Pharmacologic Considerations in the Pregnant Patient (For the PCP)

Transcription

1 Pharmacologic Considerations in the Pregnant Patient (For the PCP) Aspirin Use in Pregnancies At Risk Contemporary Treatment of the A2 Diabetic Statin Exposure in Early Pregnancy Continuation of SSRI Rx in Pregnancy

2 Old New Therapy in Pregnancy

3 Aspirin use in early pregnancy has no proven teratogenic risks. A. True B. False C. Only in animal studies D. Only when used at higher than recommended dosages True 0% 0% 0% 0% False Only in animal studies Only when used at higher t...

4 Medical-Legal Concerns The maternal use of aspirin during pregnancy has been associated with the following birth defects: Amniotic Band Syndrome (ABS) Clubfoot (congenital talipes equinovarus) Anophthalmia (also known as anophthalmos) Microphthalmia (also known as microphthalmos, nanophthalmia or nanophthalmos) Cleft Palate Spina Bifida

5 Amniotic Band

6 Clubfoot

7 Anopthmalmia & Micropthalmia

8 Cleft Lip/Palate

9 Spina Bifida

10 Aspirin Near Term

11 Conclusion: EAGeR Randomized Trial RCT 1228 patients between June 2007 July 2011 Low dose ASA vs Placebo- Preconception 1. No significance benefit of LowDose ASA in livebirth or pregnancy loss rates in women with one to two losses 2. No adverse events to either mother of fetus *No increase in adverse fetal sequelae in maternal doses up to 150 mg/ daily Knight M, et al. Cochrane Database Syst Rev 2000; 2:CD Duly L, et al. BMJ 2001; 322: CLASP; Lancet 1994; 343:619-29

12 Benefits of Aspirin in Pregnancy

13 Arachidonic Pathway

14 Cox Inhibitors on Arachidonic Pathway

15 When should low-dose ASA be initiated? A. Pre-conception B. After 12 wks EGA C. After 16 wks EGA D. Any EGA prior to symptoms 0% 0% 0% 0% Pre conception After 12 wks EGA After 16 wks EGA Any EGA prior to symptoms

16 ASA Use Proximate to Pregnancy

17 ASA Affect on HTN

18 Low-dose ASA is presently recommended for patients presenting with: A. H/O prior pregnancy with severe preeclampsia B. H/O Antiphospholipid Antibody syndrome (APS) C. Both D. Neither H/O prior pregnancy with se... 0% 0% 0% 0% H/O Antiphospholipid Anti... Both Neither

19 ASA Preeclampsia Prophylaxis Pregnancies *May be helpful in patients: 1. h/o prior preeclampsia in second trimester (severe) 2. known APS* 19

20 What pregnant patient(s) would be most likely to benefit from daily lowdose ASA preventative therapy? A. Patient with family h/o preeclampsia B. Patient with chronic renal disease C. Patient with chronic hypertension D. Patient with h/o prior severe preeclampsia Patient with family h/o pre... 0% 0% 0% 0% Patient with chronic renal d... Patient with chronic hypert... Patient with h/o prior sever...

21 Number Needed to Treat Prevention of Pre-eclampsia Low-dose aspirin therapy for prevention of pre-eclampsia Diagnosis Baseline Event Rate (%) NNT Low-risk pregnancy Normal pregnancy Prior Severe Pre-eclampsia Renal Disease Chronic Hypertension *NNT is the number needed to treat to prevent one case of pre-eclampsia

22 Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality from Preeclampsia Clinical Summary of U.S. Preventive Services Task Force Recommendation Population Asymptomatic Pregnant Women who are at high risk for Preeclampsia Prescribe Low-dose (81 mg/d) ASA after 12 wks of gestation (Grade B) Risk Assessment Preventive Medicine Benefit vs Harm Pregnant women are at high risk for preeclampsia if they have 1 or more of the following risk factors: H/O preeclampsia, especially when accompanied by adverse outcome Multifetal gestation Chronic Hypertension Type 1 or 2 diabetes Renal disease Autoimmune disease (SLE, APS) Low-dose ASA ( mg/d) at wks gestation reduces occurrence of preeclampsia, preterm birth, and IUGR in women at increased risk The harms of low-dose ASA in pregnancy are considered to be no greater than small Substantial net benefit exists in daily low-dose ASA to reduce the risk of preeclampsia, preterm birth, & IUGR in women at risk for preeclampsia

23 Clinical Risk Assessment of Preeclampsia US Preventative Task Force Risk level Risk Factors Recommendations High History of preeclampsia, especially when accompanied by an adverse outcome Multiple gestation Chronic Hypertension Type 1 or 2 diabetes Renal Disease Autoimmune disease (ie. SLE, APS) Moderate Nulliparity Obesity (BMI > 30 Family H/O preeclampsia (mother/sister) Sociodemographics (African- American, low socioeconomic status) Age > 35 Personal history factors: SGA, previous adverse pregnancy outcome, > 10 yr interpregnancy interval Recommend low-dose ASA if the patient has at least 1 Consider low-dose ASA if several of these moderate risk factors

24 Creasy & Resnik s 7 th edition Comments on Low Dose ASA in Pregnancy 35,000 women have been included in RCT of various sizes and quality Small single-center studies suggest benefit Multi-center trials showed none Meta-analysis suggests benefit of ASA in reducing frequency: Preeclampsia Preterm Delivery Growth restriction

25 Contemporary Attitude of ASA and Pregnancy

26 Gestational A2 DM The Best Choice for Treatment

27 What oral diabetic agent do you prefer in treatment of diabetes in pregnancy? A. Glyburide B. Metformin C. Janumet D. Glypizide 0% 0% 0% 0% Glyburide Metformin Janumet Glypizide

28 Pharmacology of Diabetic Agents

29 Standard Therapy: Insulin Diabetes RX Langer et al trial (N Engl J Med 2000) Glyburide with or without insulin Fifth International Workshop-Conference in Gestational DM (2007) National Institute for Health and Care excellence (NICE) guidance (2008) ACOG practice bulletin No # 137 (2013) Castillo et al Trends in Glyburide Compared with insulin use for Gestational Diabetes treatment in the US ( ) Obstet Gynecol 2014; 123: Glyburide use increase from 7.4% to 64.5% in 2011 Glyburide most common Rx since 2007

30 Recent Comparative Rx studies Gui et al (2013) Meta-analysis of metformin vs insulin Metformin: Less maternal weight gain and PIH Insulin: Lower PTD and advanced EGA Zeng et al (2014) RCT glyburide vs insulin Glyburide: Less hypoglycemia Insulin: Lower neonatal birth weight and neonatal hypoglycemia Balsells et al (BMJ 2015) Systematic Review of the Literature Maternal and Fetal Outcomes in RCT Glyburide vs insulin Metformin vs insulin Metformin vs glyburide

31 Study Criteria (15) Randomized Controlled Trials Subjects: Women with gestational DM requiring therapy Compared Glyburide vs insulin Metformin vs insulin Metformin vs glyburide Full paper publication

32 Primary Outcomes Primary Maternal HgA1c level in third trimester Severe maternal hypoglycemia Pre-eclampsia Total Weight Gain during pregnancy C/S rates Metformin and/or Glyburide Failures Primary Fetal EGA at delivery Preterm Birth Rate Birth Weight LGA>90%ile SGA < 10%ile Neonatal hypoglycemia Perinatal Mortality

33 Secondary Outcomes Secondary Maternal Fasting and PP blood sugars Weight Gain Pregnancy Induced Hypertension Induction of labor Secondary Fetal Fetal Hyperinsulinism Abnormal Apgar scores Obstetrical trauma Severe neonatal hypoglycemia Neonatal Jaundice RDS requiring support Stillbirth/Neonatal mortality Neonatal ICU admission

34 Glyburide Glyburide Vs Insulin Higher Birth Weight: 109 gm ( gm) More macrosomia: RR 2.62 ( ) More Neonatal hypoglycemia: RR 2.04 ( ) Glyburide Failure Rate > 6.37% (20/314) Glyburide Additional side affects > 6.3%

35 Metformin vs Insulin Metformin Less maternal weight gain: kg ( ) Lower gestational age at delivery:-0.16 wks( ) Higher Preterm Birth Rate: RR 1.50 ( ) Lower neonatal hypoglycemia: RR 0.78( ) Lower PP Blood glucose: -0.14( ) Less maternal weight gain: kg( ) Less PIH: RR 0.53( ) Less severe Neonatal hypoglycemia: RR 0.62 ( ) Metformin Failure Rate: 33.8% (229/678)

36 Metformin vs Glyburide Demographic differences: Metformin group somewhat older and higher gravidity Metformin Less maternal weight gain: kg( ) Lower Birth Weight : -209 ( ) Less Macrosomia : RR 0.33 ( ) Fewer LGA newborns : RR 0.44 ( ) Treatment failure rate: 26.8% in metformin group 23.5% in glyburide group Maternal hypoglycemia were similar in both groups

37 Study Conclusions Glyburide is clearly inferior to either insulin or metformin use in treating gestational DM Metformin plus insulin when required performs better than insulin alone Glyburide should not be used for treatment of gestational DM if metformin or insulin is available

38 Alternative Rx

39 Statin use in Pregnancy Congenital Malformation Risk Statins and Congenital malformations: Cohort study Bateman BT et al BMG 2015(Mar); 350:h1035.doi /bmj.h1035

40 A 35 yo multipara with BMI of 30 on Aldomet and HCTZ for HTN and Lipitor for familiar hyperlipidemia comes to you for preconceptual counseling. Your recommendations would include: A. Avoiding pregnancy while on her statin meds secondary to known fetal teratogenicy B. Continuing all meds and discontinue only with established pregnancy C. Continuing her HTN meds and switching her statin Rx D. Referring to MFM for risks and pre-conceptual counseling Avoiding pregnancy while o... 0% 0% 0% 0% ontinuing all meds and dis... Continuing her HTN meds a.. Referring to MFM for risks a..

41 Background Most commonly used drug to treat hyperlipidemia Statins have been contraindicated in pregnancy Animal studies showing teratogenicity in high doses Disruption of cholesterol biosynthesis in fetus Use in pregnancy rare > Limited small cohort studies and case reports Contradictory studies: US FDA > lipophillic statins may cause CNS defects National Birth Defects Prevention Study > No significance

42 Category D Drugs List

43 Preconception Counseling

44 Evolutionary Use and Applications Population prevalence demographics and use regarding: Cardiovascular Disease Hypercholesterolemia Diabetes Hypertension Obesity Statin use in prevention of preeclampsia Effects on endothelial function & inflamatiommation Pravastatin human studies ongoing

45 Statin Use in Preeclampsia Prevention

46 Study Design Cohort study > Medicaid Analytic extract Joint state/federal insurance program > Low income Approximately 40% of all births in US 46 state and DC from Ages with completed pregnancies Excluded mothers who used other identified teratogenic drugs Excluded known chromosomal abnormalities

47 Statin Use Prescribed statin from LMP through 90 days post LMP Statins Noted: Simvastatin Lovastatin Pravastatin Fluvastatin Atorvastatin Cerivastatin Rosuvastatin

48 Study Cohort Groups Primary Cohort Group > 887,000 pregnancies 1152 (0.13%) filled Rx during 90 day time frame Baseline Demographic differences: Older Fewer African-Americans Higher incidence of all comorbid conditions Pre-existing Diabetes > 45% of 1152 patients in study group

49 Study Results ALL Congenital Abnormalities: Statin Use: 6.34% No Use: 3.55% RR = 1.79 with CI of Univariant stratification for Pregestational DM Use RR 1.34 with CI of ) Analysis for ALL confounders no statistical significance RR 1.07 with CI of CNS & Cardiac anomalies Unadjusted RR: 3.04 with CI % 3.05 with CI Confounder adjusted RR: No statistical significance NO cases of limb reduction or holoprosencephaly

50 Study Conclusions Statins are not likely to be major teratogens Avoiding statins in women of reproductive age group who are not practicing Birth Control unfounded Potential use of statins in reducing risk of preeclampsia should not be discouraged based on teratogenic concerns Study findings (including other supportive studies) should encourage the FDA to reconsider the classification of contraindicated in pregnancy Class X is unjustified

51 SSRI Exposure Risk of Miscarriage Jon Troerup Andersen, MD et al ACOG October 2014; Vol 124 No. 4

52 Anti-depressant Pharmacology

53 SSRI Pharmacology

54 Depression with and without Antidepressant Rx

55 What statement regarding SSRI exposure in pregnancy is most accurate? A. Patients exposed to SSRI use during pregnancy have a higher miscarriage rate. B. Stopping SSRI use for at least 3 months prior to conception reduces the miscarriage rate C. Dosage and multidrug SSRI exposure correlates with miscarriage rates D. Confounding drug use significantly affects SSRI exposed miscarriage rates Patients exposed to SSRI u.. 0% 0% 0% 0% Stopping SSRI use for at least.. Dosage and multidrug SSRI... Confounding drug use signi...

56 Background Approximately 15% prevalence of depression in pregnancy Untreated depression associated with: Preeclampsia Preterm birth Low Birth Weight Miscarriage Study (Bassiouni et al) Miscarriage associated with higher serotonin serum levels SSRI Rx may further elevate Serotonin levels with causation in pregnancy losses SSRI use up 13% in first trimester pregnancy in US

57 Study Design Cohort study comparing SSRI use during early pregnancy vs discontinuation of SSRIs 3-12 months prior to conception Denmark registry: 1,300,000 pregnancies ( ) Identified all cases of miscarriage SSRI drugs studied: Fluoxetine Citalopram Paroxetine Sertraline Escitalopram Exposure for first 35 days of gestation Hi vs low dose exposure studied

58 Study Results 1,279,840 registered pregnancies 142,093 miscaarriages (11.1%) 2,884 with SSRI exposure (1.8%) Miscarriage Rates: unexposed 11.1% vs SSRI exposed 12.6% Miscarriage Cohort Older; Lower education; Lower income; more prior miscarriages Unadjusted RR with SSRI exposure: 1.31 ( Adjusted Hazard RR with SSRI exposure: 1.27 ( ) Comparing groups 1) discontinuing use 3-12 month prior to conception 2) never used SSRI 140,157 unexposed: 11.1% vs 14,016 used but stopped 13.8% Unadjusted RR: 1.38 ( ) Adjusted RR: 1.24 ( ) *No difference between Discontinued Group and Early Exposure Groups*

59 Study Result Subset Findings No relationship with dosing levels No relationship with changing or multiple drug exposures No relationship with confounding drug exposure Antipsychotics Thyroid preparations Antithyroid preparations Oral diabetic Rx

60 Study Conclusions Women both exposing pregnancy to SSRIs and women who were using SSRIs and stopped prior to pregnancy have elevated though no different miscarriage rates SSRI exposure during pregnancy DOES NOT have a causal effect on miscarriage Elevated rates in both cohorts may be due to illness or life-style issues No congenital heart defect difference in use vs nonuse *There is NO benefit in discontinuing SSRI use in pregnancy to decrease chances of miscarriage*