1

Uma Mahadevan-Velayos MD

Associate Professor of Medicine

UCSF Center for Colitis and Crohn’s Disease

San Francisco, CA

Do I Continue or Stop

Medications During Pregnancy

and Lactation?

1

2

Prior to Pregnancy

• Discuss risks and benefits of medications

prior to pregnancy

• There is a risk to stopping medication

– A disease flare may be more harmful to the

pregnancy than the medication

• Involve the obstetrician and pediatrician for

a multidisciplinary approach

3

FDA Pregnancy Category

Category Description

A Controlled studies show no risk

B No evidence of risk in humans

C • Animal reproduction studies show adverse effects

• No adequate studies in humans

• Benefits in pregnant women may be acceptable despite

potential risk

D Positive evidence of risk

X Contraindicated in pregnancy

4

Fish Oil

• Essential Fatty acids (EFA) and

Docosahexaenoic acid (DHA)

– Potential antithrombotic effect

– Prolong gestation

– No evidence of prevention of proteinuric

pregnancy

• Benefit in Crohn’s disease?

5

Aminosalicylates (B,C)

• Meta-analysis of 7 studies of 5-ASAs in pregnant

patients with IBD

– 5-ASA (n=642)

– No medication (n=1158)

Odds Ratio 95% CI

Congenital abnormalities 1.16 0.76-1.77

Stillbirth 2.38 0.65-8.72

Spontaneous abortion 1.14 0.65-2.01

Preterm delivery 1.35 0.85-2.13

Low birth weight 0.93 0.46-1.85

Rahimi R et al. Reprod Toxicol. 2008;25:271-275.

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Aminosalicylates (B,C)

• Sulfasalazine given w/ folic acid 1 mg BID

– Folic acid: neural tube defects, CV, GU,

cleft palate

– Case reports of congenital malformation

• Placental and breast transfer occurs

– Potential allergic reaction newborn:

watery diarrhea

– SAS not associated with kernicterus or

displacement of bilirubin from albumin

• Olsalazine & Asacol: Pregnancy category C

– All other 5-ASAs, pregnancy category B

Rahimi R et al. Reprod Toxicol. 2008;25:271-275.

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Corticosteroids (C)

• Case-control study in 1st T– Increased risk of oral clefts

– Overall risk of malformations low

– In transplant setting:• Adrenal suppression in newborn

• Premature rupture of membranes

• Compatible with breast feeding

• Budesonide (Entocort)– Orally inhaled budesonide not associated with

increase risk of fetal abnormalities

– 8 CD patients treated with oral budesonide 1

1. Beaulieu Inflamm Bowel Dis. 2009 Jan;15(1):25-8

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Antibiotics

• Metronidazole (B) /Ciprofloxacin (C)

– Low risk of teratogenicity

• Metronidazole: prospective controlled study, 2 meta-analysis

– However, 2nd, 3rd T use, 1st T cleft lip, palate

• Ciprofloxacin: prospective controlled study low risk of defects

– Affinity for bones, arthropathy in children

– Breast feeding not advised on MNZL, probably compatible with ciprofloxacin

– Minimal benefit in CD and UC with longer use-avoid

• Rifaximin: Pregnancy C

– Teratogenicity in animal studies

– Safety in humans in pregnancy/breastfeeding unknown

• Augmentin: Pregnancy B

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6MP/AZA (D)

• Teratogenic in animals (mice, rabbits, rats)– Given IV/IP at supratherapeutic doses. (low oral

bioavailability: 47% AZA, 16% 6MP)

– Increased cleft palate, ocular, skeletal,urogenital anomalies, hydrocephalus

– Poor oral bioavailability may produce levels too low to have substantial teratogenic effect

• Fetal liver in early pregnancy lacks inosinate pyrophosphorylase to convert AZA to active metabolites

Polifka and Friedman (Teratology 65:240-261. 2002)

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Azathioprine and Teratogenicity

• 189 pregnant women on AZA who contacted 1 of 7 teratogen

information services compared to 230 pregnant women who

took non-teratogenic treatments

AZA No AZA P

Rate of major

malformations

3.5% 3.0% .775

(OR 1.17;

95% CI 0.37-3.69)

Birth weight 2995 3252 .001

Gestational age 37.8 39.1 .001

Premature birth 21.4% 5.2% .001

Low birth weight 23% 6.0% .001

Goldstein Birth Defects Res A Clin Mol Teratol. 2007 Sep 10;79(10):696-701

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Azathioprine/6MP

• Swedish Medical Birth Register

– 476 women used AZA in early pregnancy

– Most common indication was IBD (>300)

– Rate of CA 6.2% AZA vs. 4.7% other• OR 1.41, 95% CI: 0.98-2.04

– Increased rate of VSD/ASD • OR 3.18, 95% CI: 1.45-6.04

– Increased rate of preterm, LBW, SGA• Likely disease effect

Cleary. Birth Defects Research 85:647-654, 2009

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Breastfeeding on AZA/6MP

• 8 lactating women received Aza 75-200 QD– Milk and plasma at 30, 60 min and every

hour x 5

• Variation in bioavailability reflected in wide range in milk an plasma first 3 hours

• Major excretion in breast milk within 4 hours of drug intake

• Worst case scenario: max concentration 0.0075 mg/kg– In most cases, will be <10% of maximum

concentration

Christensen APT 2008:28, 1209-1213

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Avoid Use

Drug Pregnancy

Category

Notes

Diphenoxylate C Teratogenic in animals

Loperamide B Increase in CV defects in 1 study

Bisphosphonates C • Animal studies: Alendronate

crosses placenta

• 24 pregnancies, no increased

teratogenic risk1

Methotrexate X • Known abortifacent

• Teratogenic (skeletal defects; cleft

palate)

Thalidomide X • Birth defects

1. Ornoy. Reproductive Toxicology 22 (2006:578)

14Adapted from: Hanauer SB. Rev Gastroenterol Disord. 2004;4(Suppl. 3):S18-S24.

Monoclonal

antibody

Infliximab Adalimumab

IgG

1Fc

Fab

HumanChimeric

Fab′

Certolizumab

pegol

PEG

PEGylated

humanized

Fab′ fragment

2 × 20 kDa

PEG

Biologics

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Transfer Across Placenta

• Fetal immunity is acquired by transfer of Ab as IgG from maternal to fetal circulation

• IgG is actively transported across the placenta– Smooth linear rise in fetal IgG as early as 13

weeks (earliest examined), after 32 weeks, significant increase in ratio

• Preferential transport– IgG1>IgG4>IgG3>IgG2

• Certolizumab is a Fab’ fragment – Likely passive diffusion

Kane AJG Jan 2009;104:228-233

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Placental Transfer of IgG Ab

• INF and ADA are IgG1 antibodies

• Fc portion of IgG actively transported across placenta by specific neonatal FcR

• Highly efficient transfer in 3rd T leads to elevated levels of drug in newborn

Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins

During human pregnancy. Am J Reprod Immunol 1996; 36(5):248-55.

Image Courtesy of Sundana Kane MD

r2=0.87, p<0.04

B: Fetal

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Infliximab (B) Safety Database

0

Pro

po

rtio

n o

f P

ati

en

ts (

%)

General

population

Crohn’s

disease

All infliximab

patients

(N=96)

Infliximab

patients with

CD (N=82)

10

20

30

40

50

60

70

80

67 66 67 67

17 16 17

1115

19 20

13

Live births

Therapeutic

termination

Miscarriages

Outcomes of Women Exposed to

Infliximab During Pregnancy

Katz JA, et al. Am J Gastroenterol. 2004;99:2385-2392.

Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59

Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.

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Adalimumab (B)

• OTIS (Organization for Teratology Information Specialists) reports 27 women enrolled in a prospective study of adalimumab in pregnancy and an additional 47 adalimumab exposed pregnant women in a registry– The rate of spontaneous abortion and stillbirth was

similar to the diseased comparison and the general population. The rates of congenital malformation and preterm delivery are also within the expected range

Chambers CD The OTIS Autoimmune Diseases in Pregnancy Project. Personal communication. July 13, 2007 .

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Biologics and Pregnancy (cont)

• Certolizumab (C): data on file

– 16 pregnancies:

• 4 healthy infants, 8 IAB, 1 SAB, 1 preterm, 2 unknown

– Reduced placental transfer

– Not detected in breast milk

• Natalizumab (C):

– IgG4, placental transfer in third trimester

– 143 pregnant patients exposed to tysabri

– No birth defects reported

Mahadevan ACG 2008

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FDA Database: Anti-TNF’s

• 61 reported CA’s/ 41 offspring (12/2005): – 22 etanercept, 19 INF

– 15 (37%) > 1 CA

– Most common is cardiac defect

– 1 VACTERL (ETN) Separate VACTERL in ADA• 24/41 (59%) had some component of VACTERL (11

INF)

• 24/41 cases (59%) mother on no other meds

• Vertebral, anal atresia, cardiac defect (VSD), tracheosphageal fistula with esoph atresia, renal, limb abnormality (radial dysplasia)

– Associated with DM: Inhibition of cholesterol-dependent sonic-hedgehog morphogenetic pathway

Carter J J Rheumaol 2009;36:3

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Malignancies

• Three malignancies have been reported in

infants exposed to anti-TNF in utero

– 3 wks/M: sacrococcygeal teratoma

• 3 infusions to mother. On AZA, pred

– 2 mo/F: neuroblastoma of liver, kidneys,

stomach

• 1 infusion 1 month prior to conception

– 4 years: leukemia.

• Unknown dose and duration of therapy. AZA

Centocor Data on File

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Infliximab in Cord Blood

Pt #

* Breastfed 1 2 3* 4* 5* 6 7* 8* 9 10

Last Dose

(days)30 3 14 90 120 55 46 35 70 74

Mother INF

(mcg/ml)15.1 1.4 19.2 3.8 4.8 14.5 16.5 2.2 4.1 5.1

Cord Blood -- 2.0 26.5 3.3 8.8 20.5 26.5 8.4 13.6 20.4

Newborn 25.3 2.9W:2*

23.6 4.2 8.7 28.2 27.5 10.6 4.72m*

8.41m*

INF undetected

6 2 7 2 3 5 5 4 >3 4

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Certolizumab Placental Transfer

Interval:

Last dose to

delivery

(weeks)

Maternal

Level DOB

(μg/ml)

Cord Blood

Level DOB

(μg/ml)

Newborn

level DOB

(μg/ml)

Pt 1 2 18.83 1.65 --

Pt 2 < 1 59.57 0.94 1.02

Pt 3 4 4.87 1.19 1.22

Pt 4 2 20.13 0.57 0.44

LOQ 0.41 μg/ml

Mahadevan U Gastroenterology. 2009:Abstract 960.

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Response to Vaccines

Mean

LevelsRange

(Normal

Range)

# Response

Inadequate

IgG (mg/dl) 416 297-510 (217-904) 0

IgA (mg/dl) 26 12-46 (11-90) 0

IgM (mg/dl) 46 17-129 (34-126) 4/7*

HiB (mcg/ml) 1.09 0.36-9 ( > 1.0 ) 1/9*

Tetanus

Toxoid (IU/ml)4.91 0.33-3.2 ( > 0.15 ) 0

*Only 7/9 patients had Ig levels assessed

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Timing of Biologics

• Our practice

– Discontinue infliximab at week 30

gestation

– Discontinue adalimumab at week 30-34

– Continue certolizumab throughout

pregnancy

– If mom flares, treat her!

• Breast feeding compatible

• No live virus vaccine to infant if INF/ADA in

utero

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PIANO:

• Patients classified by exposure to four groups of drugs taken b/w conception and delivery:– Unexposed: no immunomodulators/biologics

• (mesalamine, steroids, antibiotics allowed)

– Group A: AZA/6MP• +/- Unexposed medications

– Group B: INF, ADA, CZP• +/- Unexposed medications

– Group AB: Combination therapy• +/- Unexposed medications

Mahadevan DDW 2010

Pregnancy in Inflammatory

Bowel Disease And Neonatal Outcomes

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Results

• 605 women enrolled (4/1/2010)

• 417 pregnancies ended (+2 missing outcomes)– Unexposed: n = 166

– Group A: n = 102

– Group B: n = 108• 96 INF

• 59 ADA

• 13 CZP

• 3 Natalizumab

– Group AB: n = 42

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Results (cont)

• Medication use not associated with

increased risk of:

– Any Complication

– Preterm Birth

– Low Birth Weight

– Cesarean section

– Congenital Anomalies

• 17 anomalies/15 births

• Biologic exp: increased risk of NICU stay

• Combination exp: increased risk of

infection at 1 year of age28

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Summary

• Compatible with use in pregnancy– 5 asa

– Corticosteroids (1st T risk of cleft palate)

– Antibiotics (mnzl after T1)

– Azathioprine/6mp

– Infliximab (discontinue week 30)

– Adalimumab (discontinue week 30-34)

– Certolizumab (continue throughout)

• All of the above compatible with use in lactation– Except metronidazole

– Dose azathioprine/6MP 4 hours prior to feeding

• Recommendations:– Control disease prior to conception

– Continue most medications

– Multidisciplinary approach: High Risk Obstetrician, pediatrician, surgeon if needed