Choosing Wisely. Obstetrics / Maternal Fetal Medicine Things Providers and Patients Should Question

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1 Choosing Wisely Obstetrics / Maternal Fetal Medicine Things Providers and Patients Should Question Michelle Owens, MD, FACOG David Rindfusz, MD, FACOG April Bleich, MD, FACOG Kathleen Crowley, MD 1

2 Discuss the Risk Benefits and Alternative Options for Induction of Labor 2

3 it has become apparent that infants born between 37 0/7 and 38 6/7 weeks gestation experience morbidities that are associated with prematurity compared to births at 39 0/7 through 40 6/7 weeks when infant mortality is lower than at any other time in human gestation Spong. JAMA

4 The American College of Obstetricians and Gynecologists Don t schedule elective, non-medically indicated inductions of labor or Cesarean deliveries before 39 weeks 0 days gestational age. Delivery prior to 39 weeks 0 days has been shown to be associated with an increased risk of learning disabilities and a potential increase in morbidity and mortality. There are clear medical indications for delivery prior to 39 weeks 0 days based on maternal and/or fetal conditions. A mature fetal lung test, in the absence of appropriate clinical criteria, is not an indication for delivery. 4

5 The American College of Obstetricians and Gynecologists Don t schedule elective, non-medically indicated inductions of labor between 39 weeks 0 days and 41 weeks 0 days unless the cervix is deemed favorable. Ideally, labor should start on its own initiative whenever possible. Higher Cesarean delivery rates result from inductions of labor when the cervix is unfavorable. Health care practitioners should discuss the risks and benefits with their patients before considering inductions of labor without medical indications. 5

6 Non-Invasive PreNatal Testing 6

7 Society for Maternal-Fetal Medicine Don t offer noninvasive prenatal testing (NIPT) to low-risk patients or make irreversible decisions based on the results of this screening test. NIPT has only been adequately evaluated in singleton pregnancies at high risk for chromosomal abnormalities (maternal age >35, positive screening, sonographic findings suggestive of aneuploidy, translocation carrier at increased risk for trisomy 13, 18 or 21, or prior pregnancy with a trisomy 13, 18 or 21). Its utility in low-risk pregnancies remains unclear. False positive and false negative results occur with NIPT, particularly for trisomy 13 and 18. Any positive NIPT results should be confirmed with invasive diagnostic testing prior to a termination of pregnancy. If NIPT is performed, adequate pretest counseling must be provided to explain the benefits and limitations. 7

8 Non-Invasive PreNatal Testing April Bleich, MD, FACOG 8

9 ANEUPLOIDY SCREENING April Bleich, MD, FACOG Maternal Fetal Medicine Obstetrix Medical Group of Texas 9

10 Objectives Review history of aneuploidy screening Discuss what types of aneuploidy screening are available Discuss who should be offered testing Review diagnostic testing options 10

11 History of Aneuploidy Screening 1970s 1980s 1990s 2000s 2010s AFP screening for neural tube defects AFP screening for Down syndrome Triple and Quadruple marker screening Ultrasound markers for Down syndrome 1 st trimester Down syndrome screening Combined 1 st and 2 nd trimester screening Non invasive prenatal testing (NIPT) 11

12 Nicolaides KH, Fetal Medicine Foundation, London,

13 ANEUPLOIDY At least 8% of conceptions have associated aneuploidy 50% of first trimester abortions 5-7% of all stillbirths and neonatal deaths 13

14 Who should be offered screening? ACOG Practice Bulletin 77, January

15 ACOG Practice Bulletin 77, January

16 Available Aneuploidy Screening/Diagnostic Testing Ultrasound Quad screen First trimester screening Nuchal translucency Integrated/serum integrated Sequential screen Non-invasive prenatal testing (NIPT) Diagnostic testing Chorionic villus sampling Amniocentesis Percutaneous umbilical blood sampling 16

17 Chorionic Villus Sampling (CVS) Primary advantage is that results are available earlier in pregnancy Complications similar to amniocentesis CVS in the standard window of weeks does not increase the risk of congenital anomalies Sampling before 10 weeks is associated with 1-2% risk of limb reduction defects 17

18 CVS Performed at weeks for genetic testing May be done transcervically or transabdominally 18

19 Amniocentesis Can be performed after 15 weeks Early amniocentesis associated with higher pregnancy loss rates and increased complications 19

20 Complications of Amniocentesis Genetic amniocentesis Vaginal spotting 1-2% Transient leakage of amniotic fluid 1-2% Chorioamnionitis <0.1% Fetal loss We quote 1 in 200 but most recent studies suggest it is closer to 1 in Amniotic cell culture failure 0.1% 20

21 Ultrasound 5.3 mm 21

22 Soft Signs Nuchal fold >6 mm Echogenic bowel Short humerus Short femur Echogenic intracardiac focus Renal pelvis dilatation 22

23 Aneuploidy Risks ACOG Practice Bulletin No 88. Invasive Prenatal Testing for Aneuploidy,

24 Quad Screen Offered at weeks gestation Multiple-marker screening test used in second trimester AFP, β-hcg, Estriol, Inhibin A AFP βhcg Estriol Inhibin A Trisomy 21 Trisomy 18 24

25 Williams Obstetrics, 23rd edition, Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. McGraw Hill

26 Maternal Serum AFP Abnormal levels also associated with: Aneuploidy Neural Tube Defects/anencephaly Ventral wall defects Omphalocele Gastroschisis Fetal demise Placental abnormalities-accreta, previa Normal gestation Unexplained elevation in msafp is associated with increased risk of adverse pregnancy outcomes (preterm birth, growth restriction, stillbirth) 26

27 Screening for Neural Tube Defects Maternal serum AFP should be offered to all women at weeks gestation Cut-off of 2.5 MoMs is expected to detect 80% of spina bifida and 90% of anencephaly ACOG Practice Bulletin 44, July

28 Diagnosis of Neural Tube Defects Traditional diagnostic test was amniocentesis for amniotic fluid AFP and acetylcholinesterase If msafp is elevated, we now offer level II ultrasound as a diagnostic test, performing amniocentesis in only a small subset Reported sensitivity of ultrasound is > 97% ACOG Practice Bulletin 44, July

29 How to handle positive quad screen Confirm dating Discuss results and significance with patient Refer for genetic counseling and level II ultrasound 29

30 First Trimester Screening 30

31 What is the NT? A measurement of the collection of fluid under the skin behind the fetal neck Performed between /7 weeks (39-84 mm CRL) Operator dependent: Imaging expertise is essential 31

32 Nuchal Translucency Increased NT is associated with an increased risk of aneuploidy and other anomalies (most commonly cardiac malformations) One-third of fetuses with an increased NT measurement will have chromosomal abnormalities and Down syndrome accounts for approximately half of these 32

33 NT may be useful in the evaluation of multiple gestations, for which serum screening is not as accurate (twins) or is unavailable (triplets or higher) NT alone detects 64-70% of fetuses with Down Syndrome 33

34 First Trimester Serum Markers First trimester serum markers Pregnancy Associated Plasma Protein A (PAPP-A) complex glycoprotein produced by the placenta Free β-hcg Combined NT and biochemical screening (PAPP-A and β-hcg) will identify 79-87% of Trisomy 21 34

35 Williams Obstetrics, 23rd edition, Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. McGraw Hill

36 Non-Invasive Prenatal Testing Circulating cell free fetal DNA compromises 3-13% of the total cell free maternal DNA Derived from placenta and cleared from maternal blood within hours of delivery Utilizes massively parallel genomic sequencing or selective sequencing 36

37 NIPT Options 37

38 Sensitivity/Specificity MaterniT21 Trisomy %/99.9% Trisomy 18 >99.9%/99.6% Trisomy %/99.7% Harmony Trisomy 21 >99%/>99.9% Trisomy 18 >98%/>99.9% Trisomy 13 80%/>99.9% Panorama Trisomy 21 >99% Trisomy 18 >99% Trisomy 13 >99% 38

39 New additions 22q deletion syndrome (DiGeorge) 5p (Cri-du-chat syndrome) 15q (Prader-Willi/Angelman syndromes) 1p36 deletion syndrome 4p (Wolf-Hirschhorn syndrome) 8q (Langer-Giedion syndrome) 11q (Jacobsen syndrome) Trisomy 16 Trisomy 22 39

40 Levine BA, Goldschlag D. Noninvasive prenatal testing: A new standard of care Contemporarary Ob/Gyn

41 AMA High Risk (per ACOG) Fetal ultrasound findings suggestive of increased risk aneuploidy History of prior pregnancy with trisomy Positive screening test indicating increased risk of aneuploidy Parental balanced Robertsonian translocation carrier with increased risk of Trisomy 13 or 21 41

42 Can still offer maternal serum AFP Does not replace diagnostic testing Results may be non-reportable Risk of false negative/false positive results Need for genetic counseling available Positive results should be confirmed with diagnostic testing 42

43 Diagnostic Advantages over NIPT Evaluates the FULL fetal karyotype Can detect balanced translocations Allows you to do microarray Allows for identification of genetic abnormalities in 6% of fetuses with abnormal ultrasound findings and normal karyotype Allows for identification of genetic abnormalities in 1.7% of fetuses with normal appearing ultrasound and normal karyotype 43

44 References The use of chromosomal microarray analysis in prenatal diagnosis. Committee Option No 581. ACOG. Obstet Gynecol 2013;122: Williams Obstetrics, 23 rd edition, Cunningham FG, Leveno KJ, Bloom SL, et al. McGraw Hill Levine BA, Goldschlag D. Noninvasive prenatal testing: A new standard of care. Contemporarary Ob/Gyn 2014 Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin No 77. January Invasive prenatal testing for aneuploidy. ACOG Practice Bulletin No 88. December Neural tube defects. ACOG Practice Bulletin No 44. July 2003, reaffirmed

45 Use of Low Dose Aspirin in Pregnancy to Prevent Preeclampsia 45

46 Rx Pharmacologic Concerns

47 Public Perception of NSAIDS

48 EAGeR Randomized Trial RCT 1228 patients between June 2007 July 2011 Conclusion: Low dose ASA vs Placebo- Preconception No significance benefit of LDA in livebirth or pregnancy loss rates in women with one to two losses 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

49 Benefits of Aspirin in Pregnancy

50 ASA Pharmacology

51 Preeclampsia and AA Pathway

52 ASA Preeclampsia Prophylaxis High Risk Pregnancies *May be helpful in patients: preeclampsia in second trimester (severe) APS* 1. h/o prior 2. known 52

53 ASA Treatment to Benefit

54 ASA in Reducing Preeclampsia General OB Population

55 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 Recommendation Prescribe Low-dose (81 mg/d) ASA after 12 wks of gestation (Grade B) Risk Assessment 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) Preventive Medicine 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 Benefit vs Harm Substantial net benefit exists in daily low-dose ASA to reduce the risk of preeclampsia, preterm birth, & IUGR in women at risk for preeclampsia

56 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 > 1 Consider low-dose ASA if several of these moderate risk factors Low Previous uncomplicated full-term delivery Do not recommend low-dose ASA

57 World Health Organization Recommends starting use of low dose ASA (75 mg/d) wks gestation Women with high risk factors h/o preeclampsia in past Diabetes Chronic HTN Renal/Autoimmune disease Multifetal

58 American Heart Association Start Low-dose ASA from 12 wks EGA to delivery in women Chronic Hypertension Previous Primary or Secondary Hypertension Previous pregnancy related hypertension

59 American Academy of Family Practice Recommends Low-dose ASA (81 mg/day) after 12 wks EGA in women at high risk for preeclampsia

60 National Institute of Health Recommends low-dose ASA (75 mg/d) in women at high risk for preeclampsia: H/o Hypertension in previous pregnancy Chronic kidney disease Autoimmune disease Type 1 & 2 diabetes Chronic hypertension Recommends in women for > 1 moderate risk factor Daily dosing of 75 mg/daily 12 wks through delivery

61 American College of Obstetricians and Gynecologists Recommends Low-dose ASA (60-80 mg/d) during late first trimester to prevent preeclampsia in women with: Early onset preeclampsia resulting in preterm deilvery < 34 wks EGA History of preeclampsia in more than one previous pregnancy

62 British Journal of Haemotology March 5, , Randomized Control Trials (ASA/placebo on PE) -Bujold et al, 2010 & Roberge et al, 2012 Conclusion: Low-dose ASA < 16 wks EGA 1) modestly reduced the risk of severe PE 2) did not reduce risk of FGR/SGA or mild/term PE -Rey and Rivard, 2011 Conclusion: 1) Aspirin resistance prevalence may impact affect of Low-dose ASA in the setting of pregnancy

63 Critical Comments British Journal of Haematology Current Treatment of pregnancy complications is imprecise, generalized by outcome and not stratified by disease mechanism As disease mechanisms can vary with the gestation of the event, this will impact use and timing of interventions Taxonomy of disease will require better elaboration of disease process and biomarkers to guide treatment We should be wary of reaching the wrong conclusion form RCTs performed with inadequate precision in selection patient groups.

64 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

65 Creasy Conclusion Given the lack of significant adverse effects in ASA therapy, the degree of efficacy may warrant therapy, especially in high-risk pregnancies.

66 Never as Bad or Good as we thought

67 A 22 yr old female presented for preconception counselling with her husband of 2 years. They have been using oral contraceptives for birth control. Her general medical history and physical examination did not indicate any potential problems. She did ask about preeclampsia since her sister had a very complicated first pregnancy due to preeclampsia. Her sister delivered by Csection a 3 lb 4 oz male infant at 32 weeks when her preeclampsia became very severe resulting in a seizure episode and evidence of organ damage to her kidney and liver. She has read about preeclampsia and the use of low-dose aspirin for the prevention of morbidity and mortality from preeclampsia. What is your advice? 67

68 Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality from Preeclampsia Who is at clinical risk for development of preeclampsia? What is the appropriate dose of aspirin? What is the appropriate schedule? When to start When to stop Are there potential harms to taking low-dose aspirin in pregnancy? 68

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70 Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality from Preeclampsia Who is at clinical risk for development of preeclampsia? What is the appropriate dose of aspirin? What is the appropriate schedule? When to start When to stop Are there potential harms to taking low-dose aspirin in pregnancy? 70

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72 New Era in Anticoagulant Therapy 72

73 A 30-year-old patient presents at 24 weeks with her first pregnancy with a 1 day onset of left calf tenderness and swelling. She has had no medical problems, no complications in her pregnancy and is on no medications. On examination her uterus is compatible with a 24 week gestation and the fetal heart is 142/min. Examination of her extremities reveal a markedly swollen, tender bluish left calf with swelling extending to her knee. You suspect a venous thrombosis clinically and it is confirmed by ultrasound doppler. What are your thoughts for initial therapy? What are your thoughts for long term therapy? Is there a role for the newer oral anticoagulants in pregnancy? Mechanism of actions Safety 73

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75 Stroke Prophylaxis Atrial Fibrillation VTE Treatment VTE/hip, knee proph Dabigtran (Pradaxa) CrCl > mg bid 150 bid 150 bid (Canada) bid - < Rivaroxaban (Xarelto) > bid x 21 d 20 daily 10 daily x 14 d - <15 - < Apixaban (Eliquis) Weight <60 Creat >1.5 Age > 80 5 mg bid 2.5 bid 10 bid x 7 d 5 bid 2.5 bid x 35 days hip, x 12 days knee 75

76 PT prolonged with Rivaroxaban, Apixaban INR variable with different reagents, cannot be used for monitoring Thrombin Time prolonged with Dabigatran not useful monitoring 76

77 Direct Thrombin Inhibitor Assay diluted TT for quantitative measurement of Dabigatran Factor X inhibitor assay 77

78 NOA : Interference APC resistance assay Lupus anticoagulants Protein C clot based activity assay Protein S Antithrombin activity If on NOA, cannot accurately assess thrombophilia 78

79 Elective Surgery: Standard Bleeding Colonoscopy, uncomplicated laparoscopy, non spinal tabs Cr Cl > 50 Cr Cl < 50 Cr Cl < 30 Dabigatran dc 2 days pta 3 days 4 days Rivaroxaban dc 24 hrs Apixaban 2 days 2 days 79

80 High Bleeding Procedure Cr Cl > 50 Cr Cl < 50 Cr Cl < 30 Dabigatran dc 2 days 4 days 6 days Rivaroxaban dc 2 days Apixaban 4 days 4 days 80

81 Post OP NOA If good hemostasis, start 4-6 hrs post with reduced dose (D = 75, R = 10, A = 2.5) If major abdominal surgery, start when hemostasis assured 81

82 Emergency Surgery Anticipate bleeding complications Normal TT, PTT rules out significant Dabigatran Normal anti X - Rivaroxaban If normal renal function, most bleeding stops at 48 hrs 82

83 Emergency Bleeding : Dabigatran American College Cardiology 2011 Recommends FFP, prbc, surgical intervention FFP debatable as no evidence to support as does not reverse inhibition of coagulation factors Hemodialysis removes about 60% of drug as only 35% protein bound 83

84 Non Specific Hemostatic Agents Recombinant Factor VII (Novoseven) Activates Factor X Four Factor Prothrombin Complex (Beriplex) II VII IX X Non Active Three Factor Prothrombin (Profilnine) II IX X Low VII Activated Prothrombin Complex (FEIBA) II IX IX Activated VII 84

85 Evidence Based Management Plan for Obese Pregnant Women Michelle Owens, MD 85

86 Evidence Based Methods for Prediction, Prevention and Management of Women at Risk for Preterm Birth 86

87 Williams Obstetrics, 23 rd ed. 87

88 Evidence-Based Methods for Prediction, Prevention and Management of Women at Risk for Preterm Birth Cerclage 17P Alpha Hydroxyprogesterone Vaginal Progesterone Tocolysis 88

89 A 31 year old female presents for prenatal care with her 2 nd pregnancy at 13 weeks gestation. Her first pregnancy resulted in her going into premature labor at 31 weeks and delivering a viably male infant 2 years ago. After several weeks in the NICU, the baby was discharged and is doing well. She is currently in good health. What are your recommendations? 89

90 A 27 year G1 P0 female presents for her prenatal care at 12 weeks. She is found to be in good health with a 12 week gestation. She was seen at monthly intervals and the pregnancy progressed well. At approximately 26 weeks she became aware that her uterus was contracting mildly to moderately. On occasion the contractions would be as frequent as every 5 minutes. However, most of the time they were more widely spaced. On examination you note that her cervix seems to have shortened when compared to previous examinations. You perform a transvaginal ultrasound and the cervical length is 20 mm. Cervix is soft and admits 1 finger. What would you recommend? 90

91 Choosing Wisely Don t use progestogens for preterm birth prevention in uncomplicated multifetal gestations. The use of progestogens has not been shown to reduce the incidence of preterm birth in women with uncomplicated multifetal gestations. 91

92 A 33-year-old woman, G2P0101, at 18 weeks' gestation presents for routine prenatal care. She has a history of pre-term labor at 32 weeks with her previous pregnancy, and she is currently receiving vaginal micronized progesterone suppositories (100 mg) daily. Transvaginal ultrasound examination demonstrates a cervical length of 16 mm and funneling of the membranes. She denies painful contractions, leakage of fluid, or vaginal bleeding. Which of the following is the most appropriate next step in the management of this patient? A. Place patient at bedrest B. Substitute 17-hydroxyprogesterone caproate for the micronized progesterone suppositories C. Perform a reduction amniocentesis D. Perform a cerclage E. Evacuate the uterus 92

93 Choosing Wisely Don t place a cerclage in women with short cervix who are pregnant with twins. Women with a short cervical length who are pregnant with twins are at very high risk for delivering preterm, but the scientific data, including a meta-analysis of data published on this issue, shows that cerclage in this clinical situation not only in not beneficial, but may in fact be harmful, i.e., associated with an increase in preterm births. 93