logging in or signing up GR2012-02 Maternal Fetal Medicine- Don't Believe Everything You Think chiefhgh Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 32 Category: Education License: All Rights Reserved Like it (0) Dislike it (0) Added: February 03, 2012 This Presentation is Public Favorites: 0 Presentation Description No description available. Comments Posting comment... Premium member Presentation Transcript Don’t Believe Everything You Think: Don’t Believe Everything You Think AKA: Don’t Punish My Patient For Being Pregnant . Mickye Adams, MD Maternal Fetal MedicineWho are my patients? : Who are my patients? JM is a 29 yo w / relapsing remitting MS very well controlled on beta-interferon prior to pregnancy Stopped at 5-6 wk gestation -> much worse when I saw her at 18 weeks. PT is a 25 yo with progressive CRI and nephrotic syndrome Unplanned pregnancy AD is a 30 yo with mechanical TV on Coumadin Unplanned pregnancy KP is a 16 yo with HTN Cardiomyopathy Unplanned pregnancyJust Yesterday: Just Yesterday 37 yo G2 P0100 at 7+ weeks Hx Severe Pre-Eclampsia at 35 wks -> Fetal Demise Hx Severe HTN -> admitted HGH 1/6/12-1/8/12 Admission BP 213/133, Facial Droop, + LVH Ruled out for CVA, Dx Bell’s and Essential HTN Started on Nifed 30/d + UPT on f/u in Medicine, BP 145/90 Nifed stopped due to “Cat C Med” and nothing started, no PNV Referred to GYN (Ref Track) Pt dropped in to GYN worried she needed Anti HTN BP 200/117 Nifed 30 restarted, home BP cuff, f/u 1 wkCauses of Congenital Malformations: Causes of Congenital Malformations 65% Mulitfactorial 25% Genetic 4% Maternal Condition 3% Maternal Infection 1-2% Mechanical Deformations <1% Drugs, Chemicals, Radiation, Hyperthermia MothersRisk.comChallenge: Challenge Ask first: What would I recommend for this pt if she were NOT pregnant? Ask second: What do I need to modify due to the pregnancy and WHY ? Outline: Outline History Lesson – A Tale of Two Drugs Case 1 – Is Withholding Treatment Best? INH Case Case 2 – Is Withholding Treatment Best? Metformin Case Case 3 – Is Withholding Treatment Best? Breast Cancer Case Case 4 – Preconception Counseling Conundrum Renal Panc Transplant Case Resources – Where to goThalidomide: Thalidomide Sedative patented 1954 Drs thought placenta blocked drug passage Helped Morning Sickness – used by countless thousands OTC internationally Never approved in US 20,000 samples distributed to drs /pts by companyPowerPoint Presentation: Lancet publishes Letter by Dr William McBride Thalidomide and Congenital Abnormalities Date: December 16, 1961 10-20,000 babies with defects – phocomelia US Changes Laws re: Drugs in Pregnancy in 1962PowerPoint Presentation: 1962: Frances Kelsey gets honor from JFK for blocking Thalidamide from FDA approvalFDA Approved Drugs for Use in Pregnancy 1962-2010: FDA Approved Drugs for Use in Pregnancy 1962-2010FDA Approved Drugs for Use in Pregnancy 1962-2010: FDA Approved Drugs for Use in Pregnancy 1962-2010 Oxytocin Cervadil Obstetrics & Gynecology:April 2010;115:4 pp 825-833Bendectin: Bendectin Pyridoxine (Vitamin B6) Doxylamine (Antihistamine Unisom, Preg Cat A)Bendectin: Bendectin 31,564 women (prospectively analyzed) Any Major Malformation OR 1.0 (0.8-1.4) Teratology . 1989;40:151-5.Bendectin Meta-Analysis: Bendectin Meta-Analysis Study N Exposed E- Malform Non-Exp NE- Malfor RR CI 154,469 16,345 375 138,124 5797 0.95 0.62-1.45 Drug Intel1 Clin Phar- macol . 1988;22:813-24.Bendectin: Bendectin Only drug approved by FDA for N/V in preg Approved prior to 1962 33 million used 1 in 10 preg women in US 300 law suits 1 = $750,000 -> off market in 13 days Dr. W. McBride – lead plaintiff expert in many cases Did basic and clinical research on risks of bendectin in preg Merrell: Insurance rate $10M Only $3M net profit NYT 6/19/1983 " The Independent" on 20 February 1993Bendectin: Bendectin FDA review panel 1983: No association between Bendectin and birth defects had been demonstrated. …no way to prove the absolute safety of any drug in all women under every circumstance, there must remain a ''residual uncertainty'' about how this drug affects an unborn child. NYT 6-19-1983Bendectin: Bendectin BENDECTIN: REVIEW OF THE MEDICAL LITERATURE OF A COMPREHENSIVELY STUDIED HUMAN NONTERATOGEN AND THE MOST PREVALENT TORTOGEN-LITIGEN Comprehensive review: All human, animal, in vitro, dose-response, biological plausability …. Conclusion: “ T herapeutic use of Bendectin has no measurable teratogenic effects .” Reproductive Toxicology, Vol. 9, No. 4, pp. 337-349, 1995Bendectin: Bendectin Dr. William McBride falsified data on Bendectin License revoked in 1993 All cases overturned on appeal, no $ from MerrellProven Teratogens 1962-1997: Proven Teratogens 1962-1997 Only 35 drugs have been proven teratogens in past 35 years! Partial List of Proven Teratogens AED Phenetoin – FHS, Carbamazapine , Valproate ->NTD Isotretinoin – Accutane Syndrome Thalidomide – phocomelia ACE inhibitors – renal failure Lithium – Ebstein’s Anomaly N Engl J Med 1998; 338:1128 MothersRisk.orgFDA Approved Drugs for Use in Pregnancy 1962-2010: FDA Approved Drugs for Use in Pregnancy 1962-2010 Oxytocin Cervadil Wikipedia – FDA Pregnancy Categories 2012 One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be considered Pregnancy Category A in other countries are allocated to Category C by the FDA.Case 1: Case 1 JR is a 24 yo Guatemalan woman in US for 8 months. PPD positive, Asx , Neg CXR -> Started INH in May + UPT in July in K6 Medicine Your Advice: 1. Stop Immediately 2. Continue Medicine?LTBI – CDC 2010 and UTD 2012: LTBI – CDC 2010 and UTD 2012 CDC: Pregnancy In the absence of risk factors, wait until after the woman has delivered to avoid administering unnecessary medication during pregnancy. INH daily or twice weekly (using DOT) is the preferred regimen. Consider delaying treatment for LTBI until 2–3 months post-partum unless there is a high risk of progression to TB disease (e.g., HIV infected, recent contact). UTD: Don’t Test if Low Risk If TST + but low risk -> Don’t Treat If TST + but high riks -> Treat High Risk: Immunocompromised , Recent ExposureCase 1 – Ms JR: Case 1 – Ms JR Advice now: 1. Stop Medicine? 2. Continue Medicine? Who changed their mind? 1. Yes – changed 2. No – didn’t changeLTBI – Rationale for Treatment: LTBI – Rationale for Treatment Historically, LTBI -> 12.8% Active TB within 10 years High Risk Conditions HIV +, IVDA, Homeless, Incarcerated Recent Immigrant from Endemic Country Known Exposure to Active TB, Recent Conversion Transplant, Renal Insuff , others INH Tx decreases TB by 25-90% Most if 9-12 mo completed 0.15-2% INH Hepatitis -> 0.001% deaths Am Thor Society July, 1999 Obstet Gynecol 2000;96:757-62Is CXR Safe in Pregnancy?: Is CXR Safe in Pregnancy? Modern CXR -> dose to fetus 0.00007 rad (0.7 mrad ) So low it can’t be measured with most instruments! Risk: All agree < 5 rad is safe at any point in preg Limit CXR to < 70,000 during pregnancy, please. Documented Fetal Risk: >20 rad Background Radiation at Sea Level – 2-10 days Background Radiation at Higher Elevation – 8 hours Radiation from flying SF to NYC (approx) 3.5 X higher than CXR, One Way Am Fam Physician. 1999 Apr 1;59(7):1813-1818 wwqw.doh.wa.gov/ehp/rp/factsheets/factsheets-htm/fs10bkvsman.htm hps.org/publicinformation/ate/faqs/commercialflights.htmlIs INH Safe in Pregnancy?: Is INH Safe in Pregnancy? FDA Pregnancy Cat C Multiple Experts (CDC, ATS, ACOG, UTD) INH is NOT a human teratogen . No Adverse Neonatal Effects shown from in uterio INH ExposureINH Toxicity May Be Up in Pregnancy : INH Toxicity May Be Up in Pregnancy US: Hispanic Prenatal Clinic in 1980s (54% PPD +) INH given to 3681 pt 3 mo Supply, Seen every 3 months for 12 months LFTs if pt c/o sx at the 3 mo visits 5 Hepatitis (2-7 mo into tx ) 2 Deaths – both PP (3 mo and 5 mo) Retrospective female Control group NS diff in Hep or Death but SMALL (2.5 X higher, NS) Recommendations for INH Then and Now Only 30 pills at a time Screen for Sx Hepatitis Monthly! Subsequent Recommendations: Do Not Treat Low Risk Women in Pregnancy or Imm PP Public Health Rep. 1989 Mar-Apr; 104(2): 151–155.Should Tx LTBI be delayed PP?: Should Tx LTBI be delayed PP? NYC Immigrants: >50% PPD+, most newly dx’d Only 9.3% completed tx PP 30% not referred, 18% didn’t attend, 35% Noncompl Conclusion: Prenatal Setting a “Missed Opportunity” SF General: 32% PPD+ Only 18% completed tx PP (min 6 mo) 42% referred If same provider for OB care: 67% started -> 62% completed (42% of original) Conclusion: Despite opportunity in PNCare , only 18% Am J Obstet Gynecol 2006;194:451 Am J Obstet Gynecol 2005;192:1455Tx in Preg: Risks vs Alternatives: Tx in Preg : Risks vs Alternatives Markov Decision Analysis Model 3 Groups compared: No Tx , AP (6mo AP, rest PP), PP start LTBI = PPD 10mm and CXR Neg Not Other HR Factors No Tx -> 3.3/1000 get TB AP -> 1.4/1000 get TB More Hep deaths (assumed 2.5X higher) Longest Life Expectancy Most Cost Effective PP -> 1.8/1000 get TB AP Not Best Option Only if 10X more Hep deaths AND 10X less TB deaths than existing data and assumptions Obstet Gynecol 2000;96:757LTBI in Preg: LTBI in Preg Many of our women have RF F/U INH tx unlikely to be completed 25% of those who started tx at EWC Chest Clinic INH does not pose risk to Fetus Maternal INH should be monitored 30 d Rx only, Educate pt Sx (Seen < 30 day anyway) Check Sx every 30 days (Seen < 30 day anyway) Check LFTs at baseline and monthly Very conservative approachCase 1: Case 1 JR is a 24 yo Guatemalan woman in US for 8 months. PPD positive, Asx , Neg CXR -> Started INH in May + UPT in July in your office Your Advice: 1. Stop Immediately? 2. Continue Medicine? 3. If no Sx , Check LFT, cont med and refer for care with OB experienced in INH tx ? or cont INH monitoring in your clinic?Case 2: Case 2 RS is a 29 yo with Type II DM for 3 years On Metformin from your office Calls with + home Preg Test Unsure LMP about 6 weeks ago 1. Stop Med? 2. Continue Med?Embryogenesis DM, and Metformin: Embryogenesis DM, and Metformin Background rate of major malformations 3% at birth, 5% recognized by 5 yo Neural Tube – closes at 4-5 wk postconception 6-7 wk post-LMP Heart – folds at 5-6 wk postconception 7-8 wk post-LMPHyperglycemia = Bad in Embryos: Hyperglycemia = Bad in Embryos Infants of Diabetic Mothers – 7X malformations 15X more NTDs 18X more Congenital Cardiac Defects Linear Relationship of HgA1C -> Malformations and SABs HgA1C < 7 -> 3% Malf 15% SAB HgA1C 7-9 -> 7% HgA1C 9-12 -> 15% HgA1C > 12 -> 25% Malf 50% SAB Pediatrics;85(1) 1990:1-9 Teratology [1989, 39(3):225 AJOG [1989, 161(2):426Metformin Risks in Pregnancy: Metformin Risks in Pregnancy FDA Pregnancy Cat B Package label states “Do not take Metformin if: ...you are pregnant, planning to get pregnant or are breast-feeding.” Meta-analysis of 8: Metformin in 1 st T for PCOS Yes Metformin -> 1.7% malformations No Metformin -> 7.2% malformations Matched for various RF -> 57% PROTECTIVE effect DM pts – 93 1 st T exposure -> No difference in outcome 1 st T Metformin Stopped on Dx Preg -> 30% SAB Cont throughout 1 st T -> 16% Still: “Not enough data, crosses, don’t use….” in US Fertility and Sterility; 86 (2006) 658 Diabet Med 23 (2006) 318 Gynecol Endocrinol 22: 680–684, 2006Case 2: Case 2 RS is a 29 yo with Type II DM for 3 years On Metformin from your office Calls with + home Preg Test Unsure LMP about 6 weeks ago 1. Stop Med? 2. Continue Med? 3. Continue metformin until we can get you in to start insulin? Oh, and start a PNV today.Case 3 Hx: Case 3 Hx 39 yo G5 P3013 at 12 weeks pregnant, highly desired 4 X 2 cm Mass noted in left breast 1 week ago FNA shows poorly differentiated intraductal adenoCA 1. Terminate pregnancy and treat Br CA 2. Continue pregnancy and treat Br CA after preg 3. Cont preg and have surgery no chemo/radiation until after preg 4. Cont preg and have surgery and chemo No radiation until after preg 5. Cont preg and have all CA tx , no modificationsCase 3 – Initial Advice: Case 3 – Initial Advice Pt was told by her MD in Mexico that she could not receive any surgery, chemo, or radiation in pregnancy and she should terminate or delay tx to PP. Pt presented to me at 14 weeks refusing any treatment “Rather die and save the baby.” What’s the rationale? Where’s the data?Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Pregnancy Hurts Mom – Br Ca worse? Surgery in Preg puts fetus at risk? Chemotherapy in Preg puts fetus at risk? Radiation in Preg puts fetus at risk? Delaying treatment won’t hurt mom?Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Pregnancy will worsen mom’s Br CA progression. She should terminate to help herself. Br CA dx later and more advanced in pregnancy. Prognosis the same matched for stage Termination of pregnancy never shown to improve maternal prognosis for Br CA Arch Surg 1985;120:1221 Clin Oncol 1989;1:11Case 3: Rationale for Advice: Case 3: Rationale for Advice Breast Surgery will be bad for fetus. She should terminate or delay treatment. Anesthesia and Surgery -> No incr risk Malformations Possible incr risk SAB in 1 st T Increase risk PTL or FGR (Roughly 10->20%) Unclear if these risks are due to Surg or underlying Ds Majority of PTL and FGR infants do well without sequelae Arch Gynecol Obstet. 1998;261(4):193 Am J Obstet Gynecol 1989;161:1178 Anesthesiology 1986;64:790Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Chemotherapy is bad for Fetus. She should terminate or delay treatment. All chemo agents are FDA Cat D Known harm but benefit may outweigh risk 1 st T: 16-30% malformations 2/3 rd T: background risk (1.7%)malformations Total about 300 pts Drug Therapy in Preg , 3 rd Ed. 2001 Semin Oncol 1989;16:337Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Chemotherapy is bad for Fetus. She should terminate or delay treatment. Prospective trial of Flurouracil , Cyclophosphamide , Doxyrubicine in 24 preg women with Br CA Not given in 1 st T No malformations PTDel in 3 (one induced at 33 wk for Pre-Eclampsia) 1 each: TTN, FGR, transient leukopenia Prospective Registry of 231 gestations – various CA 3 year f/u No Difference in matched non-CA pregnancies for Malformations, PT Birth, FGR Many more small, retrospective series Similar good outcomes J Clin Oncol 1999;17:855 Am J Clin Oncol . 2010;33:221Case 3 – Caveats for Chemo: Case 3 – Caveats for Chemo MTX is bad. Use near delivery Increased neonatal myelosuppression Time cycles for delivery 3-4 wks after chemo and just before next cycle to minimize risk Doxorubicin – limited pediatric f/u re: cardiotoxic risks over timeCase 3 – Rationale for Advice: Case 3 – Rationale for Advice Radiation is bad for the fetus. She should terminate or delay treatment. OK, You’re right about that one. RT is substantial and shielding is insufficient. 1 st T gets less because fetus is further from source. Still enough for real risk of harm Limited data, mostly older, shows risk is real Malformations, SABs , FGR Some cases of normal outcome reported Lancet Oncol 2005;6:328Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Delaying Tx for 6 months won’t hurt mom. She should delay until after delivery. Delay in Tx -> Increases ax LN metastases by 5-10% Approximately 1% per month May be OK for 1-2 mo to allow XRT, conserve breast Ax LN Positive -> doubles mortality Obstet Gynecol 1996;87:414 Cancer 1980;45:2917Case 3 Hx: Case 3 Hx 39 yo G5 P3013 at 12 weeks pregnant, highly desired 4 X 2 cm Mass noted in left breast 1 week ago FNA shows poorly differentiated intraductal adenoCA 1. Terminate pregnancy and treat Br CA 2. Continue pregnancy and treat Br CA after preg 3. Cont preg and have surgery no chemo/radiation until after preg 4. Cont preg and have surgery and chemo No radiation until after preg 5. Cont preg and have all CA tx , no modificationsCase 3 – Br CA Treatment: Case 3 – Br CA Treatment Mod Rad mastectomy 11/2009 at 18 wk gestation Poorly differentiated Invasive ductal CA 3.7 cm, Margins neg 4/13 LN Positive T2N2, Hormone R +, HERS 2 + Adjuvant Chemo – delayed until near 28 wks!! 3 rounds in preg of Adriamycin and Cytoxan PP – Last course delayed by c/s healing, added Taxol PP Radiation Now TamoxifenCase 3 – Pregnancy outcome: Case 3 – Pregnancy outcome Induced at 38 weeks to allow less gap between chemo cycles Long induction, FHR decels -> C/Section Baby girl 3124 gm (6# 14 oz) Apgars 9 & 9 Now 21 months, doing very well with no delay per her proud parents.Montana Thunderstorm: Montana ThunderstormCase 5 - Preconception: Case 5 - Preconception GT is a 37 yo G2 P1011 Hx Type I DM -> Renal failure Renal Panc Transplant UCSF 2007 Several “Mild” rejection episodes Most recently hosp at UCSF last Mo – med changed Referred to me by GYN for Secondary Infertility Attempting preg for 1 ½ yearsCase 5 – Current Meds/Labs: Case 5 – Current Meds/Labs MMF ( CellCept ), Tacrolimus , Prednisone Bactrim , Valgancyclovir , Fluconazole Metoprolol , Pepsid . ASA S Creat 1.05, 0.96, 1.1Case 5: Case 5 37 yo s/p renal panc transplant Recent rejection Multiple meds Strongly desires pregnancy 1. You must never conceive? 2. Work up for infertility, try clomid ? 3. Call Dr. Lorig ? 4. Research, team consult, counsel pt in 2-3 mo? Start temporary contraceptionCase 5 – You Must Never Conceive: Case 5 – You Must Never Conceive She’s not listening to you.Case 5 – Rx Clomid: Case 5 – Rx Clomid MMF – Risk SAB and Malformations 11/26 SAB, 4/15 Malformations Azathioprene ( Imuran ) has good safety profile (FGR/PTL same as others) and may substitute Tacrolimus – limited preg data, Same as other regimens for PTL/FGR Prednisone – Incr Cleft Lip/Palate (4X) Safe in 2 nd 3 rd T Transplantation 2006;82:1698 Arthritis Res. Ther.2006; 8: 209 Teratology 2000 62: 385Case 5 – Outcomes: Case 5 – Outcomes Pregnancy Registries for Transplant Outcome better if s creat < 1.5 30% FGR, PTDel , Pre- Ecl S Creat > 2 -> 50-60% perinatal compl Minimal rejection problems if stable for 12-24 mo Am Transplant 2009;9:1541 Transplant Rev 2008;22:223Case 4 - Counseled: Case 4 - Counseled PCP, UCSF Transplant team contacted Data reviewed Extensive counseling w /pt Plan: 1. Delay any med change until rejection free for 12 mo 2. Change MMF to Azathioprene or Incr Pred 3. Attempt conception after 3-6 mo IUD placedCase 5 – Current status: Case 5 – Current status No rejection for 16 months Lost MediCal so followed at Renal here No med changes yet – now 38+ years Pt reports conflicting info: UCSF Transplant and me– can conceive (per our plan) Renal ACMC – cannot conceive MediCal reinstated-> Making apmt for UCSF Transplant teamResources: Resources Your ever-ready OB/GYN service and Perinatalogist Google!! Pub Med Drugs.com (read the full txt, not just summary) Perinatalogy.com Clearing house for other resources Many links are to subscription services Motherisk , SafeFetus , ReproTox , Drug Registries Maternal Fetal Medicine 6 th Ed 2009 Creasy and Resnick Lactation: Medications and Mother’s Milk Tom Hale, MD – Our library, In peds UTD – Excellent in many ways MFM written by Internists, growing drugs section Pharmacists – often have little except FDA categoryConclusion: Don’t Believe Everything You Think: Conclusion: Don’t Believe Everything You Think FDA Categories are inadequate Drug companies not researching pregnancy Withholding tx in pregnancy is often not necessary and carries risk Patients should be very involved in decision making Data is always limited And often hard to find The 1 st thing pt hears is what she believes Contraception and PNVits for Everyone!Challenge: Challenge Ask first: What would I recommend for this pt if she were NOT pregnant? Ask second: What do I need to modify due to the pregnancy and WHY ? You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
GR2012-02 Maternal Fetal Medicine- Don't Believe Everything You Think chiefhgh Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 32 Category: Education License: All Rights Reserved Like it (0) Dislike it (0) Added: February 03, 2012 This Presentation is Public Favorites: 0 Presentation Description No description available. Comments Posting comment... Premium member Presentation Transcript Don’t Believe Everything You Think: Don’t Believe Everything You Think AKA: Don’t Punish My Patient For Being Pregnant . Mickye Adams, MD Maternal Fetal MedicineWho are my patients? : Who are my patients? JM is a 29 yo w / relapsing remitting MS very well controlled on beta-interferon prior to pregnancy Stopped at 5-6 wk gestation -> much worse when I saw her at 18 weeks. PT is a 25 yo with progressive CRI and nephrotic syndrome Unplanned pregnancy AD is a 30 yo with mechanical TV on Coumadin Unplanned pregnancy KP is a 16 yo with HTN Cardiomyopathy Unplanned pregnancyJust Yesterday: Just Yesterday 37 yo G2 P0100 at 7+ weeks Hx Severe Pre-Eclampsia at 35 wks -> Fetal Demise Hx Severe HTN -> admitted HGH 1/6/12-1/8/12 Admission BP 213/133, Facial Droop, + LVH Ruled out for CVA, Dx Bell’s and Essential HTN Started on Nifed 30/d + UPT on f/u in Medicine, BP 145/90 Nifed stopped due to “Cat C Med” and nothing started, no PNV Referred to GYN (Ref Track) Pt dropped in to GYN worried she needed Anti HTN BP 200/117 Nifed 30 restarted, home BP cuff, f/u 1 wkCauses of Congenital Malformations: Causes of Congenital Malformations 65% Mulitfactorial 25% Genetic 4% Maternal Condition 3% Maternal Infection 1-2% Mechanical Deformations <1% Drugs, Chemicals, Radiation, Hyperthermia MothersRisk.comChallenge: Challenge Ask first: What would I recommend for this pt if she were NOT pregnant? Ask second: What do I need to modify due to the pregnancy and WHY ? Outline: Outline History Lesson – A Tale of Two Drugs Case 1 – Is Withholding Treatment Best? INH Case Case 2 – Is Withholding Treatment Best? Metformin Case Case 3 – Is Withholding Treatment Best? Breast Cancer Case Case 4 – Preconception Counseling Conundrum Renal Panc Transplant Case Resources – Where to goThalidomide: Thalidomide Sedative patented 1954 Drs thought placenta blocked drug passage Helped Morning Sickness – used by countless thousands OTC internationally Never approved in US 20,000 samples distributed to drs /pts by companyPowerPoint Presentation: Lancet publishes Letter by Dr William McBride Thalidomide and Congenital Abnormalities Date: December 16, 1961 10-20,000 babies with defects – phocomelia US Changes Laws re: Drugs in Pregnancy in 1962PowerPoint Presentation: 1962: Frances Kelsey gets honor from JFK for blocking Thalidamide from FDA approvalFDA Approved Drugs for Use in Pregnancy 1962-2010: FDA Approved Drugs for Use in Pregnancy 1962-2010FDA Approved Drugs for Use in Pregnancy 1962-2010: FDA Approved Drugs for Use in Pregnancy 1962-2010 Oxytocin Cervadil Obstetrics & Gynecology:April 2010;115:4 pp 825-833Bendectin: Bendectin Pyridoxine (Vitamin B6) Doxylamine (Antihistamine Unisom, Preg Cat A)Bendectin: Bendectin 31,564 women (prospectively analyzed) Any Major Malformation OR 1.0 (0.8-1.4) Teratology . 1989;40:151-5.Bendectin Meta-Analysis: Bendectin Meta-Analysis Study N Exposed E- Malform Non-Exp NE- Malfor RR CI 154,469 16,345 375 138,124 5797 0.95 0.62-1.45 Drug Intel1 Clin Phar- macol . 1988;22:813-24.Bendectin: Bendectin Only drug approved by FDA for N/V in preg Approved prior to 1962 33 million used 1 in 10 preg women in US 300 law suits 1 = $750,000 -> off market in 13 days Dr. W. McBride – lead plaintiff expert in many cases Did basic and clinical research on risks of bendectin in preg Merrell: Insurance rate $10M Only $3M net profit NYT 6/19/1983 " The Independent" on 20 February 1993Bendectin: Bendectin FDA review panel 1983: No association between Bendectin and birth defects had been demonstrated. …no way to prove the absolute safety of any drug in all women under every circumstance, there must remain a ''residual uncertainty'' about how this drug affects an unborn child. NYT 6-19-1983Bendectin: Bendectin BENDECTIN: REVIEW OF THE MEDICAL LITERATURE OF A COMPREHENSIVELY STUDIED HUMAN NONTERATOGEN AND THE MOST PREVALENT TORTOGEN-LITIGEN Comprehensive review: All human, animal, in vitro, dose-response, biological plausability …. Conclusion: “ T herapeutic use of Bendectin has no measurable teratogenic effects .” Reproductive Toxicology, Vol. 9, No. 4, pp. 337-349, 1995Bendectin: Bendectin Dr. William McBride falsified data on Bendectin License revoked in 1993 All cases overturned on appeal, no $ from MerrellProven Teratogens 1962-1997: Proven Teratogens 1962-1997 Only 35 drugs have been proven teratogens in past 35 years! Partial List of Proven Teratogens AED Phenetoin – FHS, Carbamazapine , Valproate ->NTD Isotretinoin – Accutane Syndrome Thalidomide – phocomelia ACE inhibitors – renal failure Lithium – Ebstein’s Anomaly N Engl J Med 1998; 338:1128 MothersRisk.orgFDA Approved Drugs for Use in Pregnancy 1962-2010: FDA Approved Drugs for Use in Pregnancy 1962-2010 Oxytocin Cervadil Wikipedia – FDA Pregnancy Categories 2012 One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be considered Pregnancy Category A in other countries are allocated to Category C by the FDA.Case 1: Case 1 JR is a 24 yo Guatemalan woman in US for 8 months. PPD positive, Asx , Neg CXR -> Started INH in May + UPT in July in K6 Medicine Your Advice: 1. Stop Immediately 2. Continue Medicine?LTBI – CDC 2010 and UTD 2012: LTBI – CDC 2010 and UTD 2012 CDC: Pregnancy In the absence of risk factors, wait until after the woman has delivered to avoid administering unnecessary medication during pregnancy. INH daily or twice weekly (using DOT) is the preferred regimen. Consider delaying treatment for LTBI until 2–3 months post-partum unless there is a high risk of progression to TB disease (e.g., HIV infected, recent contact). UTD: Don’t Test if Low Risk If TST + but low risk -> Don’t Treat If TST + but high riks -> Treat High Risk: Immunocompromised , Recent ExposureCase 1 – Ms JR: Case 1 – Ms JR Advice now: 1. Stop Medicine? 2. Continue Medicine? Who changed their mind? 1. Yes – changed 2. No – didn’t changeLTBI – Rationale for Treatment: LTBI – Rationale for Treatment Historically, LTBI -> 12.8% Active TB within 10 years High Risk Conditions HIV +, IVDA, Homeless, Incarcerated Recent Immigrant from Endemic Country Known Exposure to Active TB, Recent Conversion Transplant, Renal Insuff , others INH Tx decreases TB by 25-90% Most if 9-12 mo completed 0.15-2% INH Hepatitis -> 0.001% deaths Am Thor Society July, 1999 Obstet Gynecol 2000;96:757-62Is CXR Safe in Pregnancy?: Is CXR Safe in Pregnancy? Modern CXR -> dose to fetus 0.00007 rad (0.7 mrad ) So low it can’t be measured with most instruments! Risk: All agree < 5 rad is safe at any point in preg Limit CXR to < 70,000 during pregnancy, please. Documented Fetal Risk: >20 rad Background Radiation at Sea Level – 2-10 days Background Radiation at Higher Elevation – 8 hours Radiation from flying SF to NYC (approx) 3.5 X higher than CXR, One Way Am Fam Physician. 1999 Apr 1;59(7):1813-1818 wwqw.doh.wa.gov/ehp/rp/factsheets/factsheets-htm/fs10bkvsman.htm hps.org/publicinformation/ate/faqs/commercialflights.htmlIs INH Safe in Pregnancy?: Is INH Safe in Pregnancy? FDA Pregnancy Cat C Multiple Experts (CDC, ATS, ACOG, UTD) INH is NOT a human teratogen . No Adverse Neonatal Effects shown from in uterio INH ExposureINH Toxicity May Be Up in Pregnancy : INH Toxicity May Be Up in Pregnancy US: Hispanic Prenatal Clinic in 1980s (54% PPD +) INH given to 3681 pt 3 mo Supply, Seen every 3 months for 12 months LFTs if pt c/o sx at the 3 mo visits 5 Hepatitis (2-7 mo into tx ) 2 Deaths – both PP (3 mo and 5 mo) Retrospective female Control group NS diff in Hep or Death but SMALL (2.5 X higher, NS) Recommendations for INH Then and Now Only 30 pills at a time Screen for Sx Hepatitis Monthly! Subsequent Recommendations: Do Not Treat Low Risk Women in Pregnancy or Imm PP Public Health Rep. 1989 Mar-Apr; 104(2): 151–155.Should Tx LTBI be delayed PP?: Should Tx LTBI be delayed PP? NYC Immigrants: >50% PPD+, most newly dx’d Only 9.3% completed tx PP 30% not referred, 18% didn’t attend, 35% Noncompl Conclusion: Prenatal Setting a “Missed Opportunity” SF General: 32% PPD+ Only 18% completed tx PP (min 6 mo) 42% referred If same provider for OB care: 67% started -> 62% completed (42% of original) Conclusion: Despite opportunity in PNCare , only 18% Am J Obstet Gynecol 2006;194:451 Am J Obstet Gynecol 2005;192:1455Tx in Preg: Risks vs Alternatives: Tx in Preg : Risks vs Alternatives Markov Decision Analysis Model 3 Groups compared: No Tx , AP (6mo AP, rest PP), PP start LTBI = PPD 10mm and CXR Neg Not Other HR Factors No Tx -> 3.3/1000 get TB AP -> 1.4/1000 get TB More Hep deaths (assumed 2.5X higher) Longest Life Expectancy Most Cost Effective PP -> 1.8/1000 get TB AP Not Best Option Only if 10X more Hep deaths AND 10X less TB deaths than existing data and assumptions Obstet Gynecol 2000;96:757LTBI in Preg: LTBI in Preg Many of our women have RF F/U INH tx unlikely to be completed 25% of those who started tx at EWC Chest Clinic INH does not pose risk to Fetus Maternal INH should be monitored 30 d Rx only, Educate pt Sx (Seen < 30 day anyway) Check Sx every 30 days (Seen < 30 day anyway) Check LFTs at baseline and monthly Very conservative approachCase 1: Case 1 JR is a 24 yo Guatemalan woman in US for 8 months. PPD positive, Asx , Neg CXR -> Started INH in May + UPT in July in your office Your Advice: 1. Stop Immediately? 2. Continue Medicine? 3. If no Sx , Check LFT, cont med and refer for care with OB experienced in INH tx ? or cont INH monitoring in your clinic?Case 2: Case 2 RS is a 29 yo with Type II DM for 3 years On Metformin from your office Calls with + home Preg Test Unsure LMP about 6 weeks ago 1. Stop Med? 2. Continue Med?Embryogenesis DM, and Metformin: Embryogenesis DM, and Metformin Background rate of major malformations 3% at birth, 5% recognized by 5 yo Neural Tube – closes at 4-5 wk postconception 6-7 wk post-LMP Heart – folds at 5-6 wk postconception 7-8 wk post-LMPHyperglycemia = Bad in Embryos: Hyperglycemia = Bad in Embryos Infants of Diabetic Mothers – 7X malformations 15X more NTDs 18X more Congenital Cardiac Defects Linear Relationship of HgA1C -> Malformations and SABs HgA1C < 7 -> 3% Malf 15% SAB HgA1C 7-9 -> 7% HgA1C 9-12 -> 15% HgA1C > 12 -> 25% Malf 50% SAB Pediatrics;85(1) 1990:1-9 Teratology [1989, 39(3):225 AJOG [1989, 161(2):426Metformin Risks in Pregnancy: Metformin Risks in Pregnancy FDA Pregnancy Cat B Package label states “Do not take Metformin if: ...you are pregnant, planning to get pregnant or are breast-feeding.” Meta-analysis of 8: Metformin in 1 st T for PCOS Yes Metformin -> 1.7% malformations No Metformin -> 7.2% malformations Matched for various RF -> 57% PROTECTIVE effect DM pts – 93 1 st T exposure -> No difference in outcome 1 st T Metformin Stopped on Dx Preg -> 30% SAB Cont throughout 1 st T -> 16% Still: “Not enough data, crosses, don’t use….” in US Fertility and Sterility; 86 (2006) 658 Diabet Med 23 (2006) 318 Gynecol Endocrinol 22: 680–684, 2006Case 2: Case 2 RS is a 29 yo with Type II DM for 3 years On Metformin from your office Calls with + home Preg Test Unsure LMP about 6 weeks ago 1. Stop Med? 2. Continue Med? 3. Continue metformin until we can get you in to start insulin? Oh, and start a PNV today.Case 3 Hx: Case 3 Hx 39 yo G5 P3013 at 12 weeks pregnant, highly desired 4 X 2 cm Mass noted in left breast 1 week ago FNA shows poorly differentiated intraductal adenoCA 1. Terminate pregnancy and treat Br CA 2. Continue pregnancy and treat Br CA after preg 3. Cont preg and have surgery no chemo/radiation until after preg 4. Cont preg and have surgery and chemo No radiation until after preg 5. Cont preg and have all CA tx , no modificationsCase 3 – Initial Advice: Case 3 – Initial Advice Pt was told by her MD in Mexico that she could not receive any surgery, chemo, or radiation in pregnancy and she should terminate or delay tx to PP. Pt presented to me at 14 weeks refusing any treatment “Rather die and save the baby.” What’s the rationale? Where’s the data?Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Pregnancy Hurts Mom – Br Ca worse? Surgery in Preg puts fetus at risk? Chemotherapy in Preg puts fetus at risk? Radiation in Preg puts fetus at risk? Delaying treatment won’t hurt mom?Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Pregnancy will worsen mom’s Br CA progression. She should terminate to help herself. Br CA dx later and more advanced in pregnancy. Prognosis the same matched for stage Termination of pregnancy never shown to improve maternal prognosis for Br CA Arch Surg 1985;120:1221 Clin Oncol 1989;1:11Case 3: Rationale for Advice: Case 3: Rationale for Advice Breast Surgery will be bad for fetus. She should terminate or delay treatment. Anesthesia and Surgery -> No incr risk Malformations Possible incr risk SAB in 1 st T Increase risk PTL or FGR (Roughly 10->20%) Unclear if these risks are due to Surg or underlying Ds Majority of PTL and FGR infants do well without sequelae Arch Gynecol Obstet. 1998;261(4):193 Am J Obstet Gynecol 1989;161:1178 Anesthesiology 1986;64:790Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Chemotherapy is bad for Fetus. She should terminate or delay treatment. All chemo agents are FDA Cat D Known harm but benefit may outweigh risk 1 st T: 16-30% malformations 2/3 rd T: background risk (1.7%)malformations Total about 300 pts Drug Therapy in Preg , 3 rd Ed. 2001 Semin Oncol 1989;16:337Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Chemotherapy is bad for Fetus. She should terminate or delay treatment. Prospective trial of Flurouracil , Cyclophosphamide , Doxyrubicine in 24 preg women with Br CA Not given in 1 st T No malformations PTDel in 3 (one induced at 33 wk for Pre-Eclampsia) 1 each: TTN, FGR, transient leukopenia Prospective Registry of 231 gestations – various CA 3 year f/u No Difference in matched non-CA pregnancies for Malformations, PT Birth, FGR Many more small, retrospective series Similar good outcomes J Clin Oncol 1999;17:855 Am J Clin Oncol . 2010;33:221Case 3 – Caveats for Chemo: Case 3 – Caveats for Chemo MTX is bad. Use near delivery Increased neonatal myelosuppression Time cycles for delivery 3-4 wks after chemo and just before next cycle to minimize risk Doxorubicin – limited pediatric f/u re: cardiotoxic risks over timeCase 3 – Rationale for Advice: Case 3 – Rationale for Advice Radiation is bad for the fetus. She should terminate or delay treatment. OK, You’re right about that one. RT is substantial and shielding is insufficient. 1 st T gets less because fetus is further from source. Still enough for real risk of harm Limited data, mostly older, shows risk is real Malformations, SABs , FGR Some cases of normal outcome reported Lancet Oncol 2005;6:328Case 3 – Rationale for Advice: Case 3 – Rationale for Advice Delaying Tx for 6 months won’t hurt mom. She should delay until after delivery. Delay in Tx -> Increases ax LN metastases by 5-10% Approximately 1% per month May be OK for 1-2 mo to allow XRT, conserve breast Ax LN Positive -> doubles mortality Obstet Gynecol 1996;87:414 Cancer 1980;45:2917Case 3 Hx: Case 3 Hx 39 yo G5 P3013 at 12 weeks pregnant, highly desired 4 X 2 cm Mass noted in left breast 1 week ago FNA shows poorly differentiated intraductal adenoCA 1. Terminate pregnancy and treat Br CA 2. Continue pregnancy and treat Br CA after preg 3. Cont preg and have surgery no chemo/radiation until after preg 4. Cont preg and have surgery and chemo No radiation until after preg 5. Cont preg and have all CA tx , no modificationsCase 3 – Br CA Treatment: Case 3 – Br CA Treatment Mod Rad mastectomy 11/2009 at 18 wk gestation Poorly differentiated Invasive ductal CA 3.7 cm, Margins neg 4/13 LN Positive T2N2, Hormone R +, HERS 2 + Adjuvant Chemo – delayed until near 28 wks!! 3 rounds in preg of Adriamycin and Cytoxan PP – Last course delayed by c/s healing, added Taxol PP Radiation Now TamoxifenCase 3 – Pregnancy outcome: Case 3 – Pregnancy outcome Induced at 38 weeks to allow less gap between chemo cycles Long induction, FHR decels -> C/Section Baby girl 3124 gm (6# 14 oz) Apgars 9 & 9 Now 21 months, doing very well with no delay per her proud parents.Montana Thunderstorm: Montana ThunderstormCase 5 - Preconception: Case 5 - Preconception GT is a 37 yo G2 P1011 Hx Type I DM -> Renal failure Renal Panc Transplant UCSF 2007 Several “Mild” rejection episodes Most recently hosp at UCSF last Mo – med changed Referred to me by GYN for Secondary Infertility Attempting preg for 1 ½ yearsCase 5 – Current Meds/Labs: Case 5 – Current Meds/Labs MMF ( CellCept ), Tacrolimus , Prednisone Bactrim , Valgancyclovir , Fluconazole Metoprolol , Pepsid . ASA S Creat 1.05, 0.96, 1.1Case 5: Case 5 37 yo s/p renal panc transplant Recent rejection Multiple meds Strongly desires pregnancy 1. You must never conceive? 2. Work up for infertility, try clomid ? 3. Call Dr. Lorig ? 4. Research, team consult, counsel pt in 2-3 mo? Start temporary contraceptionCase 5 – You Must Never Conceive: Case 5 – You Must Never Conceive She’s not listening to you.Case 5 – Rx Clomid: Case 5 – Rx Clomid MMF – Risk SAB and Malformations 11/26 SAB, 4/15 Malformations Azathioprene ( Imuran ) has good safety profile (FGR/PTL same as others) and may substitute Tacrolimus – limited preg data, Same as other regimens for PTL/FGR Prednisone – Incr Cleft Lip/Palate (4X) Safe in 2 nd 3 rd T Transplantation 2006;82:1698 Arthritis Res. Ther.2006; 8: 209 Teratology 2000 62: 385Case 5 – Outcomes: Case 5 – Outcomes Pregnancy Registries for Transplant Outcome better if s creat < 1.5 30% FGR, PTDel , Pre- Ecl S Creat > 2 -> 50-60% perinatal compl Minimal rejection problems if stable for 12-24 mo Am Transplant 2009;9:1541 Transplant Rev 2008;22:223Case 4 - Counseled: Case 4 - Counseled PCP, UCSF Transplant team contacted Data reviewed Extensive counseling w /pt Plan: 1. Delay any med change until rejection free for 12 mo 2. Change MMF to Azathioprene or Incr Pred 3. Attempt conception after 3-6 mo IUD placedCase 5 – Current status: Case 5 – Current status No rejection for 16 months Lost MediCal so followed at Renal here No med changes yet – now 38+ years Pt reports conflicting info: UCSF Transplant and me– can conceive (per our plan) Renal ACMC – cannot conceive MediCal reinstated-> Making apmt for UCSF Transplant teamResources: Resources Your ever-ready OB/GYN service and Perinatalogist Google!! Pub Med Drugs.com (read the full txt, not just summary) Perinatalogy.com Clearing house for other resources Many links are to subscription services Motherisk , SafeFetus , ReproTox , Drug Registries Maternal Fetal Medicine 6 th Ed 2009 Creasy and Resnick Lactation: Medications and Mother’s Milk Tom Hale, MD – Our library, In peds UTD – Excellent in many ways MFM written by Internists, growing drugs section Pharmacists – often have little except FDA categoryConclusion: Don’t Believe Everything You Think: Conclusion: Don’t Believe Everything You Think FDA Categories are inadequate Drug companies not researching pregnancy Withholding tx in pregnancy is often not necessary and carries risk Patients should be very involved in decision making Data is always limited And often hard to find The 1 st thing pt hears is what she believes Contraception and PNVits for Everyone!Challenge: Challenge Ask first: What would I recommend for this pt if she were NOT pregnant? Ask second: What do I need to modify due to the pregnancy and WHY ?