‐ University of Texas Medical School at Houston E‐mail: [email protected] 43 Texas Two-Step Conference, Januar 9 - 10, 2015 L&D Unit vs. Aircraft Carrier March 1‐March 28, 2014 CMH OB service TOTALS • What was the highest number of admissions in one 24 hour period? N= 32 • What was the highest number of births in one day? N= 24 • What was the highest number of cesarean deliveries done 7 am – 7 pm? N=13 (2 rooms) March 1‐March 28, 2014 CMH OB service • How many different attending physicians performed cesarean delivery? N=44 • Of these, how many did < 4 for the month (less than 1 per week)? N=10 44 Texas Two-Step Conference, Januar 9 - 10, 2015 March 1‐March 28, 2014 CMH OB service • How many different physicians worked on the OB service during this time? > 60 • How many different nurses worked on the OB service during this time? > 100 • How many total different patients were under our care over this time period? > 500 March 1‐March 28, 2014 CMH OB service TOTALS • In one shift (7 am‐7pm), how many different people work on L&D? • Not 1 doctor, 1 patient, and 1 nurse • In one shift (7am‐7pm), how many patients and their family members travel through our unit? • Perviable PTB • HELLP • Normal labor • PTC’s Nuclear Submarine & Safety 45 Texas Two-Step Conference, Januar 9 - 10, 2015 Nuclear Submarine = Pregnant woman • Expectation that those in charge (OB physician and nursing) will NOT fail • Adverse events (harm to pregnant woman or newborn child) = disaster We have 2 patients = Mother & unborn/newborn child Nuclear Submarine & Safety What do women desire/expect when they come to the hospital? 46 Texas Two-Step Conference, Januar 9 - 10, 2015 What do women desire/expect when they come to the hospital? 1. Do not harm me. 2. Treat my condition to make me better 3. Be nice What do women EXPECT when they come to TMC? What do women & families EXPECT from us? • Experts • Best practice • Leaders in Safety and Quality • Innovation 47 Texas Two-Step Conference, Januar 9 - 10, 2015 Case Presentation Initial Presentation • 27 y.o. Gravida 1 at 39w 0 d presents to OB triage • Contractions and vaginal spotting • Early prenatal care with private physician • Moved to Texas for OB care from Russia Clinical course • OB intern assessed patient • Bedside ultrasound = no previa • Called chief resident who evaluated patient after initial work up 48 Texas Two-Step Conference, Januar 9 - 10, 2015 April 21, 2014 @ 11:00 AM 180 150 120 April 21, 2014 @ 11:13 AM April 21, 2014 @ 11:20 AM 49 Texas Two-Step Conference, Januar 9 - 10, 2015 April 21, 2014 @ 11:27 AM April 21, 2014 @ 11:34 AM April 21, 2014 @ 11:41 AM 50 Texas Two-Step Conference, Januar 9 - 10, 2015 April 21, 2014 @ 11:48 AM April 21, 2014 @ 11:56 AM April 21, 2014 @ 12:00 PM 51 Texas Two-Step Conference, Januar 9 - 10, 2015 April 21, 2014 @ 12:01 PM April 21, 2014 @ 12:15 PM • SSE: approx 20 cc blood seen pooled in vaginal vault and evacuated digitally; no bleeding/LOF per os on valsalva. • Exam repeated under R4's supervision approx 10 minutes later, where minimal amount of blood was seen in vaginal vault protruding from cervix with clear‐yellow fluid and slight vernix seen leaking per os this time. Cervical os visibly closed. April 21, 2014 @ 12:23 PM Decision was made to admit patient for SROM in latent labor for augmentation with pitocin and clindamycin for GBS ppx. 52 Texas Two-Step Conference, Januar 9 - 10, 2015 April 21, 2014 @ 12:33 PM April 21, 2014 @ 12:37 PM April 21, 2014 @ 12:44 PM Cervix = 4 cm 200ml new bleed in L&D room 53 Texas Two-Step Conference, Januar 9 - 10, 2015 April 21, 2014 @ 12:51 PM Decision for CD At 12:46 CD AT 12:54 Presumed placental abruption Outcome • She was taken to the OR for suspected abruption. • Emergent cesarean was performed under GETA. • After delivery of the infant and placenta, the placenta was examined and it was noted that there was a velamentous cord insertion as well as vessels traveling through the membranes from one placental lobe to the other. Timeline Summary Time Event 4/21/14 11:00 AM Triage evaluation for vaginal bleeding and CTx 4/21/14 11:13 AM Evaluation by Junior resident, Concern for FHTs: “Difficult to interpret with a pseudo‐sinusoidal pattern/ Upper level called” Bedside US: No previa 4/21/14 11:18 4/21/14 11:44 Evaluation by senior resident: strip review Change in dilation noted: 0 ‐> 3 cm 4/21/14 12:22 Transferred to L&D for labor, SROM 4/21/14 12:40 Bradycardia, 200ml Fresh bleeding 4/21/14 12:46 Decision for CD 4/21/14 12:54 STAT CD 54 Texas Two-Step Conference, Januar 9 - 10, 2015 Outcome • Neonate handed to awaiting Neo team • “Ashen” white c/w exsanguination • Unable to insert umbilical lines to give volume • Expired at 25 minute of life Vasa Previa Definition: Vasa previa is a condition in which the umbilical vessels, unsupported by either the umbilical cord or placental tissue, traverse the fetal membranes of the lower segment above the cervix. Initial Summary • Causation due to undiagnosed vasa previa • From decision to delivery = 8 minutes • Undiagnosed vasa previa, the risk of fetal/neonatal death > 50% • “Nothing we could have done, inevitable adverse outcomes.” This is nature of obstetrics … 55 Texas Two-Step Conference, Januar 9 - 10, 2015 Evaluation of the Case • Review medical records including prenatal ultrasound reports • Interview with patient and family • Root cause analysis • M&M review Interview with Patient • Husband in oil business from Russia; moved to US for better health care. Then switched to UT physician to get best care in TMC. • Thought intern was student – Asked same questions x 3 (when is last time had sex) – Told “joke” about accent – Intern told patient she was going home, reversed by chief resident • Chief resident did “teaching” 5‐10 minutes in room – GBS treatment • After event, our physician team met with the patient. The husband’s interpretation of the discussion (< 20 minutes after newborn death), was that what was emphasized that “we” did nothing wrong and they could have another child Triage Dynamics • Intern issues – Intern was in 1st day of rotation; had not worked at TMC (from different hospital). – Intern had decided to leave OB for general surgery. – Just returned from leave for “burnout” • L&D triage nurse – Told intern that this was possible sinusoidal FHR strip – Told this to chief resident – Called her charge nurse and told her sinusoidal FHR and “be ready” • Chief resident – FHR fine and you are over‐reacting – She and triage nurse had history • No one called attending physician who was on floor and in lounge (2 min away) • Attending not involved until called to room for bradycardia and bleeding 56 Texas Two-Step Conference, Januar 9 - 10, 2015 RCA • Why didn’t call the attending physician ? – Residents “If I called for every abnormal FHR or problem then I would be talking to them a lot and not be in charge; plus they don’t want to know everything” – Nurses “Not my job” – Attending “If they call me too much they won’t learn” Swiss Cheese Theory What do we want & expect from you? 57 Texas Two-Step Conference, Januar 9 - 10, 2015 Assessment of Situation • WTF moment • Culture problem – Communication – Escalation – Accountability • Could this happen at your place? • How often are we just lucky (near miss)? • What would it take for you to be part of the solution vs. part of the problem? – Don’t be selfish 3 inescapable facts 1. No one tries to be unsafe. 2. OB is complex, fast, and requires team care. 3. Unrealistic (and impossible) for every physician and/or nurse to be an expert and/or current in everything related to OB. What do we want/expect from you? 1. Put the patient first 2. Don’t walk by a problem 3. Be nice 4. What we do matters (in a big way)…. Communication is the #1 reason for failures, not lack of expertise, mistakes, inexperience, etc. 58 Texas Two-Step Conference, Januar 9 - 10, 2015 Ram mificcatio ons o of Laapses in Detaail Duri D ng EEndo oscop pic SSurgery Mich hael B Baggissh, M.D. 59 Texas Two-Step Conference, Januar 9 - 10, 2015 INTERACTTIVE DEB BATEE: Rob boticc Surrgeryy forr GYN – Fad or the F t Future? Micchael Adlerr, M.D D. Saraa Holccomb be, D.O O. 60 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotics for Benign GYN Surgery: Fad or the Future? Michael Adler, M.D. and Sara Holcombe, D.O. Generalist Division UT‐Health Robotic Surgery ‐ Future Michael T. Adler, M.D. Assistant Professor Generalist Division – Ob/Gyn UT‐Health Disclosure • No relevant financial relationships with commercial interests related to the content of this presentation. 61 Texas Two-Step Conference, Januar 9 - 10, 2015 Objectives • Describe the benefits and risks associated with robotic gynecologic surgery. • List the procedures that are able to be completed via robotic surgery. Robotic Surgery • Goal: Perform the right surgery with the best possible outcome for the patient – Minimize complications – Minimize time in hospital – Minimize recovery time at home • Use the right tool for the job (Vaginal, Laparoscopic, Open?) Robotic Surgery 62 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery • The da Vinci Robot (Intuitive Surgical,Inc.) is a valuable tool and will continue to be valuable in the future Robotic Surgery Robotic Surgery ‐ Background • Early robotic platforms (AESOP, HERMES, ZEUS) • Da Vinci commercially available for Gynecologic Surgery since 2005 (FDA Approved – April, 2005) • 1.5 million procedures in various specialties completed to date • Currently fourth generation of da Vinci Surgical Platform 63 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery ‐ Background • Gynecologic surgery • Cardiac Surgery • Urologic surgery • Thoracic Surgery • General Surgery • Head and Neck Surgery Robotic Gyn Procedures Hysterectomy Myomectomy Endometriosis Adnexal surgery (oopherectomy, cystectomy, salpingectomy) • Sacrocolpopexy/vault suspension • Oncology procedures, lymphadenectomy • • • • Robotic Surgery ‐ Benefits • Approx. 600,000 hysterectomies/year – Rate of open hysterectomy? • Robotics may allow minimally invasive approach – – – – – Shorter hospital stay Decreased blood loss Fewer complications Less narcotic usage Faster recovery with smaller scars 64 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery ‐ Benefits • Compared to traditional laparoscopy: – Improved dexterity of instruments (Endo‐wrist) • Improved precision vs loss of tactile feedback • Elimination of unintended hand movement – – – – – Excellent visualization: 3D HD camera system Ergonomics, surgeon fatigue Obese patients Less need for skilled assistant Decreased learning curve Robotic Surgery – Learning Curve • Robot does not eliminate need for good judgment and appropriate patient selection for selected procedure • Walk before you run! • Need for structured training and credentialing Robotic Surgery – Learning Curve 65 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery ‐ Training • AAGL Credentialing/Privileging Guidelines • Initial Training – Train surgeons with adequate case volumes to get through learning curve – More intense validated simulation training – Perform simple/basic procedures with proper supervision before attempting more complex cases (protoring) Robotic Surgery ‐ Training • Annual Currency – Perform at least 20 procedures annually, with at least one case every 8 weeks – If operate less, then proficiency should be demonstrated on simulator • Annual Recertification – Demonstrate proficiency regardless of case volume Robotic Surgery ‐ Cost 66 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery ‐ Cost • • • • High initial investment Replacement of instruments Maintenance Longer operating times? Will Robotic Surgery continue to be a financially viable option in the future? Robotic Surgery ‐ Cost • Statement by ACOG President James T. Breeden (March 3, 2013) – “Robotic surgery not the only or best minimally invasive approach for hysterectomy. Nor is it the most cost‐efficient.” – “Studies show there is a learning curve with new surgical technologies, during which there is an increased complication rate.” – “…The use of expensive medical technology should be questioned when less costly alternatives provide equal or better patient outcomes.” – “It is important to separate the marketing hype from reality when considering the best surgical approach for hysterectomies.” http://www.acog.org/About‐ACOG/News‐Room/News‐ Releases/2013/Statement‐on‐Robotic‐Surgery Robotic Surgery • Letter of Response: – At their peak, vaginal and laparoscopic approaches performed in only slightly > 1/3 of patients despite availability for decades – Despite widespread and prolonged availability, neither has reduced the laparotomy rate – Multitude of studies comparing learning curve robotic cases to steady‐state laparoscopic cases, which substantially skew the results. 67 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery • Letter of Response: “The facts are unassailable: despite widespread availability…… for decades, neither materially impacted the laparotomy rate. Robotic surgery, in a fraction of that time, has enabled minimally invasive surgery for nearly every one of our patients, and >100,000 more women were offered minimally invasive hysterectomy in 2012 as compared to 2005 as a direct result of the robotic platform. The relevant comparator is laparotomy, not vaginal or laparoscopy.” Robotic Surgery “Is she being offered a minimally invasive approach? The data indicates that prior to Robotic Surgery that was not the case for the majority of women. This carries a substantial cost benefit to the patient and to society which has not been acknowledged.” http://www.businesswire.com/news/home/20130316005039/en/Minimally‐Invasive‐ Surgeons‐Group‐Responds‐ACOG‐Presidents#.VI4ibmd0zIU Robotic Surgery AAGL Position Statement: Robotic‐Assisted Laparoscopic Surgery in Benign Gynecology • Robotic‐assisted laparoscopic surgery should not replace conventional laparoscopic or vaginal procedures for women who could otherwise undergo conventional laparoscopic or vaginal surgery for benign gynecologic diseases. • Efforts should be focused on the proper credentialing and privileging of surgeons to utilize robotic surgical systems as a means to minimize cases otherwise performed by laparotomy. • Additional research is needed. 68 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery Responsible for decrease in vaginal hysterectomy? Any procedure performed robotically, can be performed via laparoscope or vaginal route? Robotic Surgery Robotic Surgery 69 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery • Deja‐Vu? – Traditional laparoscopy initially criticized • • • • • Dangerous and unproven Expensive Longer operating times Unnecessary “Unethical” Robotic Surgery for GYN surgery: Fad or the Future Michael Adler, M.D. and Sara Holcombe, D.O. Generalist Division UT‐Health Robotic Surgery ‐ Fad Sara B. Holcombe, D.O. Assistant Professor, Generalist Division 70 Texas Two-Step Conference, Januar 9 - 10, 2015 Disclosures • I do not have relevant financial relationships with commercial interests related to the content of this presentation. FAD noun \`fad\ : something (such as an interest or fashion) that is very popular for a short time : a practice or interest followed for a time with exaggerated zeal : CRAZE Robotic Surgery in Gynecology • 1990 First robot approved by FDA • 2000 daVinci Surgery System – 10 updates released since – Rates of use increasing 71 Texas Two-Step Conference, Januar 9 - 10, 2015 Point 1 • With the rapid increase in robotic‐assisted hysterectomy we are seeing a decline in vaginal hysterectomy. 72 Texas Two-Step Conference, Januar 9 - 10, 2015 Green Journal, 2013 • Cohort of 7,438,452 women underwent hysterectomy • 1998 ‐ 2010 • Nationwide Inpatient Sample – random sample of 20% of discharges from all hospitals in the U.S. • Results: Decline in all other routes of hysterectomy Wright T, Herzog T, Tsul J, et al. Nationwide trends in inpatient hysterectomy in the United States. Obstet Gynecol. 2013:122(2):233‐241. Route of Hysterectomy Robot 8.2% Lap 10.6% Lap 8.6% Vag 24.8% 1998 Abd 65% Vag 16.7% 2010 Abd 54.2% Wright T, Herzog T, Tsul J, et al. Nationwide trends in inpatient hysterectomy in the United States. Obstet Gynecol. 2013:122(2):233‐241. 73 Texas Two-Step Conference, Januar 9 - 10, 2015 JAMA, 2013 • 264,758 women, 441 hospitals, 2007 – 2010, hysterectomy • Malignancy excluded • Hospitals where robotic hysterectomy available: – Massive increase in robotic hysterectomy and decline in all other forms (vag, lsc, abd) • Hospitals with no robot – Decline in both vaginal and abdominal but increase in laparoscopic 74 Texas Two-Step Conference, Januar 9 - 10, 2015 Point 1 • Increasing robotic hysterectomy leads to decrease in vaginal hysterectomy • Evidence: 2 recent large cohort studies with supporting data 75 Texas Two-Step Conference, Januar 9 - 10, 2015 Point 2 • Robotic‐assisted gynecologic surgery is too expensive. Cost • • • • • • Approximately $2 million initial Hundreds of thousands annually Robotic arm replacements after 10 uses OR time? Lifespan of robot? Versus laparoscopy, costs of robotic‐assisted hysterectomy are 16‐34% higher Wright, Jason D. et al. “An Economic Analysis of Robotically Assisted Hysterectomy.” Obstetrics and gynecology 123.5 (2014): 1038–1048. Green Journal, 2014 76 Texas Two-Step Conference, Januar 9 - 10, 2015 Cost Laparoscopic ($) Robotically Assisted ($) P Cost Differential ($) Total cost 6,535 8,152 <0.001 1,617 Variable cost 2,965 3,591 <0.001 626 Fixed cost 3,440 4,384 <0.001 944 Wright, Jason D. et al. “An Economic Analysis of Robotically Assisted Hysterectomy.” Obstetrics and gynecology 123.5 (2014): 1038–1048. Cost • Does cost decrease as surgeon and hospital volume increases? Surgeon Volume Hospital Volume Wright, Jason D. et al. “An Economic Analysis of Robotically Assisted Hysterectomy.” Obstetrics and gynecology 123.5 (2014): 1038–1048. 77 Texas Two-Step Conference, Januar 9 - 10, 2015 Point 2 • Robotic hysterectomy is 16 – 34% more expensive than laparoscopy. • 40‐50% more expensive than vaginal hysterectomy! Wright, Jason D. et al. “An Economic Analysis of Robotically Assisted Hysterectomy.” Obstetrics and gynecology 123.5 (2014): 1038–1048. Woelk, JL, et al. “Cost Differences Among Robotic, Vaginal, and Abdominal Hysterectomy.” Obstetrics and gynecology 123.2 (2014): 255-262. Does the evidence support the expense? 78 Texas Two-Step Conference, Januar 9 - 10, 2015 Point 3 • Robotic‐assisted gynecologic surgery has not been proven to improve patient outcomes. Cochrane, 2012 2 RCTs, 158 patients Robotic versus laparoscopic hysterectomy Comparable rates of conversion to laparotomy Analysis showed longer OR time and higher cost in robotic group (MD 66.00, 95% CI; P < 0.00001; MD 1936.00, 95% CI; P = 0.01) • SAME outcomes, complications, LOS, quality of life • • • • JAMA, 2013 • Retrospective cohort 264,758 women, hysterectomy for benign indication • Robotic versus laparoscopic hysterectomy – No significant difference in complications (5.5% vs 5.3%) – No significant difference in transfusion rates (1.4% vs 1.8%) – Robotic‐assisted less likely to have LOS > 2 days (19.6% vs 24.9%) 79 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotics Offers No Benefit Compared to Conventional Laparoscopy “Robotic‐assisted laparoscopic surgery should not replace laparoscopic or vaginal procedures… for benign gynecologic diseases.” “At a time when there is a demand for more fiscal responsibility and transparency in health care, the use of expensive medical technology should be questioned when less costly alternatives provide equal or better patient outcomes.” 80 Texas Two-Step Conference, Januar 9 - 10, 2015 Point 3 • Robotic‐assisted gynecologic surgery has not been proven to improve patient outcomes. • Need further studies to support the continued use of this expensive technology. Some other things to consider… • Marketing • Haptics • Training 81 Texas Two-Step Conference, Januar 9 - 10, 2015 “Aggressive direct‐to‐consumer marketing of the latest medical technologies may mislead the public into believing that they are the best choice. Our patients deserve and need factual information about all of their treatment options, including costs, so that they can make truly informed health care decisions.” “It is important to separate the marketing hype from the reality when considering the best surgical approach for hysterectomies.” 82 Texas Two-Step Conference, Januar 9 - 10, 2015 • 432 hospital websites analyzed • 44.4% contained marketing for robotic gyn surgery • Most sites reported “improved perioperative outcomes” • Limitations of robots including cost, complications, and operative time were discussed only 3.7%, 1.6%, and 3.7% of the time • Guidelines for privileging for robotic‐assisted gynecologic laparoscopy, 2014 – Initial training – Annual currency – Annual recertification Guidelines for privileging for robotic‐assisted gynecologic laparoscopy. J Minim Invasive Gynecol. 2014;21(2):157–167. Some other disadvantages • • • • Absence of tactile sensation Special staff Larger OR More incisions 83 Texas Two-Step Conference, Januar 9 - 10, 2015 Robotic Surgery Pro Con Bottom Line • Any operation that can be done with the robot can be done with the laparoscope in: – Less time – Less money – Same outcomes Turning Fad into Future • Need high quality studies showing patient benefit • More cost efficient • Rigorous training guidelines • Don’t abandon preferred route of hysterectomy 84 Texas Two-Step Conference, Januar 9 - 10, 2015 Dr. Holcombe Dr. Adler 85 Texas Two-Step Conference, Januar 9 - 10, 2015 W Whaat Evvery OB//GYN N Should d Know abou a ut Hospiital O Operatio ons Anthony Johnson, D D.O. 86 Texas Two-Step Conference, Januar 9 - 10, 2015 What Every Ob/Gyn Needs to Know About In Utero Fetal Surgery Anthony Johnson, D.O. Professor of Obstetrics and Gynecology Professor of Pediatric Surgery University of Texas School of Medicine at Houston Co-Director The Fetal Center Children’s Memorial Hermann Hospital Disclosures • Receive royalty payments for authorship of the twin twin transfusion syndrome chapters in UpToDate® • Have no Off-Label disclosures Objectives • Describe the current diagnoses that would be eligible for in utero fetal surgery • Discuss the various research activities regarding in utero surgery with specific diseases 87 Texas Two-Step Conference, Januar 9 - 10, 2015 Current Therapy Offered • • EXIT procedure Open fetal surgery for certain lessions (CCAM, sacrococcygeal teratoma & fMMC) • Placental laser ablation for TTTS • Selective reduction for discordant fetal anomalies in MC twins • Shunt placement (thoracic/urinary) • Intrauterine transfusions Future Therapy Offered • • • • • Tracheal occlusion for diaphragm hernia (FETO) Invasive fetal cardiac therapy Placental laser ablation in TAPS & sIUGR Robotic surgery for fMMC or gastroschisis? Fetal stem cell transplant Definition of Maternal-Fetal Surgery • Operating on two patients simultaneously where both incur risks • Benefits to mother probably not medically definable • Opportunity to correct a surgically-treatable lesion or diminish its sequelae 88 Texas Two-Step Conference, Januar 9 - 10, 2015 Myelomeingocoele (fMMC) The prevalence of spina bifida in Texas 3.52 per 10,000 live births Canfield MA, et al Paediatr Perinat Epidemiol. 2009 Jan;23(1):41-50. 89 Texas Two-Step Conference, Januar 9 - 10, 2015 Normal sheep spine Spina bifida @ 75 days Followed by closure @ 100 days Spina bifida @ 75 days w/o closure Meuli et al. J Pediatr Surg 1996;31:397-402 In utero repair ~ neurologic rescue Historical Perspectives •1994: Bruner attempts laparoscopic repair of NTD (4 cases performed before stopping) • 1998: Tulipan reports open repair at 28-30 weeks gestation in 4 fetuses – All with absent hindbrain herniation at birth – 2 required ventricular shunts • 244 open cases; • 170-VUMC, 52-CHOP, 12-UCSF & 10 -UNC • NIH consensus Am J Obstet Gynecol 1997;176:256-7; Pediatr Neurosurg 1998;29:274-8 90 Texas Two-Step Conference, Januar 9 - 10, 2015 Feb 2003 – Dec 2010 $22.5 million MOMS Inclusion Criteria (maternal) • • • • • • Singleton pregnancy Gestational age at randomization of 190/7 to 256/7 weeks Maternal age > 18 years Body mass index < 35 No previous uterine incision in the active uterine segment No risk factors for preterm birth (short cervix, history of previous preterm delivery) MOMS Exclusion Criteria (maternal) • Insulin-dependent diabetes • Infection with hepatitis B or C • HIV infection • Red cell/platelet alloimmunization • Unwillingness to accept blood transfusions for religious or other reasons 91 Texas Two-Step Conference, Januar 9 - 10, 2015 MOMS Inclusion Criteria (fetal) • fMMC defect between levels T1 to S1 • No evidence of kyphosis (curved spine) • No major fetal anomaly unrelated to the spina bifida • Normal chromosomes by amniocentesis 92 Texas Two-Step Conference, Januar 9 - 10, 2015 MOMS Outcomes (12 months) Outcome Fetal surgery Postnatal surgery 68% 98% Primary outcome Death 2 2 Shunt criteria met 65% 98% Shunt placement 40% 82% Any hindbrain herniation 64% 96% MOMS Outcomes (30 months) Outcome Fetal surgery Postnatal surgery Bayley MDI 89.7 + 14.0 87.3 + 18.4 ∆ motor/anat level 0.58 + 1.94 ‐0.69 + 1.99 32% 12% 42% 21% > 2 levels higher Walking independently MOMS Outcomes (Maternal) Fetal surgery Postnatal surgery Membrane separation Outcome 26% 0% Rupture of membranes 46% 8% Pulmonary edema 6% 0% Abruption 6% 0% Infection 3% 0% Decreased amniotic fluid 21% 4% Status of uterine incision at delivery Very thin 25% Partial separation 10% 93 Texas Two-Step Conference, Januar 9 - 10, 2015 MOMS Outcomes (Neonatal) Outcome Gest Age (wks) Fetal surgery Postnatal surgery 34.1 + 3.1 37.3 + 1.1 < 30 wks 13% 0% 30 – 34 wks 33% 5% 33% 2383 + 688 8% 3039 + 469 21% 6% 35 – 36 wks Birthweight (gms) Respiratory distress syndrome 1 in 5 delivered at term MOMs Centers Current U.S. Centers 94 Texas Two-Step Conference, Januar 9 - 10, 2015 Outcomes The Fetal Center Cohort (N = 22) MOMS Trial (N = 78) Gestational age at Surgery 24.8 ± .8 23.6 ± 1.4 Gestational age at Delivery 34.2 ± 3.4 34.1 ± 3.1 Delivery < 30 weeks 2 (9%) 10 (13%) Delivery 30 ‐ 34 weeks 9 (41%) 26 (33%) Delivery 35‐36 weeks 4 (18%) 26 (33%) Delivery ≥ 37 weeks 7 (32%) 16 (21%) Perinatal Death VP Shunt at 1 year 1 (5%) 2 (3%) 8/14 (57%) 31 (40%) fMMC Repair • Open in utero surgery for fMMC is not a cure or a panacea • Selection of appropriate candidates is essential • New centers providing fMMC repair should follow MOMs protocol until comparable safety and efficacy is established with expansion of sites. • Focus on reducing maternal and fetal risks – Fetoscopic access – Membrane Healing/Scaffold ~ “fix the flat” 26% membrane separation 46% PPROM 80% PTD < 36 weeks NEXT PREGNANCY 14% rupture 14% dehiscence 95 Texas Two-Step Conference, Januar 9 - 10, 2015 Current Approaches • Coverage with patch 9 What is the correct material ¾ Will it adhere to the underlying dura (tethered cord in future)? ¾ Will it allow for overgrowth of skin or will it require revision after birth? • Operating in CO2 environment 9 Damage to fetal membranes 9 Fetal acidosis Kohl et al. Surg Endos 2010;24:432-44 Dermafill® with underwater adhesive coacervate Amnioguard® with suture A B A B C D C D 96 Texas Two-Step Conference, Januar 9 - 10, 2015 Results Dermafill® + UAC Amnioguard® with suture Twin-twin transfusion 97 Texas Two-Step Conference, Januar 9 - 10, 2015 Twin Twin Transfusion Syndrome Diagnosis Single placenta with thin dividing membrane Polyhydramnios (8cm) / oligohydramnios (2cm) Concordant for sex +/- Discordant size Monochorionic Twins/ TTTS Staging Stage 1 Donor MVP <2 cm; Recipient MVP >8-10 cm 14 cm Stage 2 Absent bladder in donor twin; normal Doppler studies Monochorionic Twins/ TTTS Staging Umbilical Artery Donor Umbilical Vein Recipient Ductus Venosus Middle Cerebral Artery 98 Texas Two-Step Conference, Januar 9 - 10, 2015 Monochorionic Twins/TTTS Staging Stage 4 Stage 5 One or both fetuses have died Laser Photocoagulation Laser vs. Amnio for TTTS RR = 2.04 A B C D 99 Texas Two-Step Conference, Januar 9 - 10, 2015 TTTS Neurologic Outcome Author N Percent follow-up Age @ follow-up Normal Minor abnormal Major abnormal Salomon 73 96% 60 mo 84% — 16% Rossi 895 96.8% Birth * 94% — * 6% 1255 96.8% 6-48 mo # 89% — # 11% • No difference between donor and recipient Salomon et al. Am J Obstet Gynecol 2010;203:444.e1-7 Rossi et al. Obstet Gynecol 2011;118:1145-50 Laser Criteria • 16 – 26 weeks gestation • Stage II – stage IV TTTS • Stage I TTTS with the following additional conditions: 9symptomatic polyhydramnios 9shortening cervix 9cardiac dysfunction in recipient twin RCT Stage 1 TTTS Laser vs. Observations Laser Centers 100 Texas Two-Step Conference, Januar 9 - 10, 2015 Diaphragm Hernia R Lung L R X X L 101 Texas Two-Step Conference, Januar 9 - 10, 2015 Diaphragm Hernia (LHR Ratio) LHR = Transverse area of contralateral lung Head circumference (mm) Diaphragm Hernia (LHR Ratio) LHR Liver N Survival > 1.4 NA 10 80% 1.0 – 1.4 ↓ 7 71% ↑ 7 57% ↓ 12 42% ↑ 17 6% < 1.0 Fetoscopic Tracheal Occlusion (FETO) Deprest, et al. Ultrasound Obstet Gyn 24:121, 2004 102 Texas Two-Step Conference, Januar 9 - 10, 2015 Diaphragm Hernia • 26 – 28 weeks’ gestation • General maternal anesthesia • IM fetal pancuronium, atropine, • • fentanyl 1.2 mm scope; 0.8 ml balloon Remove at 34 weeks Deprest et al. Semin Perinatol 2005;29:94-103 Fetoscopic tracheal occlusion for diaphragm hernia (FETO) Severe Diaphragm Hernia* • 210 cases • 47% PPROM – median: 30 days post-procedure – within 3 wks of procedure: 17% – Gest age at delivery: 35.3wks (30% @ < 34 wks) • 10 neonatal deaths related to balloon removal • Overall survival – L sided: 24% → 49% – R sided: 0% → 35% Jani et al. Ultrasound Obstet Gynecol 2009;34:304-10 *LHR < 1 w/ liver herniation 103 Texas Two-Step Conference, Januar 9 - 10, 2015 TOTAL TRIAL TRACHEAL OCCLUSION TO ACCELERATE LUNG GROWTH) Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) vs. Expectant Management During Pregnancy in Fetuses with Isolated Left Sided Diaphragmatic Hernia TOTAL Trial • Moderate disease 9 Left sided CDH 9 LHR 25 – 35% O/E or 35 – 45% w/liver up 9 Outcome: pulmonary function at 6 months of age • Severe disease 9 Left sided CDH 9 LHR< 25 % O/E 9 Outcome: Survival US FETO Consortium Philadelphia, Baltimore, Cincinnati, Houston, Denver & San Francisco FDA IDE ~ 2015-16 Fetal Stem Cell Amniocentesis • Mesenchymal stem cells harvested from amniotic fluid • Bioengineering to form allograft •Tendon •Muscle •Skin •Cartilage •Bone • Avoids ethical controversy associated with abortion Isolated MSC 1.8% Cultured cells Biodegradable scaffold D Fauza, Children’s Hospital Boston 2007 104 Texas Two-Step Conference, Januar 9 - 10, 2015 Fetal Stem Cell Tissue Bioengineering Congenital Diaphragm Hernia D Fauza, Children’s Hospital Boston 2007 Time Line for Future Events in Fetal Intervention Open Fetal Surgery Fetoscopic Surgery Fetal Tissue Engineering Fetal Stem cell & Gene Tx Fetal Therapy CDH with Liver Herniation 1980 1990 2000 2010 2020 In Utero Maternal-Fetal Surgery 1 year post in utero fMMC repair “Proceed with caution…and enthusiasm” Thank you for you attention 105 Texas Two-Step Conference, Januar 9 - 10, 2015 Majo M or Comp plicaation ns fro om Inap I pprop priatte G Gynecolo ogic Laparosscop pic Proceedurres Mich hael B Baggissh, M.D. 106 Texas Two-Step Conference, Januar 9 - 10, 2015 Major Complications from Inappropriate Gynecologic Laparoscopic Procedures Michael Baggish, M.D. St. Helena’s Women’s Center San Francisco, Calif. CONSEQUENCE OF ENDOSCOPIC SURGICAL ERRORS • INJURY TO THE PATIENT AND UNFAVORABLE, UNEXPECTED OUTCOME. • INEVITABLE MALPRACTICE SUIT. • LETTER REQUESTING MEDICAL RECORDS SIGNED BY PATIENT. • M.D. NEEDS TO NOTIFY MALPRACTICE INSURANCE CARRIER PROMPTLY. SIGNIFCANT INJURIES • Retroperitoneal Great Vessel Punctures/Lacerations • Small or Large Bowel Perforation • Bladder Laceration/ Ureteral Burn, Tear, Ligation • DEATH 107 Texas Two-Step Conference, Januar 9 - 10, 2015 STANDARD OF MEDICAL CARE • AN ACCEPTABLE STANDARD OF MEDICAL OR SURGICAL CARE • IS DEFINED AS: THE REASONABLY EXPECTED OUTCOME WHEN PERFORMED BY A SIMILARLY TRAINED PERSON IN THE SAME SPECIALTY ACTING IN A PRUDENT MANNER Progression of a Lawsuit Expert Witnesses are retained Medical records are reviewed Affidavit of merit is produced Discovery Initiated Depositions begin with the defendant and then the plaintiff • The defense side completes depositions first including the plaintiff’s expert then the plaintiff deposes the defense expert (s) and fact witnesses • Experts testify relative to: Causation, Standard of Care,and Damages. • • • • • Costs to initiate malpractice suits • An average cost to plaintiff’s attorney amounts $100,000. Defense may spend more. • Occasionally before a trial ends a High‐Low agreement is reached with the insurance carrier • Sometimes a jury is hung triggering a mistrial • On average 75% of verdicts are in favor of the defense 108 Texas Two-Step Conference, Januar 9 - 10, 2015 GOOD HABITS • Diictate or write details of informed consent. • Include drawings AND GET PATIENT TO SIGN HER UNDERSTANDING. • Get data of past surgery and other treatments • Dictate detailed op notes and specify when and how the ureter and bowel were inspected for injury • Give details about alternative treatments insituted and offered prior to surgery HOW TO AVOID MALPRACTICE LITIGATION • Do not take unnecessary chances • Always provide alternatives to surgery and document • Always provide a detailed consent and document • Dictate a detailed op note with specific notation of bowel and ureter inspection • Act promptly when pathway deviates from normal ENERGY DEVICES More or less required for laparoscopic and hysteroscopic surgery Know the physics and tissue interaction of electrosurical and ultrasonic devices MD is obligated to prevent unintended thermal injury Standard of care focuses on injury recognition 109 Texas Two-Step Conference, Januar 9 - 10, 2015 Minimally Invasive Non‐Hysteroscopic ENDOMETRIAL ABLATION • Most are thermal and many instill liquid • Perforation with heat=bowel burn/perforation • Safety features to detect leakage of fluid or gas not fool‐proof • If an indicator indicates fluid or gas loss STOP IMMEDIATELY. • Any perforation with thermal component = • abdominal exploration ADHESIONS • Prior abdominal surgery equates to presence of adhesions • Multiple prior abdominal operations means more adhesions • Subumbilical entry in presence of adhesions=russian roulette • Do not hesitate to convert to an open procedure ADVANTAGES OF LAPAROSCOPY • • • • • • • Minimally invasive Up close magnification Rapid recovery Minimal adverse cosmetic effect Less post op pain Early discharge More rapid return to normal activities 110 Texas Two-Step Conference, Januar 9 - 10, 2015 DISADVANTAGES OF LAPAROSCOPY 2 dimensional viewing—poor depth percep. Limited angles for manipulation of structures Requires trocar entry No tactile sensation Additional peculiar risks beyond beyond operative procedure • Suturing difficult and time consuming • • • • • POST OP ASPECTS • PATHWAY FOR LAPAROSCOPY=PROGRESSIVE IMPROVEMENT Post op problems require face to face eval.(avoid telephone Dx and Rx.) Differentional diagnosis should start with a complication of the just completed surgery Early diagnosis is key to rectify complication(s) Tests: cbc with diff. elec, creatinine, ct scan KNOWLEDGE OF PELVIC ANATOMY • Relationships of pelvic and abdominal • Know how to safely gain entry to retroperitoneum • topographical 111 Texas Two-Step Conference, Januar 9 - 10, 2015 112 Texas Two-Step Conference, Januar 9 - 10, 2015 Obturator neurovascular bundle Umbilical vessels Uterine vessels Vaginal vessels Inferior vesical vessles Anterior division of hypogastric artery Urethra Ureter Obturator internus muscle Vagina Posterior division of hypogastric artery Common iliac artery and vein Ureter Levator ani Iliolumbar vessels Rectum Arcus tendineus fascia pelvis (white line) L 4-5 Sciatic nerve Lumbosacral nerve trunk (L 4-5) Hypogastric vessels Ischial spine Superior gluteal vessels S1 Inferior gluteal vessels Internal pudendal vessels 113 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE ONE 50 year old woman with BMI 25 and strong family history of breast and ovarian cancer BRCA mutation positive Scheduled for prophy BSO via robotic laparoscopy 11‐26‐09 Incision several cm above umbilicus Veress needle inserted and pressure to 17 mm hg 114 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 1 (CONT) A 28 cm long disposable trocar thrust through anterior abdominal wall. Camera attached and intra‐peritoneal location confirmed 2 additional trocars under direct vision Anes. Reports precip. Drop BP End tidal CO2 also drops Surgeon views and sees blood in paracolic gutter CASE 1 (CONT) • Anes. advises no BP and EKG shows pulseless activity • Pneumo evacuated and trocar tip has blood on it and it is secured • Stat laparotomy performed (4 minutes since BP drop) • CPR simultaneously started with laparotomy • A large retroperitoneal hematoma above aortic bifurcation and Inf.vena cava CASE 1 (CONT) Gen. Surg. Called finds clotted and liquid blood on opening retroperitoneum Vascular Surgeon scrubs‐in and finds 1.5 cm. lacer of distal aorta Cell saver called for and 12,000 ml. blood loss recorded Aorta and common iliacs cross clamped Through and through lacerations of aorta sewn with 5‐0 prolene. Aorta very narrowed 115 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 1 (CONT) • Decision to replace distal aorta and 14 mm dacron graft anastomosed • More retroperitoneal bleeding noted • Laceration of inferior mesenteric repaired • Numerous small venous bleeding controlled • Intestine inspected and hole in transverse colon identified • General surgeon who had scrubbed out recalled to repair perforation. Perforated segment resected and divided stapled colon dropped back because it was dusky CASE 1 (CONT) Patient very unstable hypotensive and coagulopathic Abd. Packed and covered with sterile cassette film, towels cover open wound Patient to PACU guarded condition While in ICU BP drops and back to OR Bleeding from right common iliac controlled with 5‐0 prolene CASE 1 (CONT) • Nov.27 (day after surg) returned to OR for 3rd time • Bilateral S&O and transverse colostomy • Bcause of colonic injury vascular surgeon feels graft contaminated • Returns to OR for 4th time; graft taken down and left femoral autograft taken and reconstructive conduit created for terminal aorta • Three additional procedures to repair anterior abdominal wall with mesh • Mesh infected and removed • After a month in hospial patient transferred to long term care facility 116 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 1 (CONT) • Patient suffers long term neurologic inury from prolonged hypoxia • Continues to require supportive care • Incidentally she is a doctors wife 117 Texas Two-Step Conference, Januar 9 - 10, 2015 ANALYSIS OF CASE ONE • • • • Causation ? Standard of Care ? Damages ? Verdict ? 118 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 2 • 36 year old woman para 3‐0‐0‐3 youngest 11 mos. • 5 ft. 2 inches; 209 lbs; BMI greater than 30. • Procedure scheduled in free standing physician owned surgicenter in rural community • Plan: Hysteroscopy, D&C, Laparoscopic BPS • Diagnosis: Irreg. Blding, elective sterilization CASE TWO (CONT) • HYSTEROSCOPY DONE FOLLOWED BY UNEVENTFUL D&C • HUMI CANULA PLACE IN UTERUS • SUBUMBILICAL INCISION FOLLOWED BY VERESS NEEDLE • 3.5 L CO2 INSUFFLATED • DISPOSABLE 11‐12 MM TROCAR THRUST • LAPAROSCOPE INSERTED AND FAT VIEWED CASE TWO (CONT) • REPEAT TROCAR THRUSTS X 2‐SAME RESULT • EXTRA LONG TROCAR OBTAINED AND THRUST AND PERITONEAL CAVITY ENTERED (4TH TRY) • UTERUS AND ADNEXA NORMAL; 5 MM TROCAR PLACED SUPRAPUBICALLY AND BLUNT PROBE INSERTED • BOWEL MOVED AND BLOOD SEEN; FIELD BECOMES UNCLEAR 119 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE TWO (CONT) • BLUNT PROBE OUT AND BLOOD SPURTS FROM SUPRAPUBIC SITE • ALL TROCARS REMOVED • STAT LAPAROTOMY DONE VIA PFANNENSTIEL INCISION‐BELLY FULL OF BLOOD • 2 GENERAL SURGEONSCALLED AND SCRUB. A VERTICAL INCISION IS MADE • PATIENT SEVERLY HYPOTENSIVE CASE TWO (CONT) • SURGEONS DESCRIBE BLOOD EMITTING THROUGH A HOLE IN THE PERITONEUM OVERLYING THE VENA CAVA AND AORTA; ALSO A LARGE RETROPERITONEAL HEMATOMA • NO BLOOD IN SURGICENTER • NEAREST BLOOD BANK 45 MINUTES AWAY • CAR SENT FOR BLOOD CASE TWO (CONT) • SURGEONS WORK TO SUTURE TO SUTURE PERFORATION IN “VENA CAVA” FOR 2 ½ HOURS • 2 UNITS OF BLOOD ARRIVE VIA CAR RUNNER THE PATIENT IS TRANSPORTED TO LOCAL HOSPITAL (10‐15 MINUTES AWAY AFTER ACRIMONIOUS ARGUMENTS BETWEEN SURGICENTER AND LOCAL HOSPITAL 120 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE TWO (CONT) ARRESTS IN AMBLANCE AND RESUSCITATED ANOTHER 2 UNITS OF BLOOD IN AMBULANCE ARRIVES AT LOCAL HOSPITAL ER ARRESTS SECOND TIME AND DIES MEDICAL EXAMINER: DEATH SECONDARY TO EXSANGUINATION • POST MORTUM REVEALS LACERATIONS OF RIGHT COMMON ILIAC ARTERY AND VEIN • NO SUTURES FOUND IN THESE VESSELS • • • • • SUMMATION • • • • Causation ? Standard of Care ? Damages ? Verdict? CASE 3 • 37 YEAR OLD WOMAN; HXOF HYSTERECTOMY, • ADHESIOLYSIS, STERILIZATION, CHOLECSTECTOMY • RECENTLY UNDERWENT LAPAROSCOPY FOR BSO (DX PELVIC PAIN) • OPERATION CONVERTED TO LAPAROTOMYFOR SEVERE ADHESIONS AND TOOK SEVERAL HOURS 121 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 3 (CONT) • POST BSO DEVEL. LEFT HYDRONEPHROSIS • URETERAL STENT PLACED (INFLAM. CYST) • REF. TO GYN. ONCOLOGIST FOR PERSISTING PELVIC PAIN • OCT.29, 2007 UNDERWENT OPERATIVE LAPAROSCOPY; ADHESIOLYSIS AND APPENDECTOMY • NO RETROPERIT. EXPLORATION CASE 3 (CONT) • 10 MM PORT EXCISION ENLARGED TO 3 CM TO ALLOW INSPECTION DESCENDING COLON • ADMITTED TO HOSPITAL FOR POST OP PAIN • 10‐31‐07 T=102 degrees, TACHYCARD., TACHYPNEA, WBC, 2900 • DISCHARGED HOME CASE 3 (CONT) • • • • • • NEXT AM RETURNS TO HOSPITAL ER WORSE ABD. PAIN, WEAKNESS, SOB 95.8 DEGREES, HR=135, R=32, BP=100/68 ABD.=DISTENDED, GUARDING ALL QUADS BS=HYPOACTIVE; WBC=4200 CT SCAN (NO CONTRAST): FREE AIR IN ABD.;PNEUMOMEDIASTINUM, SUBQ GAS ABD. WALL AND CHEST WALL 122 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 3 (CONT) • FOLLOWING DAY WBC DIFF=BANDS ELEVATED TO 25 • CARDIAC CONSULT DIAGNOSE HEART FAILURE ANDNOTES PNEUMOMEDIATINUM SHOULD NOT OCCUR POST ABDOMINAL SURGERY • THAT EVENING GYN ONCOLOGIST DOES LAPAROTOMY AND FINDS FECAL CONTENTS IN PERITONEAL CAVITY CASE 3 (CONT) • A “2MM” PERFORATION IS NOTED IN DISTAL RECTOSIGMOID • ONCOLOGIST STAPLES AREA BELOW DEFECT AND DOES DESCENDING LOOP COLOSTOMY • POST OP PATIENT REMAINS SEPTIC AND VEGETABLE MATTER REMOVED FROM ONE OF DRAINS • GENERAL SURGERY CONSULT CALLED 11‐9‐07 CASE 3 (CONT) • OPERATION # 3 ON 11‐9‐07 • NECROSIS, HEMORRHAGE, ACUTE INFLAM. OF COLOSTOMY • COLOSTOMY SEPARATED BY NECROSIS FROM ITS ANT. ABD. WALL LOCATION • NECROSIS OF EXPOSED MUCOSA AT HARTMAN POUCH SITE • PARTIAL COLECTOMY WITH NEW END COLOSTOMY AND RESECTION OF DISTAL COLON BACK TO RECTUM AND CLOSURE OF NEW HARTMAN POUCH • NUMEROUS INTRA‐ABDOMINAL ABSCESSES DRAINED 123 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 3 (CONT) • 2 DAYS LATER PATIENT BACK TO OR FOR ABSCESS (MULTIPLE) DRAINAGE • DISCHARGED HOME 1 MONTH LATER CASE 3 (CONT) • JANUARY 2008 ER WITH NAUSEA AND VOMITING PLUS ABD. PAIN • ADM. TO HOSPITAL WHERE 5 DAYS LATER A PLASTIC SURGEON DOES EXTENSIVE SKIN GRAFTING FOR CHRONICALLY OPEN ABD. WOUND • MARCH 12 BACK TO ER ABD. PAIN ADMITTED NG TUBE DRAINAGE AND IV FLUIDS CASE 3 (CONT) • • • • • APRIL 26 ER WITH PAIN CT SCAN SHOWS CYSTIC MASS IN PELVIS CT GUIDED DRAINAGE JUNE, JULY SEEN IN ER 3 TIMES FOR PAIN JAN. 2009 ADM. FOR LAPAROTOMY FOR COLOSTOMY TAKE‐DOWN; ANAS., ADHESIOLYSIS AND RESECTION OF LEFT 4 CM CYST (PATH =OVARIAN TISSUE) 124 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE 3 (CONT) • SUBSEQUENTLY UNDERWENT LEFT AND RIGHT MYOCUTANEOUS FLAPS TO ABD. WALL • 16X20 CM SHEET ALLODERM TISSUE MATRIX TO DEFECT IN ABD. WALL • MARCH 2009 REPEAT DRAINAGE OF PELVIC COLLECTION • CONTINUES TO HAVEABDOMINAL PAIN ANALYSIS • • • • CAUSATION ? STANDARD OF CARE ? DAMAGES? VERDICT ? CASE # 4 • 83 yo complaining of pelvic pain and during ultrasound note to have 8mm endometrium and ? Polyp. • Hysteroscopy scheduled • Sound placed and cavity describ. as 8cm • Uterus “dilated”and operative hysteroscope in • Saw ant. Polyp or myoma • Polyp forceps removed polyp 125 Texas Two-Step Conference, Januar 9 - 10, 2015 CASE # 4 (CONT) • Hysteroscope reintroduc.another polyp seen • Polyp forceps inserted and now pull out loop of bowel • Decis. To do diagnostic laparoscopy • Patient noted to have abd. Incis. Scar midline • Incis above umbilicus; trocar inserted after pneumoperiton.Several attempts to insert • Large amount of blood seen with laparoscope CASE # 4 (CONT) • Gynec. Oncol called and laparotomy done • 0.5 cm laceration of bowel mesentery and Vasc. Surgery called to repair • “small amt. bruising” to bowel ; hole in uterus • Path revealed no polyp, no endometrium • The vascular injury to the mesentery repaired • Again large and small bowel inspected and abd. closed CASE # 4 (CONT) • In the surgical ICU patient shock, copius output from drains, sepsis, DIC • Return to O.R. and noted to have several liters of blood in belly • Ischemic colon from cecum to transverse colon ; ileoascending colon resection • Patient remains severe shock state • One day after initial surgery patient dies. 126 Texas Two-Step Conference, Januar 9 - 10, 2015 INTERACTTIVE DEB BATEE: Whaat iss the e Besst Managgem ment of Mod M de off Deliverry fo or Tw win Pregn nanccies: Is V Vagin nal D Delivvery Stilll a SSafe Opttion? Robert SSilverr, M.D D. Suneeet Ch hauhaan, M.D. 127 Texas Two-Step Conference, Januar 9 - 10, 2015 What Is Best Management of Mode of Delivery for Twin Pregnancies: Is Vaginal Delivery Still a Safe Option? Suneet Chauhan, M.D. Disclosures • I do not have relevant financial relationships with commercial interests related to the content of this presentation. Disclosures 128 Texas Two-Step Conference, Januar 9 - 10, 2015 Disclosures Disclosures 129 Texas Two-Step Conference, Januar 9 - 10, 2015 Objectives • Utilize patient criteria and evidence based practice to determine the appropriate method of delivery of twins. • Describe patient characteristics of the optimal patient for a twin vaginal delivery. Twins Births In The United States Twins: Intrapartum Mx 130 Texas Two-Step Conference, Januar 9 - 10, 2015 Twin Presentations 16 publications; N = 6,090 Experience With Twins Total deliveries 1 Year 150 5 Years 750 10 Years 1,500 Twins 5 25 51 Vtx‐Vtx 2 11 23 Vtx‐Non vtx 2 9 17 Non‐vtx‐Others 1 5 11 National Guidelines on Twin Deliveries Vertex‐Vertex ACOG (2014) Vag CNGOF RCOG (2011) (2008) No one type NM SOGC (2000) Vag Vertex‐Non‐ vertex Vag* No one type NM Vag* (1500‐4000 g) Non‐vertex‐ Other NM No one type NM NM *An obstetrician experienced in internal podalic version and vaginal breech delivery 131 Texas Two-Step Conference, Januar 9 - 10, 2015 National Guidelines on Twin Deliveries Vertex‐Vertex ACOG (2014) Vag CNGOF RCOG (2011) (2008) No one type NM SOGC (2000) Vag Vertex‐Non‐ vertex Vag* No one type NM Vag* (1500‐4000 g) Non‐vertex‐ Other NM No one type NM NM *An obstetrician EXPERIENCED in internal podalic version and vaginal breech delivery SOGC Statement SOGC Statement on Twin 132 Texas Two-Step Conference, Januar 9 - 10, 2015 Jon Barrett, M.B.Bch., FRCOG, MD, FRCSC Jon Barrett, M.B.Bch., FRCOG, MD, FRCSC • “Principal investigator of the Twin Birth Study run by the Centre for Mother, Infant and Child Research at Sunnybrook Research Institute. • The Twin Birth Study—$8.7‐million grant from the Canadian Institutes of Health Research. • More than 140 centres in 30 countries • Shown that planned vaginal birth is as safe as planned cesarean section for twin delivery—a finding that is changing clinical practice.” 133 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT Of Planned CD vs. VD With Twins • Inclusion – Twins at 320/7 to 386/7 weeks – EFW between 1,500 to 4,000 g • Excluded – – – – – Mono‐amniotic twins Fetal reduction after 13 weeks Lethal anomalies No contraindication to vaginal birth Two or more cesarean delivery Barrett JFR et al NEJM 2013 RCT Of Planned CD vs. VD With Twins • Twin A delivered • Ultrasound • Twin B – Vertex Æ VD, unless NR FHR – Non‐vertex Æ • • • • Spontaneous or assisted vaginal breech, Total breech extraction with or without internal podalic version ECV Æ VD Intrapartum CD Barrett JFR et al NEJM 2013 RCT Flow Diagram Barrett JFR et al NEJM 2013 134 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT Flow Diagram Barrett JFR et al NEJM 2013 BEAM Trial Flow Diagram for BEAM 135 Texas Two-Step Conference, Januar 9 - 10, 2015 Twin RCT vs. BEAM Twin RCT vs. BEAM With BEAM, 75% of women assessed for eligibility were excluded Twin RCT: Conclusion • Twins at 32‐38 wks • Vtx‐other • Planned cesarean vs. vaginal delivery—did not decrease or increase morbidity or mortality Barrett JFR et al NEJM 2013 136 Texas Two-Step Conference, Januar 9 - 10, 2015 Experience With Twins Total deliveries Twins 1 Year 150 5 Years 750 10 Years 1,500 5 25 51 Vtx‐Vtx 2 11 23 Vtx‐Non vtx 2 9 17 Non‐vtx‐Others 1 5 11 Experience With Twins Total deliveries Twins 1 Year 150 5 Years 750 10 Years 1,500 5 25 51 Vtx‐Vtx 2 11 23 Vtx‐Non vtx 2 9 17 Non‐vtx‐Others 1 5 11 Vtx‐Non vtx Deliveries vs. Cesarean Assuming CD rate of 25% 137 Texas Two-Step Conference, Januar 9 - 10, 2015 Vtx‐Non vtx Deliveries vs. Cesarean Assuming CD rate of 25% Planned Recruitment • 20% of eligible twins will be randomized • 0.1% of all births at a center • Need 100‐150 centers • To recruit 770 / year, need 470,000 births per year • “EXPERIENCE?” http://www.nejm.org.ezproxyhost.library.tmc.edu/doi/ suppl/10.1056/NEJMoa1214939/ suppl_file/nejmoa1214939_appendix.pdf 138 Texas Two-Step Conference, Januar 9 - 10, 2015 Corrections to RCT in NEJM • In the 2nd paragraph of the Methods section the parenthetical in the 1st sentence should have begun, “ (e.g., fetal compromise, second twin substantially larger than the first twin . . . ,” • Not “. . . first twin substantially larger than the second twin. . . .” Differentiating Weight of Twins • 242 twins • To ensure 90% certainty that actual discordance is < 25%, SEFW discordance should be …6% Obstet Gynecol 1997 A Randomized Trial of CD or VD For Twins • GA At 32 to 38 weeks • EFW between 1,500 g and 4,000 g 139 Texas Two-Step Conference, Januar 9 - 10, 2015 Prediction Limitation of Estimated Fetal Weight SEFW (g) 1,500 4,000 90% 1,081 – 2,277 95% BW (g) 9,66 – 2,392 3,265 – 4,461 3,150 – 4,576 Obstet Gynecol 1998 RCT of VD or CD for Twins • Non‐vertex twin B 1. 2. 3. 4. 5. 6. Spontaneous vaginal breech birth Assisted vaginal breech birth Total breech extraction with internal podalic version Total breech extraction without internal podalic version External cephalic version Æ Vaginal cephalic delivery Cesarean delivery Barrett JFR et al NEJM 2013 140 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT of VD or CD for Twins • Qualified obstetrician: 1.Experienced at vaginal twin delivery 2.Defined a priori as an obstetrician who judged himself or herself to be experienced at vaginal twin delivery and 3.Whose department head agreed with this judgment.17,18 Barrett JFR et al NEJM 2013 RCT of VD or CD for Twins • Qualified obstetrician: 17. Hannah ME et al Lancet 2000;356:1375‐ 83. 18. Su M et al. Am J Obstet Gynecol 2003;189:740‐5. Barrett JFR et al NEJM 2013 Experienced At Breech Delivery 141 Texas Two-Step Conference, Januar 9 - 10, 2015 Experienced At Breech Delivery • Someone who considered himself or herself to be skilled and experienced at vaginal breech delivery, with confirmation by the individual’s head of department (A priori) – A licensed obstetrician – A clinician with > 10 years of experience of vaginal breech delivery – A clinician with >20 years of experience of vaginal breech delivery Hannah ME et al Lancet 2000 Experienced At Breech Delivery Perinatal mortality, neonatal mortality, or serious neonatal morbidity A priori Licensed MD Planned CD Planned VD RR (95% CI) 1.7% 1.6% 4.9% 4.6% 0.34 (0.20‐0.58) 0.34 (0.19‐0.64) > 10 years experience 1.5% 3.5% 0.43 (0.23‐0.80) > 20 years experience 1.6% 3.2% 0.49 (0.25‐0.96) Hannah ME et al Lancet 2000 Where is the Experience? • 2,786 twins recruited • 13,930 twins delivered • 3,290,000 total births – 822,5000 CD (assuming 25% rate) • TOTAL OF 214 VAGINAL BREECH DELIVERIES • 384,246% more CD than vaginal breech http://www.nejm.org.ezproxyhost.library.tmc.edu/doi/ suppl/10.1056/NEJMoa1214939/ suppl_file/nejmoa1214939_appendix.pdf 142 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT of VD or CD for Twins: Results Barrett JFR et al NEJM 2013 RCT of VD or CD for Twins • 20 Countries with PNM < 15 / 1,000 births: Australia, Belgium, Canada, Chile, Croatia, Estonia, Germany, Greece, Hungary, Israel, the Netherlands, Oman, Poland, Qatar, Romania, Serbia, Spain, the United Kingdom, the United States, and Uruguay Barrett JFR et al NEJM 2013 143 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT of VD or CD for Twins • 7 Centers in the United States: – – – – – – – University of South Carolina, Columbia University of Iowa Hospitals and Clinics, Iowa City Jamaica Hospital Medical Center, New York Texas Tech UHSC, Lubbock University of Miami, Miami East Bay Perinatal Medical Associates, Oakland Maricopa Medical Center, Phoenix Barrett JFR et al NEJM 2013 RCT of VD or CD for Twins The 7 Centers in the US Recruited (N = 2,786): A. 2% B. 12% C. 22% D. 32% E. Do not know Barrett JFR et al NEJM 2013 RCT of VD or CD for Twins • The 7 Centers in the US Recruited (N = 2,786): 2% (N = 57) – About 8 women per center – About 1 women per center per year • Experienced clinician Barrett JFR et al NEJM 2013 144 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT of VD or CD for Twins Planned CD 1,393 Planned VD 1,393 CD for both 90% 40% ‐‐ VD and CD 1% 4% ‐‐ VD for A and B 9% 56% ‐‐ N OR (95% CI) CD, cesarean delivery; VD, vaginal delivery Barrett JFR et al NEJM 2013 RCT of VD or CD for Twins Planned CD 2,783 N 1o Outcome Death Planned VD 2,782 OR (95% CI) 2.2% 1.9% 1.16 (0.77–1.74) 0.9% 0.6% Fetal 0.5% 0.3% Neonatal 0.4% 0.3% 1.3% 1.3% Morbidity CD, cesarean delivery; VD, vaginal delivery Barrett JFR et al NEJM 2013 Conclusions 145 Texas Two-Step Conference, Januar 9 - 10, 2015 Conclusions • Unlikely that we will see a major change in use of cesarean delivery for twins nationwide – Trends in patient demographic characteristics and preferences, – Virtual disappearance of vaginal delivery in cases of breech presentation, and – Dramatic reduction in instrumented vaginal delivery (associated gradual disappearance of the skills necessary to perform these procedures among obstetricians) Greene MF et al NEJM 2013 Conclusions • Questionable CONSORT compliance • NOT generalizable to the United States • Experience = Cesarean • No improvement with vaginal delivery • Fewer than 250 vaginal breech deliveries Conclusions • Vertex‐Vertex Æ Vaginal • Vertex‐Nonvertex Æ Cesarean • Nonvertex‐Other Æ Cesarean 146 Texas Two-Step Conference, Januar 9 - 10, 2015 Multiple Gestation: Mode of Delivery Bob Silver University of Utah Salt Lake City, Utah Cesarean and Multiple Gestation P = 0.011 Multiple Gestations Cut them all? Many people think so based on current cesarean rates! 147 1 Texas Two-Step Conference, Januar 9 - 10, 2015 Multiple Gestations Cut them all? If you believe the low quality studies presented by Dr. Chauhan Multiple Gestations Cut them all? Is this the best thing to do? Cesarean and VBAC Rates 50 1970 1988 1996 2002 2006 40 % 30 20 10 0 CS Rate VBAC Rate 148 2 Texas Two-Step Conference, Januar 9 - 10, 2015 Multiple Gestations Trial of labor Fetal position is important Most would CS if A is breech It varies for twin B due to clinician training and experience Twins Presentation Cephalic / cephalic: 40% Cephalic / non-cephalic: 32% Breech / any position: 8% Non-cephalic increases with decreasing gestational age Morbidity and Mortality Associated With Mode of Delivery in Twins U.S. Vital Statistics Multiple gestations 1995 – 2000 Twins ≥ 30 weeks gestation Neonatal morbidities and death Stratified by method of delivery 450,504 infants included Stratified analyses (presentation / discordance) Peaceman et al. Am J Obstet Gynecol 2009;200:e1-462.e6 149 3 Texas Two-Step Conference, Januar 9 - 10, 2015 Infant Outcomes Outcomes Vtx/Vtx CS Vtx/Vtx Vaginal Vtx/Br CS Vtx/Br Vaginal 5 Min Apgar ≤ 3 0.1% 0.2% 0.1% 0.3% Ventilation < 30 min 2.6% 2.9% 4.5% 5.2% Ventilation ≥ 30 min 1.9% 1.6% 3.2% 2.8% Birth Injury 0.1% 0.1% 0.1% 0.5% Peaceman et al. Am J Obstet Gynecol 2009;200:e1-462.e6 Infant Outcomes Vtx/Vtx CS Vtx/Vtx Vaginal Vtx/Br CS Vtx/Br Vaginal 0 0 0.1% 0.1% Infant Death 0.6% 0.5% 0.5% 0.6% Composite 0.7% 0.8% 0.6% 1.3% Outcomes Seizure Peaceman et al. Am J Obstet Gynecol 2009;200:e1-462.e6 Morbidity and Mortality Associated With Mode of Delivery in Twins Similar results if ≥ 34 weeks gestation No increase in adverse events when twin B weighed 25% or more than twin A – Vtx / Vtx – Vtx / Non Vtx Concluded vaginal delivery and CS equivalent for Vtx / Vtx Minimal risk for vaginal delivery Vtx / Br Peaceman et al. Am J Obstet Gynecol 2009;200:e1-462.e6 150 4 Texas Two-Step Conference, Januar 9 - 10, 2015 Morbidity and Mortality Associated With Mode of Delivery in Twins Retrospective cohort study Mt Sinai 2005 – 2009 Single experienced practice “Aggressive TDT” – Breech extraction – If vtx and unengaged, internal podalic version with breech extraction Planed TOL compared to planned CS Fox et al. Obstet Gynecol 2010;115:229-33 Morbidity and Mortality Associated With Mode of Delivery in Twins N = 287 (157 planned CS; 130 planned TOL) No difference between groups – Apgar score of twin B – Low UA ph of twin B CS rate in planned TOL: 15.4% CS of B after vaginal delivery of A: 0 Factors associated with vaginal birth – Young maternal age / prior vaginal birth Fox et al. Obstet Gynecol 2010;115:229-33 Twins: RCT Planned Vaginal or Cesarean Delivery Prospective RCT Israel 1983 – 1985 Twins > 35 weeks gestation Vertex / breech and vertex / transverse Planned CS (N = 27) Planned vaginal delivery (N = 33) Primary outcomes: neonatal morbidity and mortality and maternal morbidity Rabinovici et al. Am J Obstet Gynecol 1987;156:52-6 151 5 Texas Two-Step Conference, Januar 9 - 10, 2015 Twins: RCT Planned Vaginal or Cesarean Delivery Planned CS – 4 vaginal births due to second twin spontaneously changing to vertex Planned vaginal delivery – 2 cesarean First twin had fewer low Apgar scores than second twins (regardless of delivery route) No difference in any adverse neonatal outcomes in second twins delivered vaginally or by cesarean Increased febrile morbidity in CS group No power! Rabinovici et al. Am J Obstet Gynecol 1987;156:52-6 Twins: Canadian RCT Planned Vaginal or Cesarean Delivery Multicenter, international RCT; 2003 - 2011 Twins; Cephalic twin A; 32 – 38 6/7 weeks; 1,500 – 4,000 grams Planned vaginal or cesarean delivery Elective delivery planned for 37 5/7 – 38 6/7 Primary outcome: – Composite of fetal or neonatal death or serious neonatal morbidity Unit of comparison: individual fetus Barrett et al. N Engl J Med 2013;369:1295-1305 Twins: Canadian RCT Planned Vaginal or Cesarean Delivery 1,398 women 2,795 fetuses Planned CS: 90.7% CS rate Planned vaginal delivery: 43.8% CS rate (56.2% rate of vaginal delivery) Date of delivery from randomization: – Planned CS: 12.4 days – Planned vaginal delivery: 13.3 days (P = 0.04) Barrett et al. N Engl J Med 2013;369:1295-1305 152 6 Texas Two-Step Conference, Januar 9 - 10, 2015 Twins: Canadian RCT Planned Vaginal or Cesarean Delivery Primary composite outcome: – Planned CS: 2.2% (OR 1.16 (95% CI 0.77, 1.74) – Planned vaginal delivery: 1.9% Planned stratified analysis by parity and gestational age at randomization Maternal composite outcome: – No differences among groups – Planned CS: 7.3% – Planned vaginal delivery: 8.5% (P = 0.29) Barrett et al. N Engl J Med 2013;369:1295-1305 Twins: Canadian RCT Planned Vaginal or Cesarean Delivery Planned subgroup analysis: – No interactions for primary outcome and treatment group for parity, gestational age at randomization, maternal age, presentation of second twin, chorionicity, or national perinatal mortality for country of residence Second twin was more likely to have primary outcome (OR 1.90; 95% CI 1.34, 2.69) – Not significantly related to treatment group Barrett et al. N Engl J Med 2013;369:1295-1305 Twins: Canadian RCT Planned Vaginal or Cesarean Delivery What conclusions can be made? – TOL is a reasonable option in many cases if twin A is in the cephalic presentation – Note that the obstetricians in the study were trained in vaginal breech extraction – Note that the institutions in the study had facilities comfortable with vaginal twin delivery – Note that the obstetricians used good judgment with regard to appropriate candidates for TOL before and after randomization – Should all twins be delivered by TOL? NO – Is TOL a reasonable option in most cases? YES Barrett et al. N Engl J Med 2013;369:1295-1305 153 7 Texas Two-Step Conference, Januar 9 - 10, 2015 Twins: Prediction of Safe Vaginal Delivery Prospective multicenter cohort study in Ireland / 2007 – 2009 / serial sonograms Twins 11 – 22 weeks gestation / enrollment Secondary analysis Excluded monoamnionitic twins, anomalies, aneuploidy Successful and failed TOL compared 971 twins included 441 considered a TOL Breathnach et al. Am J Obstet Gynecol 2011;205:237.e1-7 Twins: Prediction of Safe Vaginal Delivery Successful vaginal delivery in 338/441 (77%) CS rate for second twin: 4% Predictors of vaginal birth: – Multiparity – Spontaneous conception NOT associated with vaginal birth: – Advancing gestational age – Presentation of second twin! – Concordant growth! Even if B was 20% > A! Breathnach et al. Am J Obstet Gynecol 2011;205:237.e1-7 Multiple Gestations What about triplets? CS is “standard of care” 154 8 Texas Two-Step Conference, Januar 9 - 10, 2015 Triplets Planned Vaginal or Cesarean Delivery United States vital statistics Triplets ≥ 24 weeks 1995 – 1998 Assessed mode of delivery and neonatal outcomes – could not assess “intended route of delivery” 95% CS RR stillbirth (vaginal) 5.7 (3.8 – 8.5) RR neonatal death (vaginal) 2.8 (1.9 – 4.2) RR infant death (vaginal) 2.3 (1.6 – 3.3) Vintzileos et al. Am J Obstet Gynecol 2005;192:464-9 Triplets: RCT Planned Vaginal or Cesarean Delivery No such thing! Same issues as twins but more so Many case series and anecdotal reports of successful vaginal delivery Impossible to “vet” safety due to small numbers Not important for overall CS rate May be very important for individual women Highly selected cases Triplets Trial of labor Case series and retrospective cohorts No increase in morbidity with planned TOL: – – – – Northwestern: 33 cases Stony Brook: 8 cases Leiden: 39 cases Paris: 78 cases Grobman et al. Am J Obstet Gynecol 1998;179:942-5 Alamia et al. Am J Obstet Gynecol 1998;1791133-5 Wildschut et al. BJOG 1995;102:292-6 Alran et al. Acta Obstet Gynecol Scand 2004;83:554-9 155 9 Texas Two-Step Conference, Januar 9 - 10, 2015 Multiple Gestations What about triplets? Vaginal delivery is a reasonable option in selected cases Honest counseling would acknowledge the potential for unknown risks Dr. Silver Dr. Chauhan 156 10 Texas Two-Step Conference, Januar 9 - 10, 2015 O Obste etriccal M Manaagem mentt of Wom men n witth Recurrrent Preegnaancyy Losss Robert SSilverr, M.D D. 157 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Bob Silver University of Utah Salt Lake City, Utah Sporadic Pregnancy Loss 9Extremely common event • 10 - 12% clinical pregnancies • Up to 20% implantation failures • High rate of aneuploidy (60%) • de novo non-dysjunction • Other abnormalities • Normal individuals Recurrent Pregnancy Loss Epidemiology • Depends upon definition • 0.5 - 1.0% of couples • Higher than anticipated based on chance alone – 0.3 - 0.4% • Challenging and frustrating for both patients and physicians 158 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Definition • 3 or more consecutive losses – no more than one live birth • • • • ? 2 or more losses ? Consecutive losses ? Live births ? Most recent pregnancies Recurrent Pregnancy Loss Purpose of Definition • Counseling and prognosis • Research consistency • Avoidance of unnecessary tests and anxiety • Clinical Arena - Be flexible – But be honest Recurrence Risk for Pregnancy Loss Number of Recurrence Prior Losses Risk Women with livebirths 0 1 2 3 4 10%-15% 20%-25% 25%-30% 25%-30% 25%-30% Women without livebirths 1 2 3 4 15%-25% 35%-50% 159 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Types of Loss 9Characterize prior losses • • • • • • Clinical course Gestational age Sonogram Embryonic / Fetal cardiac activity Karyotype / MIcroarray Histology Preembryonic 2 4 LMP Fetal Embryonic 6 8 10 12 14 Weeks’ Gestation CONCEPTION Spontaneous Pregnancy Loss Data from Serial Transvaginal Ultrasound • 232 low risk women in early 1st trimester • Serial transvaginal ultrasound exams at 1st prenatal visit and thereafter if indicated • Overall pregnancy loss rate of 13.4% Goldstein, Obstet Gynecol 1994;84:294 160 Texas Two-Step Conference, Januar 9 - 10, 2015 Spontaneous Pregnancy Loss Data from Serial Transvaginal Ultrasound Percent 40 30 20 10 Gest Sac; 1-5 mm 6-10 mm 10-30 mm No Embryo Embryo Embryo Embryo Fetus Goldstein, Obstet Gynecol 1994;84:294 Pregnancy Loss Timing in Gestation • Implantation Failure – Positive pregnancy test • Pre-embryonic – Empty gestational sac – “blighted ovum” • Embryonic – No cardiac activity: CRL < 30mm • Fetal – No cardiac activity: CRL > 30 mm Pregnancy Loss Causes • May vary with gestation • Abnormal karyotype – 54% in best series – Higher in pre-embryonic losses and embryonic demises – Higher with advanced maternal age • APS / Thrombophilia – Stronger association with fetal death 161 Texas Two-Step Conference, Januar 9 - 10, 2015 Pregnancy Loss Timing in Gestation EAGeR Trial: 189 Losses • • • • • Implantation Failure (29.6%) Pre-embryonic (19%) Embryonic (38%) Fetal Death < 20 weeks (4.8%) Fetal Death > 20 weeks (2.1%) Recurrent Pregnancy Loss Known or Suspected Causes • • • • • • • Uterine Abnormalities Genetic Abnormalities Autoimmune Disorders (APS) Hormonal / Metabolic Disorders Thrombophilias Infections Alloimmune Disorders Recurrent Pregnancy Loss Uterine abnormalities • 10 – 15% of women with RPL • Congenital – Mullerian anomalies • 8 – 10% of women with RPL – DES exposure – Cervical Insufficiency • Acquired – Intrauterine adhesions – Fibroids 162 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Uterine abnormalities • Mechanism of pregnancy loss? – Decreased blood flow – Poor placental development – Inadequate uterine volume • Cervical insufficiency Recurrent Pregnancy Loss Mullerian Anomalies • Overall Incidence (normal women) is uncertain – Reported as 0.02 – 74% – Uterine manual exploration: 3% – Hysteroscopic tubal: 2-3% – Higher in selected populations • Outcomes vary for each anomaly – Worst for septum, best for didelphys Recurrent Pregnancy Loss Mullerian Anomalies • • • • • Prospective study (N = 1089) Three dimensional ultrasound Non-Obstetric clinical indications 9% abnormal (including arcuate) Worse obstetric outcome with uterine anomalies • Outcomes better than prior reports Woelfer et al., Obstet Gynecol 2001;98:1099 163 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Uterine Abnormalities: Diagnosis • • • • • Sonohysterogram Hysterosalpingogram Three dimensional sonogram MRI Newer modalities do not require pelviscopy 164 Texas Two-Step Conference, Januar 9 - 10, 2015 165 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Uterine Abnormalities: Treatment • Efficacy of treatment unproven • Improved outcomes reported in retrospective series – Uterine septum – Submucosal fibroids – Intrauterine adhesions – Cervical incompetence • Benefits less clear for metroplasty Recurrent Pregnancy Loss Uterine Septum: Treatment Successful Pregnancies Before Resection 12/240 (5%) (N=57) After Resection 55/63 (87%) (N=57) March and Israel, AJOG 1987;156:834 Recurrent Pregnancy Loss Antiphospholipid Antibodies Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies recognizing epitopes expressed by negatively charged phospholipids, proteins, or a protein-phospholipid complex 166 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Antiphospholipid Antibodies 9Clinical Associations • • • • • • Recurrent pregnancy loss Fetal death Severe preeclampsia / IUGR Arterial and Venous Thromboses Antiphospholipid Syndrome Connective tissue disease Recurrent Pregnancy Loss Antiphospholipid Antibodies • Best Characterized – Lupus anticoagulant – Anticardiolipin antibodies • Moderate-High titer IgG – Anti-β2-Glycoprotein-I antibodies • ? Clinical Utility – Antiphosphatidylserine antibodies – Antiprothrombin antibodies – Antiannexin antibodies – IgA antibodies Serologic Testing for aPL Lupus Anticoagulant • Detected by phospholipid-dependent clotting tests – Activated partial thromboplastin time – Dilute Russel viper venom time – Kaolin clotting time – Plasma clotting time • Citrated plasma (“blue top tube”) • Present or absent (no level) 167 Texas Two-Step Conference, Januar 9 - 10, 2015 Serologic Testing for aPL Anticardiolipin Antibodies • • • • • • • Immunoassays (ELISAs) Purified Cardiolipin Beta-2-Glycoprotein-I cofactor Standard Sera (Galvaston, TX) “GPL” and “MPL” Units Semi-quantitative “Red top” tube Serologic Testing for aPL Anti-beta-2-glycoprotein-I • • • • • • • • ? True epitope for aPL Cofactor for anticardiolipin Anticoagulant protein Immunoassays Standardized Sera (Galvaston, TX) Semi-quantitative “SGU” and “SMU” Units Red top tube Antiphospholipid Antibodies in Women with Recurrent Pregnancy Loss (RPL) Data from Petri (1987), Barbui (1988), Parazzini (1991), Parke (1991), and Out (1991) LA Medians Range IgG aCL LA or IgG aCL RPL Cntrls RPL Cntrls RPL Cntrls 7% 0% 8% 2% 11% 2.5% 7-11% 0-2% 5-14% 0-5% 10-16% 0-5% 168 Texas Two-Step Conference, Januar 9 - 10, 2015 Pregnancy Loss Rates with LA and aCL Results from Unselected Pregnancies Lockwood N=737 Pattison N=900 Lynch N=389 Yasuda LA 100% aCL 38% LA-aCL 38% Negative 6% N=718 N=2 N=16 N=16 18% 33% 16% 2% N=11 N=9 N=19 N=915 NA NA Katano N=1125 Medians 6% N=294 20% 20% 20% N=60 N=60 N=800 NA 25% 25% 0.5% N=8 N=8 N=1100 59% 29% 20% 6% NA N=860 16% N=95 Pregnancy Outcomes in RPL Patients with and without aPL 100 N=1112 aPL negative aPL positive 60 N=145 N=136 40 20 N=128 Anembryonic Pregnancy or Embryonic Death Fetal Death (>10 wks) Oshiro et al, Obstet Gynecol, 1996; 87:489 Heparin (and Low-Dose Aspirin) Versus Aspirin Alone Percent Live Births Percent 80 100 Heparin & LDA LDA alone 80 60 40 20 Kutteh Rai et al 169 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Other Autoimmune Disorders 9Thyroid antibodies • associated with sporadic pregnancy loss • Not associated with RPL • No treatment • Testing is not advised Recurrent Pregnancy Loss Other Autoimmune Disorders 9Antinuclear antibodies • 15% of women with RPL • Common in normal individuals, especially during pregnancy • No prospective association with pregnancy loss • No relationship with APS • Negative treatment trial • Testing is not advised Recurrent Pregnancy Loss Genetic Abnormalities • Balanced parental translocations – 3 - 5% of RPL couples – 5X higher than general population • Other genetic problems – Malformations (34% in one series) – Microdeletions (CNVs) – Recurrent aneuploidy – Confined placental mosaicism – ? Skewed X inactivation – Single gene disorders 170 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Parental Cytogenetic Abnormalities • Balanced parental translocations – Reciprocal – Robertsonian – Risk of pregnancy loss and abnormal live birth varies • Inversions • Translocations more common • More common in females - 2:1 Recurrent Pregnancy Loss Recurrent Aneuploidy • Karyotype in subsequent Loss in women with RPL –Abnormal in 48% of abortus specimens –Abnormal in 60% of CVS –Abnormal in over 50% of all embryos using PGD Recurrent Fetal Aneuploidy A Cause of Recurrent Pregnancy Loss? First Abortus Karyotype of Second Abortus Normal Aneuploid Normal Karyotype 81% 19% (N=175) Aneuploid 45% 55% (N=107) 171 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Why obtain karyotypes? • • • • • • Emotional closure Avoid unnecessary treatment Implications for offspring Prognosis ? Treatment – PGD Chromosomal Microarray Recurrent Pregnancy Loss Single Gene Disorders • Embryonic lethal mutations in “Knockout mice” – Placental growth factors – Angiogenic factors – Development genes • Evidence in humans – Increased female offspring: X-linked – RPL associated with some mutations 172 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Parental Cytogenetic Abnormalities • • • • IVF / PGD Theoretical benefit Good anecdotal results 192 couples with translocation – 88.3% loss rate prior to PGD – 13% loss rate after PGD • 70% success without treatment! • No efficacy in RCTs • Expensive / invasive Fischer et al, Fertil Steril 2010;94:283 Recurrent Pregnancy Loss Hormonal and Metabolic Disorders • • • • Diabetes mellitus (uncontrolled) Thyroid disease (uncontrolled) Luteal phase defect? Polycystic ovarian syndrome? Recurrent Pregnancy Loss Luteal Phase Defect • Progesterone essential to maintain early pregnancy (7 wks) – Removal of corpus luteum – RU486 • Diagnosis by endometrial biopsy – Lag of 48 hours in two cycles • Serum levels less reliable 173 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Luteal Phase Defect • 25 – 40% incidence in RPL • Improved outcome with treatment – Uncontrolled studies • Progesterone, hCG, clomid • Progesterone from ovulation through 8 – 12 weeks gestation • Optimal dose / delivery route is uncertain Recurrent Pregnancy Loss Luteal Phase Defect: Problems • Present in normal women – Up to 50% of single cycles – 25% sequential cycles • Variability in evaluation of endometrial histology • Lack of controlled studies Thrombophilias Pregnancy Loss • Fetal death • Consistent association with most thrombophilias • Early Pregnancy Loss • Weaker - No association with most thrombophilias 174 Texas Two-Step Conference, Januar 9 - 10, 2015 Thrombophilias Pregnancy Loss • • • • TIPPS trial RCT (open label) Thromophilia and prior adverse event Thromboprophylaxis – Dalteparin 5000 (daily < 20 wks; bid > 20) • Composite outcome – Adverse obstetric events – Thrombosis Rodger et al, Lancet 2014;384:1673 Thrombophilias Pregnancy Loss • • • • 12 years! Dalteparin – 143 women No Dalteparin – 141 women Intention to treat: – Dalteparin: 25/146 (17.1%) – No Dalteparin 28/143 (18.9%) • No major bleeding • Increased minor bleeding Dalteparin Rodger et al, Lancet 2014;384:1673 Recurrent Pregnancy Loss Infection • Association with sporadic losses – Listeria, toxoplasma, syphilis, BV, CMV, parvovirus, and other viruses • Requires chronic, non-debilitating organism that infects uterus • ? Endometrial mycoplasma • No convincing link to RPL • Testing is not advised 175 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Alloimmune Disorders • Maternal tolerance of the “fetus as a semi-allograft” • Concept that RPL involves an immunologic rejection of the fetus • Evidence in murine pregnancy that maternal immune system must: – Not “reject fetus” – Recognize fetus for normal placentation Recurrent Pregnancy Loss Alloimmune Disorders • Evidence in human pregnancy – Increased HLA sharing in RPL – Failure to make “blocking” antibodies – Increased T-helper type 1 cytokines – Abnormal (both increased and decreased ) natural killer cells – Embryotoxic factor • Proposed treatment – Maternal immunization – Intravenous immune globulin (IVIG) Recurrent Pregnancy Loss Alloimmune Disorders • Leukocyte immunization – Paternal – Donor • Trophoblast immunization • Initial reports of success • No increase in live birth rate in more recent RCTs and meta-analyses Scott JR, 2002;The Cochrane Library, Issue 2 176 Texas Two-Step Conference, Januar 9 - 10, 2015 RCT of Paternal Leukocyte Immunization in Couples With Idiopathic RPL 70 60 N = 85 50 40 N = 86 30 20 10 0 Immune Control Ober et al., Lancet 1999;354:365 Recurrent Pregnancy Loss Alloimmune Disorders • IVIG – Includes “blocking” antibodies – Maternal immunosupression – Benefit in one RCT • No increase in live birth rate in more recent RCTs and meta-analyses • Expensive and cumbersome Scott JR, 2002;The Cochrane Library, Issue 2 177 Texas Two-Step Conference, Januar 9 - 10, 2015 What about idiopathic recurrent pregnancy loss? At least 50% of cases Low Dose Aspirin: Recurrent Pregnancy Loss • • • • • • • • • Placebo: N = 121 LDA (100 mg): N = 120 LDA + LMWH: N = 123 Placebo and LDA started at randomization (pre-conception or < 6) LMWH started at 6 weeks gestation LDA and placebo stopped at 36 wks Standard obstetric care Contacted every 3 months Intention to treat analysis Kaandorp et al; N Engl J Med 2010;362:1586 178 Texas Two-Step Conference, Januar 9 - 10, 2015 Low Dose Aspirin: Recurrent Pregnancy Loss • Received and complied with the assigned study drug – Placebo: N = 103 (85.1%) – LDA (100 mg): N = 104 (86.7%) – LDA + LMWH: N = 103 (83.7%) • • • • Mean age 34 years Median losses: 3 Similar characteristics among groups 299 (82.1%) became pregnant Kaandorp et al; N Engl J Med 2010;362:1586 Intention to treat analysis Kaandorp et al; N Engl J Med 2010;362:1586 Analysis: Pregnancies Kaandorp et al; N Engl J Med 2010;362:1586 179 Texas Two-Step Conference, Januar 9 - 10, 2015 Low Dose Aspirin: Recurrent Pregnancy Loss • Multicenter, International (Scotland) • SPIN: 2004 – 2008 • Recurrent pregnancy loss – – – – Two or more consecutive losses < 24 wks Unexplained losses (not all had W/U) APS excluded If prior live birth, most recent two – losses • Antenatal care < 7 weeks gestation • Thrombophilia testing (blinded) Clark et al; Blood 2010;115:4162 Low Dose Aspirin: Recurrent Pregnancy Loss • Randomization – Rx: Enoxaparin (40 mg) + LDA (75 mg) N = 147 – No treatment N = 147 – Open label – All patients had intensive surveillance – Sonograms every 2 weeks until 12 weeks – Monthly sonograms 12 – 28 weeks Clark et al; Blood 2010;115:4162 Analysis: Pregnancies Clark et al; Blood 2010;115:4162 180 Texas Two-Step Conference, Januar 9 - 10, 2015 Low Dose Aspirin: Recurrent Pregnancy Loss • Canada; Toronto and Hamilton • Hep ASA Trial • Prior RPL and autoantibodies – – – – – – – 18 – 44 years of age At least 2 consecutive losses < 32 weeks Unexplained losses ANA or aPL or thrombophilia Confirmed pregnancy SLE / thrombosis excluded Evaluation every 6 weeks Laskin et al; J Rheumatol 2009;36:279 Low Dose Aspirin: Recurrent Pregnancy Loss • Randomization – LDA alone; N = 43 – LDA / LMWH; N = 45 – Open label – Dalteparin 5000 IU/day – LDA – 81 mg • 859 women with RPL screened • 88 met inclusion criteria • Trial stopped after 4 years • 47.7% had some level of aPL Laskin et al; J Rheumatol 2009;36:279 Analysis: Pregnancies Laskin et al; J Rheumatol 2009;36:279 181 Texas Two-Step Conference, Januar 9 - 10, 2015 EAGeR Trial Study Design • Aim: Assess the effects of pre-conception LDA (81mg) + folic acid on pregnancy outcomes • Prospective, double-blind, placebo, RCT • Eligibility: – healthy women (18-39 yrs) attempting pregnancy – 1-2 prior pregnancy losses – no diagnosis of / or treatment for infertility • RX: up to six menstrual cycles and / or through pregnancy (36 weeks) Schisterman et al; Lancet 2014;384:29 EAGeR Trial Study Design • Block Randomization was stratified by center and by eligibility strata: – Restricted: a single documented pregnancy loss <20 weeks of gestation in the past 12 months and no more than one live birth – General: one or two documented pregnancy losses regardless of gestational age or the date of the loss in the past and up to 2 live births (not eligible for restricted stratum) 74 EAGeR Trial Results • 1228 randomized participants – 1078 Completed the Trial – 150 (12%) withdrew early (No Differences by Rx Arm) • 131 (10%) non-pregnant • 19 (2%) pregnant • Over the trial period there were: – 728 (59%) confirmed pregnancies – 133 (11%) clinically confirmed losses – 595 (48%) live births 75 Schisterman et al; Lancet 2014;384:29 182 Texas Two-Step Conference, Januar 9 - 10, 2015 EAGeR Trial: Results RD 5.1% p=0.093 RD 9.2% p=0.039 RD 1.7% p=0.679 % Live Birth 66 62.4 61 57.8 56 52.7 53.2 LDA Placebo 53.9 52.2 51 46 Overall Restricted General Schisterman et al; Lancet 2014;384:29 Recurrent Pregnancy Loss PGD / IVF • Theoretical benefit – Especially with recurrent aneuploidy / AMA • Often done for RPL • No increase in live birth rates after IVF / PGD in women with AMA! • May be chromosomal mosaicism in early embryos • Not recommended for idiopathic RPL 77 Recurrent Pregnancy Loss Recommended Evaluation • • • • • • Uterine imaging study Parental karyotypes Lupus anticoagulant screen Anticardiolipin antibodies Anti-beta-2-glycoprotein-I antibodies Karyotype or microarray of conceptus 183 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Treatment: APS • Lupus anticoagulant or Medium-High levels of IgG anticardiolipin – Thromboprophylactic heparin (5,000 – 7,500 units bid) (or LMWH) – ? Low dose aspirin – Confirmation of viability – 6 wks PP • Low positive IgG anticardiolipin or IgM anticardiolipin – ? Heparin Recurrent Pregnancy Loss Treatment: Uterine Abnormality • Uterine septum – Hysteroscopic resection • Uterine synechia – Hysteroscopic resection • Bicornuate or didelphys – ? ? ? Metroplasty – NO! • Submucous fibroids – ? Hysteroscopic resection Recurrent Pregnancy Loss Treatment: Genetic • Balanced translocation – No treatment – Donor sperm / egg – IVF / Preimplantation diagnosis – NO proof of efficacy 184 Texas Two-Step Conference, Januar 9 - 10, 2015 Recurrent Pregnancy Loss Treatment: LPD • Luteal phase defect – Progesterone 100mg bid PO – ? IM or vaginal progesterone – ? hCG or clomid – NO proof of efficacy Recurrent Pregnancy Loss Treatment: Idiopathic • Idiopathic RPL –At least 50% of RPL • No effective treatments • Leukocyte immunization, IVIG, heparin, LDA should not be used • ? Donor sperm / egg; IVF-ET • Anti-inflammatory agents? – Plaquenil / anti-TNF / Anti-Complement Recurrent Pregnancy Loss Idiopathic • Take a sympathetic and caring approach – “TLC” • Educate the couple • Provide prognostic information • Provide treatment options, including experimental therapy 185 Texas Two-Step Conference, Januar 9 - 10, 2015 EEvide ence e‐Based Guid delin nes ffor U Use of P Proggesto ogen ns to o Preeven nt PTTB Adi Abram movicci, M..D. 186 Texas Two-Step Conference, Januar 9 - 10, 2015 Use of Progesterone for Preterm Birth Prevention: Clear As Mud Adi Abramovici, MD Assistant Professor Maternal‐Fetal Medicine Objectives • Utilize the guidelines for use of progestogens to prevent PTB in the appropriate patient population. • Describe patient characteristics of optimal candidates for the use of progestogens to prevent PTB. Disclosures • I do not have relevant financial relationships with commercial interests related to the content of this presentation. 187 Texas Two-Step Conference, Januar 9 - 10, 2015 March of Dimes Prematurity Campaign www.marchofdimes.org Incidence of Preterm Birth in the US 11 20 09 07 20 20 05 03 20 20 01 99 19 20 97 95 19 19 93 91 19 19 89 87 19 19 83 19 19 19 85 12 11 10 9 8 7 6 5 4 3 2 1 0 81 % Preterm Healthy People 2020 Goal (9.6%) Year Incidence of Preterm Birth in the US Healthy People 2020 Goal (9.6%) 188 Texas Two-Step Conference, Januar 9 - 10, 2015 March of Dimes Prematurity Initiative 2014 Report Card TEXAS GRADE = C PRETERM BIRTH = 12.3% March of Dimes Prematurity Initiative 2014 Report Card Preterm Birth Sequelae for Infants • Responsible for majority of perinatal morbidity and mortality –Cerebral palsy –Developmental delay –Visual and hearing impairment –Chronic lung disease 189 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Sequelae for Infants • Morbidity and mortality are related to GA at delivery –Mortality rate at 24 wks ~50%; <10% by 28 wks –Specialized education required for 25% born at 32‐36 wks; 45% born at 28‐31 wks My Preterm Birth Story…. Epidemiology of Preterm Birth PPROM 28 % Indicated Preterm Delivery 26 % 46 % Spontaneous Preterm Labor (Andrews 1995) 190 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention Promises and Failures Preterm Prevention Strategies • • • • • • • • Antibiotics Dental Therapy Fish Oil/Omega‐3 Fatty Acids Vitamin C Cerclage Pessary Bedrest/hospitilization Progesterone Progesterone 191 Texas Two-Step Conference, Januar 9 - 10, 2015 Biologic Activity of Progesterone • Uterine quiescence Decreased sensitivity of oxytocin receptors • Anti‐inflammatory effects Suppression of cytokines production/release Decreased cellular immune responsiveness Decreased expression of cell adhesion molecules Increased production of PIBF Delalutin 17‐Alpha‐Hydroxyprogesterone Caproate Delalutin 192 Texas Two-Step Conference, Januar 9 - 10, 2015 Delalutin • 17‐Alpha‐Hydroxyprogesterone Caproate • FDA Approved in 1956 (NDA 10‐347 ‐ Delalutin® ) through Bristol Myer Squibb • Indication (1971): Use in pregnant women for the treatment of habitual and recurrent abortion, threatened abortion, and post‐partum “after pains” Delalutin • On September 13, 1999, Bristol Myer Squibb requested withdrawal of NDA for Delalutin citing it had not marketed the drug for several years • FDA withdrew approval of Delalutin on September 30, 2000 – Not for concerns of regarding safety or efficacy • May 2003, NICHD MFMU 17OHPC RCT published in NEJM 17α‐Hydroxyprogesterone Caproate • November, 2003 ACOG Committee Opinion No. 291: Use of Progesterone to Reduce Preterm Birth “ Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior SPB due to spontaneous PTL or PPROM” 193 Texas Two-Step Conference, Januar 9 - 10, 2015 Progesterone Potential High Risk Populations • History of Previous Spontaneous Preterm Birth • Multi‐fetal Gestation • Short Cervix • Arrested Preterm Labor • PPROM History of Previous Spontaneous Preterm Birth Preterm Birth Prevention: Vaginal Progesterone • Double‐blind placebo controlled study • High‐risk women • Singleton 24‐34 weeks gestation • Randomized to receive: Placebo (n = 70) Vaginal progesterone supp. 100 mg daily (n = 72) Da Fonseca AJOG 2003 194 Texas Two-Step Conference, Januar 9 - 10, 2015 Vaginal Progesterone and PTB % Women with PTB 30 p < 0.05 20 28.5% 10 13.8% 0 Placebo Progesterone Da Fonseca AJOG 2003 Contraction Frequency Progesterone vs Placebo 7 Placebo # Contractions/hour 6 5 p = 0.004 4 3 2 Progesterone 1 0 28 29 30 31 32 33 34 Gestational Age (wks) Da Fonseca AJOG 2003 Preterm Birth Prevention: 17α-Hydroxyprogesterone Caproate (17P) • Double‐blind placebo controlled study • Women with previous SPB • Singleton 16‐20 weeks gestation • Randomized to receive: Placebo IM Injections (n = 153) 17P IM Injections 250 mg weekly (n = 310) Meis NEJM 2003 195 Texas Two-Step Conference, Januar 9 - 10, 2015 NICHD MFMU Progesterone Study High-Risk Women Relative Risk 0.66 PTB < 37 wk 0.67 PTB < 35 wk 0.58 PTB < 32 wk 0.1 1 10 Meis NEJM 2003 ACOG Committee Opinion Progesterone Use for PTB Prevention • Endorsed 17P • Single indication: Prior preterm birth • Cautions against Multiple gestation US short cervix + Fetal fibronectin ACOG Committee Opinion # 291 November, 2003 Multi‐Fetal Gestations 196 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention: Progesterone - Twins • Randomized trial (n = 661; 14 centers) • Twin gestation 16‐20 weeks • Double‐masked • Treatment: 17‐OHPC 250 mg weekly Placebo Rouse 2007 NEJM Preterm Birth Prevention: Progesterone ‐ Twins • No difference in fetal demise/PTB < 35 weeks: 41.5% Progesterone vs 37.3% Control (p=NS) • No difference in composite serious neonatal outcome: 20.2% Progesterone vs 18% Control (p=NS) Rouse 2007 NEJM Preterm Birth Prevention: Progesterone - Triplets • Randomized trial (n = 134; 14 centers) • Triplet gestation 16‐20 weeks • Double‐masked • Treatment: 17‐OHPC 250 mg weekly (n=71) Placebo (n=63) Caritis 2009 OB/GYN 197 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention: Progesterone ‐ Triplets • No difference in fetal demise/PTB < 35 weeks: 83% Progesterone vs 84% Control (p=NS) • No difference in composite serious neonatal outcome: 20.2% Progesterone vs 18% Control (p=NS) Caritis 2009 OB/GYN Preterm Birth Prevention: Progesterone – Multifetal Metaanalysis Author (Year) Mutifetal Gestation Included Reference Group n Treatment Group n Start GA Briery (2009) Twins Norman (2009) Twins Placebo 14 Placebo 250 Combs (2011) Triplets Placebo 25 Cetingoz (2011) Twins Singletons Placebo 28 Combs (2011) Twins Placebo 80 HartikainenSorri (1980) Twins Placebo 38 Rouse (2007) Twins Placebo Caritis (2009) Triplets Placebo Primary Outcome 17 alpha-Hydroxyprogesterone Caproate IM weekly 17 24-25 weeks Delivery < 35 wks 90 mg vaginal progesterone gel daily 250 24 weeks Delivery < 34 wks 17 alpha-Hydroxyprogesterone Caproate IM weekly 56 16-22 weeks Composite Neonatal Morbidity 100 mg vaginal progesterone suppositories daily 39 24 weeks Delivery < 37 wks 17 alpha-Hydroxyprogesterone Caproate IM weekly 160 16-24 weeks Composite Neonatal Morbidity 17 alpha-Hydroxyprogesterone Caproate IM weekly 39 28 weeks Perinatal Morbidity Mortality 330 17 alpha-Hydroxyprogesterone Caproate IM weekly 325 16-20 weeks Delivery < 35 wks 63 17 alpha-Hydroxyprogesterone Caproate IM weekly 71 16-20 weeks Delivery < 35 wks Preterm Birth Prevention: Progesterone – Multifetal Metaanalysis Group Odds Ratio Confidence Interval p Twins < 34 wks 1.2 0.9-1.7 0.24 Twins < 28 wks 1.4 0.76-2.4 0.30 Triplets <35 wks 1.6 0.8-3.1 0.17 Triplets < 32 wks 1.0 0.6-1.8 0.91 Triplets <28 wks 1.2 0.5-2.9 0.73 Vaginal Progesterone < 34 wks 1.3 0.9-1.9 0.22 Page-Ramsey ACOG AFD 2011 198 Texas Two-Step Conference, Januar 9 - 10, 2015 Progesterone – Twins Patient Level Meta‐Analysis • Patient level meta‐analysis from 13 RCT in twins (3768 women/7536 babies) • Neither 17P nor vaginal progesterone reduced the incidence of adverse perinatal outcome • In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome Schuit BJOG 2014 Short Cervix Preterm Birth Prevention: Progesterone – Short Cervix • Randomized trial (n = 250) • Singleton/Twin 20‐25 weeks/Cervix < 15mm • Treatment: Placebo (n=125) Vaginal Progesterone (n=125) Fonseca 2007 NEJM 199 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention: Progesterone – Short Cervix • Reduced SPB < 34 weeks: 19.2% Progesterone vs 34.4% Placebo (p=0.02) • No difference in birthweight < 2500 gm: 41.2% Progesterone vs 42.8% Placebo (p=NS) • No difference Composite Neonatal Morbidity: 8.1% Progesterone vs 13.8% Placebo (p=0.19) Fonseca 2007 NEJM Preterm Birth Prevention: Progesterone – Short Cervix • Randomized trial (n = 458) • Singleton/Cervix 10‐20 mm • Treatment: Placebo (n= 235) Vaginal Progesterone (n=458) Hassan 2011 Ultrasound Obstet Gynecol Preterm Birth Prevention: Progesterone – Short Cervix • Reduced SPB < 33 weeks: 8.9% Progesterone vs 16.1% Control (p=0.02) • Reduced SPB < 28 weeks: 5.1% Progesterone vs 10.3% Control (p=0.04) • Composite Neonatal Morbidity: 7.7% Progesterone vs 13.5% Control (p=0.04) Hassan 2011 Ultrasound Obstet Gynecol 200 Texas Two-Step Conference, Januar 9 - 10, 2015 Arrested Preterm Labor Preterm Birth Prevention: Progesterone – Arrested PTL Total N Progestin Control Latency Latency Progestin Control ∆ Neo. Morb Facchinetti 2007 60 RCT 17P IM No Rx 341 mg 2x/week 35 d 19 d 15 d * ----- Borna 2008 70 RCT Vag P4 400 mg qd Placebo 36 d 24 d 12 d * RDS * 11 vs 36% Sharami 2010 173 RCT-DB Vag P4 200 mg qd Placebo 24 d 17 d 7d* NS Vag P4 200 mg qd Historic No Rx 53 d 44 d 9d* NS Bomba-Opon 190 2011 Retro * P < 0.05 Facchinetti 2007 AJOG (194:435, e1-4); Borna 2008 ANZJOG (48: 58-63); Sharami 2010 (Int J Fertil Steril (4: 45-50); Bomba-Opon 2011 (J Matern Fetal Neonat Med (Epub) PPROM 201 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention: Progesterone – PPROM • Randomized trial (n = 69) • Singleton/PPROM/< 24 weeks • Treatment: Placebo (n=36) 17‐P (n=33) Briery 2011 AJOG Preterm Birth Prevention: Progesterone ‐ PPROM • No difference in GA at delivery: 27.3 wk Progesterone vs 29.5 wk Placebo (p=0.15) • No interval to delivery: 11.2 days Progesterone vs 14.5 days Placebo (p=0.25) • No difference neonatal morbidity: 73% Progesterone vs 78% Placebo (p=NS) Briery 2011 AJOG Preterm Birth Prevention: Progesterone – PPROM p = 0.18 Briery 2011 AJOG 202 Texas Two-Step Conference, Januar 9 - 10, 2015 ACOG Practice Bulletin #130 Prediction and prevention of preterm birth October 2012/Reaffirmed 2014 Obstet Gynecol 2012;120:964–73 ACOG Practice Bulletin #130 Progesterone - Level A Evidence • A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth (Obstet Gynecol 2012;120:964–73) ACOG Practice Bulletin #130 Progesterone - Level A Evidence • Vaginal progesterone is recommended as a management option to reduce the risk of preterm birth in asymptomatic women with a singleton gestation without a prior preterm birth with an incidentally identified very short cervical length less than or equal to 20 mm before or at 24 weeks of gestation. (Obstet Gynecol 2012;120:964–73) 203 Texas Two-Step Conference, Januar 9 - 10, 2015 ACOG Practice Bulletin #130 Progesterone - Level A Evidence • Progesterone treatment does not reduce the incidence of preterm birth in women with twin or triplet gestations and, therefore, is not recommended as an intervention to prevent preterm birth in women with multiple gestations (Obstet Gynecol 2012;120:964–73) Progesterone Products 17α‐Hydroxyprogesterone Caproate ACOG SMFM Compounded 17P Makena March of Dimes Makena Cytec Corporation 204 Texas Two-Step Conference, Januar 9 - 10, 2015 Delalutin/Gestiva/Makena • 17‐Alpha‐HydroxyprogesteroneCaproate • In May 2006, Adeza Biomedical submitted NDA 21‐945 to FDA for approval of “Gestiva” • October 2006, FDA requests more data regarding Gestiva • Adeza acquired by Cytyc Corp. on April 2, 2007 Delalutin/Gestiva/Makena • October 22, 2007, Hologic acquires rights to Gestiva • January 22, 2008, Hologic sells rights to Gestiva to KV Pharmaceutical Co (valued at $82 million) contingent on FDA approval • 2009 Gestiva not approved by FDA – additional data requested • February 4, 2011 – FDA approves Hologic/KV Pharmaceutical NDA 12‐945 for Makena: 7 years of exclusivity under Orphan Drug Act 1983 Makena – FDA Approved IM 17‐OHPC kjgjhgjhgjhghgjhjhgghhg hghghghghhgghghghgh ghhgghhgghhjjggjhhhgg hhghgjjggghghghghghh ghjjhhghggggghjjhhjghgj jggj 205 Texas Two-Step Conference, Januar 9 - 10, 2015 Makena FDA Statement – March 30, 2011 “In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products.” Makena FDA Statement – November 8,2011 “In October 2011, FDA received information from K‐V Pharmaceuticals regarding the potency and purity of samples of bulk hydroxyprogesterone caproate active pharmaceutical ingredients (APIs) and compounded hydroxyprogesterone caproate products. According to the analysis of this information provided by K‐V, there is variability in the purity and potency of both the bulk APIs and compounded hydroxyprogesterone caproate products that were tested. Although FDA has not validated or otherwise confirmed the analyses provided by K‐V, FDA has carefully reviewed the data and will conduct an on‐site review of the laboratory analyses.” Makena FDA Statement – November 8,2011 “FDA has begun its own sampling and analysis of compounded hydroxyprogesterone caproate products and the bulk APIs used to make them. That process is ongoing. In the meantime, we remind physicians and patients that before approving the Makena new drug application, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice. Therefore, as with other approved drugs, greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product.” 206 Texas Two-Step Conference, Januar 9 - 10, 2015 Makena FDA Statement – June 15, 2012 “FDA tested 16 samples of hydroxyprogesterone caproate API using the methods specified in the United States Pharmacopeia (USP) as well as the methods used in the Makena new drug application (NDA). ‐ All 16 API samples passed USP tests for potency (97‐103 percent) and purity and all 16 API samples passed the potency tests in the Makena NDA. ‐ All 16 of the API samples passed the total purity standard in the Makena NDA but failed the Makena NDA’s limit for unidentified impurities.” Makena FDA Statement – June 15, 2012 “FDA also isolated and identified four impurities that appeared at levels above those permitted in the Makena NDA. Based on information available to FDA, the impurities observed in these samples do not raise safety concerns.” Makena FDA Statement – June 15, 2012 “FDA also tested 13 samples of compounded hydroxyprogesterone caproate prepared by eight pharmacies. ‐ One of 13 samples was subpotent and was in the range of 80 percent of declared potency. (The standard for potency is 90‐110 percent). All 13 of the samples met the standard in the Makena NDA for total purity. Two of the 13 samples failed to meet the standard for unidentified impurities in the Makena NDA.” 207 Texas Two-Step Conference, Januar 9 - 10, 2015 Makena FDA Statement – June 15, 2012 “FDA also obtained the available retained samples of compounded products from the laboratories that K‐V hired to perform the tests on the compounded products that were submitted to the agency in October 2011. FDA’s testing of the retained samples found that three of 26 samples that failed the original standard for potency (90‐ 110 percent) using the method in the Makena NDA were in the 115 percent range.” Makena FDA Statement – June 15, 2012 “Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products. FDA emphasizes that it is applying its normal enforcement policies for compounded drugs to compounded hydroxyprogesterone caproate. The compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding.” Makena FDA Q & A – June 29, 2012 “Should health care professionals prescribe and patients take the FDA‐approved drug product rather than the compounded product? If there is an FDA‐approved drug that is medically appropriate for a patient, the FDA‐approved product should be prescribed and used….” 208 Texas Two-Step Conference, Januar 9 - 10, 2015 Makena KV Pharmaceutical vs FDA Makena KV Pharmaceutical vs FDA • July 7, 2012: KV Pharmaceutical and Ther‐Rx Corporation file Motion for Temporary Restraining Order and Preliminary Injunction and Compliant for Declaratory and Injunction Relief in US District Court for the District of Columbia • Listed Defendants: United States and Drug Administration United States Department of HHS Margaret A. Hamburg, MD (FDA Commissioner) Kathleen Sebelius (Secretary HHS) Makena Lumara Health • FDA prevailed in Federal Court • In 2014, KV Pharmaceutical converted to Lumara Health • November 12, 2014, AMAG Phamaceutical acquires Lumara Health • More to come…. 209 Texas Two-Step Conference, Januar 9 - 10, 2015 Compounded 17P Preparations Purity Assessments • NICHD: analysis of 18 specimens from 15 compounding pharmacies • Concentration of 17-OHPC in all samples was within the specification limits, and all tested samples passed sterility and pyrogen testing. • Only 1 of 18 samples was out of specification limits for impurities • No safety concerns when assessed for potency, sterility, pyrogen status, or impurities AJOG 2014 17P Preparations Cost • Compounded 17‐OHPC 250 mg IM Weekly: $13 per week ($260/pregnancy) • Makena 250 mg IM Weekly: $690 per week ($13,800/pregnancy) Prochieve/Crinone/Prometrium 210 Texas Two-Step Conference, Januar 9 - 10, 2015 Vaginal Progesterone Preparations Cost • Prochieve 8% Intravaginal Daily: $74/week ($1,480/pregnancy) • Crinone 8% Intravaginal Daily $160/week ($3,200/pregnancy) • Prometrium 200mg Intravaginal Daily $450/week ($9,000/pregnancy) Safety Progesterone – Safety Meis Study – Primary Outcomes Relative Risk 0.66 PTB < 37 wk 0.67 PTB < 35 wk 0.58 PTB < 32 wk 0.1 1 10 Meis NEJM 2003 211 Texas Two-Step Conference, Januar 9 - 10, 2015 Progesterone – Safety Meis Study F/U – Mean 48 months 17P (n=193) Placebo n=82) P 11% NS Scores below cut‐off on Ages & Stages Questionnaire Communication 11% Gross Motor 3% 4% NS Fine Motor 21% 18% NS Problem Solving 10% 11% NS Motor Skills Problem 1% 1% NS Developmental Delay 7% 8% NS 10% NS Diagnoses from Health Professionals Attention or Learning Problems 8% Northen Obstet Gynecol 2007 (110:865-72) Progesterone – Safety 18 Month F/U Study - Twin Trial P4 Placebo P Ages & Stages Questionnaire ASQ Scores at 6 months 215 +/‐ 38 218 +/‐ 37 NS ASQ Scores at 18 months 193 +/‐ 43 194 +/‐ 41 NS Score < 115 at 18 months 3.8% 3.7% NS Rode et al Ultrasound Obstet Gynecol 2011 Preterm Birth Prevention: Progesterone – Perinatal Loss • 2003 Meis Trial (singleton/prior SPTB) 17P: 5 miscarriages < 20 weeks, 6 IUFDs 11 losses of 306 (3.6%) Placebo: 0 miscarriages < 20 weeks, 2 IUFDs 2 losses of 153 (1.3%) • 2010 Combs Trial (triplets) 17P: Loss of 13/168 offspring (8%) IUFD/previable Placebo: 0 of 75 lost p < 0.05 212 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention: Progesterone – Safety “We should be vigilant about interfering with systems we poorly understand in the absence of benefit” Kenyon et al. Lancet 2008 Diethylstilbesterol Preterm Birth Prevention: Progesterone – Safety “The DES Story humbles us. It serves as a reminder that through the narrow lens of today might reassure us that an intervention is safe. It is only with the wisdom of time that the full consequences of our actions are revealed” Goodman et al NEJM 2011 (364:2084) 213 Texas Two-Step Conference, Januar 9 - 10, 2015 Preterm Birth Prevention: Progesterone – Safety “Because questions exist regarding miscarriage and other risks, progestins should be used only for indications where benefit has been established or in controlled clinical trials” Combs et al AJOG 2011 SUMMARY Best Evidence • 17P effective for women with singleton gestation and history of prior singleton spontaneous preterm birth • Progesterone ineffective in multifetal gestations SUMMARY Best Evidence • 17P and vaginal progesterone preparations appear to be safe • Compounded progesterone appears to be as safe to FDA approved Makena 214 Texas Two-Step Conference, Januar 9 - 10, 2015 SUMMARY Best Evidence • Whether FDA approved product or compounded, strong evidence supports progesterone as an effective intervention to prevent preterm birth in select populations Progesterone for Preterm Birth Prevention Cost Effectiveness • If universal treatment of selected population, discounted lifetime medical costs of their offspring could be reduced by more than $2,000,000,000 annually Bailit JL – AJOG 2007 Questions adi.abramovici @uth.tmc.edu 215 Texas Two-Step Conference, Januar 9 - 10, 2015 Whaat Wo ould d You u Do o? Co omp plicated Case C e Pre esentatio ons Hecctor M Mendeez‐Figgueroa, M.D. 216 Texas Two-Step Conference, Januar 9 - 10, 2015 What Would You Do: Complicated Case Presentations Hector Mendez-Figueroa, M.D. Assistant Professor Department of Obstetrics, Gynecology And Reproductive Sciences UT Health Sciences in Houston Disclosure Statement I do not have relevant financial relationships with commercial interests related to the content of this presentation. Learning Objectives 1. Understand literature and its limitations 2. Understand the limitations of some come tests used by clinicians 3. Review the ACOG/SMFM guidelines regarding timing of delivery 217 Texas Two-Step Conference, Januar 9 - 10, 2015 CLINICAL SCENARIO #1 40 y/o G2P1 @ 15 weeks is returning your call to discuss her Non‐invasive prenatal testing results. Earlier that day you discovered that she had tested “positive” for trisomy 21, Down syndrome. How do you counsel this patient? CLINICAL SCENARIO #1 A. The test is just so new that we should repeat it before we do anything else (false positive) B. Wait for the MFM sonogram, this will tell us if the baby has T21 or not C. The sensitivity and specificity of this test is over 99%, I am sure you baby has T21 D. This is still a screening test, I recommend we proceed with a diagnostic invasive test in order to confirm CLINICAL SCENARIO #1 Would you address this differently if the patient were 30 years old with no family history of genetic disorders and no past medical history? A. YES B. NO 218 Texas Two-Step Conference, Januar 9 - 10, 2015 CLINICAL SCENARIO #1 Would your approach be different if the results were “positive” for trisomy 18? A. YES B. NO VIDEO www.bostonglobe.com 219 Texas Two-Step Conference, Januar 9 - 10, 2015 CIRCULATING CELL‐FREE FETAL (CFF) NUCLEIC ACIDS Source of ccff DNA PLACENTAL and fetal‐derived cells Breakdown of fetal cells in circulation Percentage in circulation ~3‐6% of circulating DNA in maternal plasma is fetal in origin >10% in recent studies Need >4% fetal fraction in most labs for valid study Clinically available November 2011 in the United States for high risk Low risk – is currently company dependent NIPT Targeting Chromosomes 21, 13, 18, X and Y Two different quantification techniques commonly used MPSS : Generates a Z‐score for each chromosome studies ¾ ¾ ¾ Generally above Z‐score of 3 is abnormal cut‐off Sequenom (materniti21plus) = pure cut‐off Verinata (verify) = gray zone where further testing may be warranted DANSR + FORTE ‐ Digital Analysis of Selected Regions plus Fetal‐ fraction Optimized Risk of Trisomy Evaluation (Ariosa) One SNP based technique NATUS = Next‐generation Aneuploidy Test Using SNPs [NATUS] algorithm (Panorama – Natera) 220 Texas Two-Step Conference, Januar 9 - 10, 2015 Z‐Scores DANSR + FORTE Norton et al AJOG 2012 SNP BASED TESTING Rabinowitz et al from Natera 221 Texas Two-Step Conference, Januar 9 - 10, 2015 NIPT VALIDATION NIPT has been validated by prospective studies: In high risk pregnancies AMA Abnormal serum screen Family or personal hx of child with aneuploidy Abnormal ultrasound suggestive of aneuploidy Between 10‐22 weeks gestation NIPT VALIDATION Blinded nested case-control Study – high risk 212 cases trisomy 21 and 1471 matched controls • 209/212 trisomy 21 screen positive – True positive rate = 98.6% (SENSITIVITY) • 105 -1st trimester;107 - 2nd trimester, 13 samples failed 3/1471 euploid screen positive - False positive rate = 0.2% 1468/1471 euploid screen negative - True negative rate 99.8% (SPECIFICITY) 3/212 trisomy 21 screen negative - False negative rate 1.4% Palomaki et al, Genetics in Medicine 2011 More difficult to identify trisomy 18 and 13 due to higher variability of genomic representation in euploid pregnancies Trisomy 18 • 3/62 failures due to low fetal fraction • Detection rate of the 59 than were run 100% (59/59); CI [93.9‐100] • False positive rate of 0.3% (5 out of 1,688) Trisomy 13 • Detection rate of 91.7% (11/12); 95% CI [61‐99] • False positive rate of 1% (16 out of 1,688) Palomaki et al, Genetics in Medicine 2012 222 Texas Two-Step Conference, Januar 9 - 10, 2015 NIPT VALIDATION 2,882 samples from singleton pregnancies at 60 US sites High risk; having invasive procedure Sponsored by Verinata 3.0% of samples had no fetal DNA detected Trisomy 21 = 100% detection rate (89/89); CI [95.9-100] Trisomy 18 = 97.2% detection rate (35/36); CI [85.5-99.9] Trisomy 13 = 78.6% detection rate (11/14); CI [49.2 – 99.9] Monosomy X = 93.8% detection rate (15/16); CI [69.8-99.8] Bianchi et al, OB GYN 2012 NIPT VALIDATION Trisomy 21 using DANSR and FORTE algorithm • 81/81 detected (100%) • 0.03% false positive rate (1/2,888) • The 1 false positive case had risk estimate of 1.1% or 1 in 92 • Also one mosaic t21 classified as low risk Trisomy 18 • 37/38 detected (97.4%) • The 1 missed affected case had risk estimate of 1 in 10,000 • 0.07% FPR (2/2,888) • False positive cases: • 73% risk • 99% risk Approximately 0.5% of women will have scores between the >99% or Norton et al, Genetics 2012 < 1in 10,000 used in other labs WHAT ARE THE LABS REPORTING? Laboratory Technology Conditions Tested For Sensitivity Specificity Reporting Sequenom MPSS Trisomy 21 Trisomy 18 Trisomy 13 SCA T21 = 99.1% T18 = >99.9% T13 = 91.7% SCA = 96.2% T21 = 99.9% T18 = 99.6% T13 = 99.7% SCA = 99.7% Positive Negative Failure No Call SCA MPSS Trisomy 21 Trisomy 18 Trisomy 13 Monosomy X T21 = 100% T18 = 97.2% T13 = 78.6% 45X = 95% T21 = 100% T18 = 100% T13 = 100% 45X = 100% Positive Negative Unclassifiable Failure DANSR (assay) + FORTE (algorithm) Trisomy 21 Trisomy 18 Trisomy 13 T21 = 100% T18 = 97.4% T21 = 99.9% T18 = 99.9% Risk Ratio via algorithm 1/10,000 – 99/100 (MaterniT21Plus) Verinata (Verify/Illumina) Ariosa (0.5% results fell between the two extreme values) 223 Texas Two-Step Conference, Januar 9 - 10, 2015 Frozen samples on 2,049 women who had combined FTS in 2010‐2011 95.1% had a result 2.2% low fetal fraction 2.6% assay failure (1 of these 54 turned out to have t18) Trisomy 21 8/8 had high risk score (>99%) [average maternal age 39.6 in this group] No false positives Trisomy 18 2/2 had high risk score (>99%) [average maternal age 39.4 in this group] 2/1939 had false positive high risk score 9.8% 11.7% No Trisomy 13 or SCA information Ariosa group = began offering to low risk when launched Nicolaides et al, AJOG 2012 Low risk women (mean age 29.6) having routine maternal serum screening, largely combined FTS, Quad, Sequential screens Run on Verinata’s platform 1,914 women; 8 aneuploidy Serum Screens NIPT Trisomy 21 3.6% False positive (69/1909) [51/1365] 5/5 detected 4.2% PPV 0.3% false positive (6/1909) [4/1365] 5/5 detected 45.5% PPV Trisomy 18 0.6% false positive (11/1905) 2/2 detected 8.3% PPV 0.3% false positive (3/1905) 2/2 detected 40% PPV Trisomy 13 0.6% false positive (6/899) 0.1% (1/899)* (*also 2 false positive in group that had other screens that did not include t13 = 3/?1909 = 0.15%) SCA Not analyzed Bianchi et al, NEJM 2014 STATS 101 One thing to remember is that sensitivity and specificity are statistical properties of the test itself, measures validity – – – – – – Compare the test to a “gold standard” Does not take into consideration any “indeterminate” test results Independent of the prevalence of the disease How likely is the test to pick up a disease? Tests with high sensitivity are useful for ruling out a disease Sensitivity and specificity are better aimed at evaluating population 224 Texas Two-Step Conference, Januar 9 - 10, 2015 STATS 101 A more clinically important question would be to evaluate the test characteristics for an individual patient • How likely I am to have the disease if I have a positive test? • How precise is this test? PREDICTIVE VALUE PREDICTIVE VALUE ‐ PREVALENCE SENSITIVITY = 99%, SPECIFICITY = 99% Disease prevalence 5% Disease prevalence 1% Test results Sick Positive 99 99 Negative 1 9,801 100 9,900 10,000 Totals Totals Not Sick Totals Test results Sick 198 Positive 495 95 590 9,802 Negative 5 9,405 9,410 500 9,500 10,000 PPV = 99/198 = 50% Not Sick Totals PPV = 495/590 = 84% PREDICTIVE VALUE ‐ NIPT SENSITIVITY = 99.1%, SPECIFICITY = 99.9% (SEQUENOM) Age 30, Disease prevalence 1/703 Test results Sick Positive 141 100 241 Positive 1,303 99 1,402 Negative 1 99,758 99,759 Negative 13 98,585 98,598 142 99,858 100,000 Totals 1,316 98,684 100,000 Totals Not Sick Totals Age 40, Disease prevalence 1/76 PPV = 141/241 = 58.5% Test results Sick Not Sick Totals PPV = 1,303/1,402 = 92.9% 225 Texas Two-Step Conference, Januar 9 - 10, 2015 NIPT – TRISOMY 21 AGE PPV 20‐24 25‐29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 45.3% 48.3% 58.5% 61.9% 65.7% 69.8% 74.0% 78.0% 81.9% 85.4% 88.4% 90.9% 93.0% 94.7% 95.9% 97.0% 97.7% 98.3% NIPT – OTHER ANEUPLOIDIES Trisomy 18 AGE 20‐24 25‐29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Trisomy 13 PPV 9.1% 10.2% 14.7% 16.5% 18.9% 21.9% 25.6% 30.1% 35.4% 41.4% 48.0% 54.7% 61.6% 68.1% 73.9% 79.3% 83.6% 3.8% 4.2% 6.3% 7.1% 8.3% 9.8% 14.2% 14.3% 17.6% 21.5% 26.3% 31.9% 38.2% 45.1% 52.3% 59.5% 66.4% CLINICAL SCENARIO 40 y/o G2P1 @ 15 weeks with a “positive” NIPT result for trisomy 21, Down syndrome. 1. Would your approach be different if the patient were 30 years old (low‐risk)? 2. Would you approach be different if the results had been positive for trisomy 18? 226 Texas Two-Step Conference, Januar 9 - 10, 2015 FUN FACTS ‐ Between 450,000 to 800,000 NIPT tests have been performed in the United States since 2011 ‐ In one study 6.2% (22/356) of women with abnormal results terminated without an invasive confirmatory test ‐ At Stanford University, there have been at least three cases of women aborting healthy fetuses after a positive result MICRODELETIONS – MORE CONFUSION Offered as a August 2014 Sequenom Verinata Natera 22q DiGeorge 5p Cri‐du‐chat 15q PraderWilli/Angelman 1p36 4p‐ Wolf‐Hirschhorn 8q Langer Giedion 11q Jacobsen Trisomy 16 Trisomy 22 22q11 5p‐ 15q11 1p36 4p‐ 22q11 5p‐ 15q11 1p36 4p‐ 94.4% sensitivity (17/18) 99.4% specificity (156/157) 91.6% sensitivity 99.84% specificity ? Internal validation Trisomy 16 Trisomy 9 ??? MICRODELETIONS – MORE CONFUSION 22qdel 94.4% sensitivity 99.4% specificity 1/1,000 incidence PPV = 13.6% 15qdel 8qdel 94.4% sensitivity 99.4% specificity 1/10,000 incidence 94.4% sensitivity 99.4% specificity 1/50,000?? incidence PPV = 1.5% PPV = 0.31% 227 Texas Two-Step Conference, Januar 9 - 10, 2015 TIMING OF DELIVERY CLINICAL SCENARIO #2 32 y/o G2P1 @ 30 3/7 weeks with a history of a prior cesarean section has been diagnosed with complete anterior placenta previa since week 20. A recent ultrasound is now highly suspicious for placenta accreta. Does the “39 week” rule apply to everyone? When should this patient be delivered? ACOG STATEMENT “Planned deliveries before 39 weeks 0 days should occur only when there are significant health risks to a woman and/or the fetus in continuing the pregnancy” 228 Texas Two-Step Conference, Januar 9 - 10, 2015 Tita et al, NEJM 2009 • Based on the 2005, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) workshop • Infants born late preterm are more likely to have long‐term neurodevelopmental problems and infant death than those born at term • Neonates born before 39 weeks are at increased risk for significant complications compared with those born after 39 weeks • Continuing pregnancy in the face of medical or obstetric complications potentially can increase the risk to mother, the fetus, or both. Spong et al, OB GYN 2011 NEW TERMINOLOGY 1. Early preterm – < 34 0/7 weeks 2. Late preterm – 34 0/7 – 36 6/7 weeks 3. Early term – 37 0/7 – 38 6/7 weeks 4. Full Term – 39 0/7 – 40 6/7 weeks 5. Late term – 41 0/7 – 41 6/7 weeks 6. Post term ‐ ≥ 42 0/7 weeks 229 Texas Two-Step Conference, Januar 9 - 10, 2015 CLINICAL SCENARIO #2 30 3/7 weeks prior C/S with possible placenta accreta. A. B. C. D. 32 weeks? 34‐36 weeks? 37 weeks? 39 weeks? ACOG 2013 CLINICAL SCENARIO #3 You refer a 20 y/o G1 @ 35 3/7 weeks with no past medical history to the MFM ultrasound unit because her fundal height is measuring 4 weeks behind. Her pregnancy has been uncomplicated thus far. On ultrasound the fetus has an EFW at the 5th percentile with normal AFI, BPP 10/10 and a normal S/D ratio on umbilical artery Dopplers. What is the best timing for delivery? 230 Texas Two-Step Conference, Januar 9 - 10, 2015 CLINICAL SCENARIO #3 20 y/o G1 @ 35 3/7 weeks with IUGR and normal antenatal testing A. B. C. D. Deliver now 36 weeks? 37 weeks? 38‐39 weeks? ACOG 2013 CLINICAL SCENARIO #4 32 y/o G2P1 @ 35 3/7 weeks diagnosed with GDM is in your office to review her BG log. You notice she is poorly complaint with her testing and when does test, she has several postprandial values over 200 mg/dl and some fasting values over 120 mg/dl. Best timing for delivery? 231 Texas Two-Step Conference, Januar 9 - 10, 2015 CLINICAL SCENARIO #4 32 y/o G2P1 @ 35 3/7 weeks non‐compliant poorly controlled GDM A. B. C. D. Deliver now 36 weeks? 37 weeks? 38‐39 weeks? ACOG 2013 QUESTIONS? 232 ThankYou for Attending! Childrens.memorialhermann.org