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

Discuss the Risk Benefits and

Alternative Options for

Induction of Labor

2

“…it has become apparent that infants

born between 370/7 and 386/7 weeks

gestation experience morbidities that

are associated with prematurity

compared to births at 390/7 through

406/7 weeks when infant mortality is

lower than at any other time in human

gestation”

3 Spong. JAMA. 2013

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

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

Non-Invasive PreNatal Testing

6

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

Non-Invasive PreNatal Testing

April Bleich, MD, FACOG

8

ANEUPLOIDY SCREENING

April Bleich, MD, FACOG

Maternal Fetal Medicine

Obstetrix Medical Group of Texas

9

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

History of Aneuploidy Screening

1970s AFP screening for neural tube defects

1980s AFP screening for Down syndrome

1990s Triple and Quadruple marker screening

Ultrasound “markers” for Down syndrome

2000s 1st trimester Down syndrome screening

Combined 1st and 2nd trimester screening

2010s Non invasive prenatal testing (NIPT)

11

Nicolaides KH, Fetal Medicine Foundation, London, 2004

12

ANEUPLOIDY

At least 8% of conceptions have

associated aneuploidy

– 50% of first trimester abortions

– 5-7% of all stillbirths and neonatal deaths

13

Who should be offered screening?

ACOG Practice Bulletin 77, January 2007

14

ACOG Practice Bulletin 77, January 2007

15

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

Chorionic Villus Sampling (CVS)

Primary advantage is that results are available earlier in pregnancy

Complications similar to amniocentesis

CVS in the standard window of 10-13 weeks does not increase the risk of congenital anomalies

Sampling before 10 weeks is associated with 1-2% risk of limb reduction defects

17

CVS

Performed at 11-13 weeks for genetic testing

May be done transcervically or transabdominally

18

Amniocentesis

Can be performed

after 15 weeks

Early amniocentesis

associated with

higher pregnancy

loss rates and

increased

complications

19

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 300-500

– Amniotic cell culture failure 0.1%

20

Ultrasound

5.3 mm

21

Soft Signs

Nuchal fold >6 mm

Echogenic bowel

Short humerus

Short femur

Echogenic intracardiac focus

Renal pelvis dilatation

22

Aneuploidy Risks

ACOG Practice Bulletin No 88. Invasive Prenatal Testing

for Aneuploidy, 2007. 23

Quad Screen

Offered at 15-20 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

Williams Obstetrics, 23rd edition, Cunningham FG, Leveno KJ,

Bloom SL, Hauth JC, Rouse DJ, Spong CY. McGraw Hill 2010. 25

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

Screening for Neural Tube Defects

Maternal serum AFP should be offered

to all women at 15-20 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 2003

27

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 2003

28

How to handle positive quad screen

Confirm dating

Discuss results and significance with

patient

Refer for genetic counseling and level II

ultrasound

29

First Trimester Screening

30

What is the NT?

A measurement of the

collection of fluid

under the skin behind

the fetal neck

Performed between

11-13 6/7 weeks (39-84

mm CRL)

Operator dependent:

Imaging expertise is

essential

31

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

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

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

Williams Obstetrics, 23rd edition, Cunningham FG, Leveno KJ,

Bloom SL, Hauth JC, Rouse DJ, Spong CY. McGraw Hill 2010. 35

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

NIPT Options

37

Sensitivity/Specificity

MaterniT21 – Trisomy 21 99.1%/99.9%

– Trisomy 18 >99.9%/99.6%

– Trisomy 13 91.7%/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

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

Levine BA, Goldschlag D. Noninvasive prenatal testing: A new standard of care

Contemporarary Ob/Gyn 2014

40

High Risk (per ACOG)

AMA

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

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

Advantages over NIPT

Diagnostic

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

References

The use of chromosomal microarray analysis in prenatal diagnosis. Committee Option No 581. ACOG. Obstet Gynecol 2013;122:1374-7.

Williams Obstetrics, 23rd edition, Cunningham FG, Leveno KJ, Bloom SL, et al. McGraw Hill 2010.

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 2007.

Invasive prenatal testing for aneuploidy. ACOG Practice Bulletin No 88. December 2007.

Neural tube defects. ACOG Practice Bulletin No 44. July 2003, reaffirmed 2013.

44

Use of Low Dose Aspirin in Pregnancy

to Prevent Preeclampsia

45

Rx Pharmacologic Concerns

Public Perception of NSAIDS

„EAGeR Randomized Trial

RCT 1228 patients between June 2007 – July 2011

Low dose ASA vs Placebo- Preconception

Conclusion:

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:CD000492

Duly L, et al. BMJ 2001; 322: 329-33

CLASP; Lancet 1994; 343:619-29

Benefits of Aspirin in Pregnancy

ASA Pharmacology

Preeclampsia and AA Pathway

52

ASA Preeclampsia Prophylaxis High Risk

Pregnancies

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

ASA Treatment to Benefit

ASA in Reducing Preeclampsia

General OB Population

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 (60-150 mg/d) at 12-28 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

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)

Recommend low-dose ASA if the

patient has > 1

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

Consider low-dose ASA if several of

these moderate risk factors

Low Previous uncomplicated full-term delivery Do not recommend low-dose ASA

World Health Organization

Recommends starting use of low dose

ASA (75 mg/d) 12-20 wks gestation

Women with high risk factors

– h/o preeclampsia in past

– Diabetes

– Chronic HTN

– Renal/Autoimmune disease

– Multifetal

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

American Academy of Family

Practice

Recommends Low-dose ASA (81

mg/day) after 12 wks EGA in women at

high risk for preeclampsia

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

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

British Journal of Haemotology

March 5, 2014 165, 585-599

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

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.

Creasy & Resnik‟s 7th 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

Creasy Conclusion

“Given the lack of significant adverse

effects in ASA therapy, the degree of

efficacy may warrant therapy,

especially in „high-risk‟ pregnancies.”

„Never as Bad or Good as we

thought‟

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?

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Low-Dose Aspirin Use for the Prevention of

Morbidity and Mortality from Preeclampsia

Who is at clinical risk for development of pre-

eclampsia?

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?

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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?

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71

New Era in Anticoagulant Therapy

72

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

74

Dabigtran

(Pradaxa)

CrCl

>30

15-30

<15

150 mg bid

75 bid

-

150 bid

-

-

150 bid (Canada)

Rivaroxaban

(Xarelto)

>50

15-50

<15

20

15

-

15 bid x 21 d

20 daily

<30 -

10 daily x 14 d

-

-

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

Stroke Prophylaxis

Atrial Fibrillation

VTE

Treatment

VTE/hip, knee

proph

75

PT – prolonged with Rivaroxaban,

Apixaban

INR variable with different reagents,

cannot be

used for monitoring

Thrombin Time – prolonged with

Dabigatran not useful monitoring

76

Direct Thrombin Inhibitor Assay – diluted

TT for quantitative measurement of

Dabigatran

Factor X inhibitor assay

77

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

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

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

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

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

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

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

Evidence – Based Management

Plan for Obese Pregnant Women

Michelle Owens, MD

85

Evidence –Based Methods for

Prediction, Prevention and

Management of Women at

Risk for Preterm Birth

86

87

Williams Obstetrics, 23rd ed.

Evidence-Based Methods for Prediction,

Prevention and Management of Women at

Risk for Preterm Birth

Cerclage

17P Alpha Hydroxyprogesterone

Vaginal Progesterone

Tocolysis

88

A 31 year old female presents for prenatal care with her

2nd 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

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

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

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.

92

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

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.

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