tuberculosis in pregnancy and postpartum - jyoti mathad.pdf · irr 1.95 postpartum tb risk of tb in...

Jyoti S. Mathad, MD MScAssistant Professor

Center for Global HealthWeill Cornell Medical College

North American Regional Meeting of IUTLDMarch 2, 2018

Diagnosing and Treating TB in Pregnant Women: Current Practices

and Research Opportunities

Weill Cornell Medicine

CENTER FOR GLOBAL HEALTH

Objectives

• Epidemiology– What is the burden of TB in pregnancy?

• Immunology and pathophysiology– Does pregnancy impact the course of

TB?– Does pregnancy impact the treatment

or prevention of TB?

• Outcomes– How does maternal TB impact maternal

and infant outcomes?

• Screening and Treatment

Weill Cornell Medical College


WHAT IS THE BURDEN OF TB IN PREGNANCY?



~500,000 died

3.5 million

WHO Global TB Report, 2017Weill Cornell Medicine


TB incidence in US-born vs. foreign-born persons, 1993-2016

0

5,000

10,000

15,000

20,000

U.S.-born Foreign-born

US CDC TB Report, 2016Weill Cornell Medicine


TB Case Rates by Age and Sex, United States, 2015

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Under 5 5 - 14 15 - 24 25 - 44 45 - 64 ≥65

Cas

es

pe

r 1

00

,00

0

Age, years

Male Female



TB incidence peaks in women of reproductive age

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Under 5 5 - 14 15 - 24 25 - 44 45 - 64 ≥65

Cas

es

pe

r 1

00

,00

0

Age, years

Male Female



Global estimate of TB in pregnancy

Based on total population, crude birth rate, age distribution, TB case notification by age/sex

Sugarman, Lancet Global Health 2014

IRR 1.95 Postpartum TB

Risk of TB in Pregnancy: UK primary care cohort 1996-2008

• 192,801 women enrolled with 264,136 pregnancies

• Mean follow-up 9.1 years, (1,745,834 PY)

• 177 TB events; • Postpartum 15.4 vs. 9.1

per 100,000 PY

Zenner AJRCCM 2011Weill Cornell Medicine


Postpartum

Immune changes during pregnancy increase risk of disease

Figure adapted from Kourtis NEJM 2014

• Increased risk of malaria, listeria• Increased severity of flu, varicella



Immunology of latent TB

Adapted from Griffiths, Nat Med Review 2010

CD4+ T cells release IFN-γ, TNF-α

IFN-γ, TNF-α stimulate macrophages



HOW DO YOU SCREEN FOR TB IN PREGNANT WOMEN?



Latent TB tests

Pai, Lancet 2004

Pregnancy impacts LTBI test performance

0%

5%

10%

15%

20%

25%

30%

35%

40%

HIV+, India(n=125)

HIV-, India(n=143)

HIV+, Kenya(n=89)

Pe

rce

nt

po

sit

ivit

y

TST+

IGRA+

*

*

*

37%

14%

32%

17%

29%

11%

1 Mathad, AJRCCM 2016; 2Mathad PLOS One 2014; 3LaCourse, JAIDS 2017



Treatment of latent TB in pregnancy

HIV negative HIV positive

Low burden Defer until postpartum, unless recent household contact

INH 300mg + Vit B6 (10-25mg) daily for 6-9 mos1,2

High burden No official guidance INH 300mg + Vit B6 (10-25mg) daily for 6-9 mos1,2

1CDC 2013, 2WHO 2010



Active TB screening & diagnosis

• WHO-recommended symptom screen

– Cough

– Fever

– Night sweats

– Weight loss (lack of weight gain during pregnancy)

• Shielded chest X-ray

• Sputum AFB/ culture

– EPTB: biopsy



What is the sensitivity of the TB symptom screen?

1415 HIV+ screened1

226 (16%) symptoms

1189 (84%) no symptoms

16/226 (7%) active TB

19/1189 (1.6%)active TB

NPV: 98%, PPV 4.4%Spec: 84%, Sens: 28%

• Effect of Gene Xpert • Modified symptom screen?2

1Hoffmann PLOS One 2013; 2LaCourse JAIDS 2016;

Shielded chest Xray is safe in pregnancy

• ACOG2

– Exposure <5 rad (50 mGy) notassociated with pregnancy loss or fetal anomalies

– Ultrasound and MRI are notassociated with known adverse fetal effects

Comparison of the estimated mean fetalabsorbed dose from radiographic procedures1

1Patel, Radiographics 2007; 2ACOG, Obstet Gynecol 2004



DOES PREGNANCY IMPACT ACTIVE TB TREATMENT?



Treatment of Pulmonary TB in Pregnancy

HIV negative HIV positive

Low Burden1 INH 5mg/kg/d x 9 moRIF 10mg/kg/d x 9moEMB wt-based x 2 moB6 25mg/d x 9 mo

INH 5 mg/kg/d × 6 moRIF 10 mg/kg/d × 6 moEMB 15mg/kg/d x 2 moPZA 25mg/kg/d x 2 moB6 10-25mg/d x 6 mo

High Burden2 INH 300 mg/d × 6 moRIF 600 mg/d × 6 moEMB wt-based x 2moPZA wt-based × 2 moB6 25mg/d x 6 mo

INH 5 mg/kg/d × 6 moRIF 10 mg/kg/d × 6 moEMB 15mg/kg/d x 2 moPZA 25mg/kg/d x 2 moB6 10-25mg/d x 6 mo

DIFFERENCE IN PZA guidance

1 CDC, ATS, IDSA guidelines; 2 WHO, British thoracic Society, RNTCP and IUATLD guidelines

First line drugs for TB in pregnancy

Drug FDA Crosses placenta

Breast-milk

Issues in pregnant women

Isoniazid NR Yes Yes Hepatotoxicity

Rifampin NR Yes Yes Drug interactions with NNRTIs, PIs; increased bleeding risk?

Rifabutin PS Unk Unk Drug interactions w PIs, increased bleeding risk? limited experience

Ethambutol PS Yes Yes

Pyrazinamide NR Unk Unk Different guidance

Brost Obstet Gyn Clin 1997;Bothamley Drug Safety 2001;Shin CID 2003; Micromedex; Mathad & Gupta CID 2012



NR= not recommended; PS= potentially safe based on animal studies

Maternal complications

• Risk of pregnancy complications vs. no TB

– Pre-eclampsia & eclampsia (2 fold)

– Vaginal bleeding (2 fold)

– Hospitalization (12 fold)

– Miscarriage (10 fold)

– Mortality

• 25 fold for HIV-uninfected

• 37 fold for HIV-infected

Jana Int J Gyn Obstet 1994Jana NEJM 1999Chin HC BJOG 2010Bjerkedal 1975

Bothamley 2001Pillay Lancet ID 2000; Mathad CID 2012Khan M AIDS 2001



Fetal and infant complications

• Risk of complications vs. no TB

– Infant mortality (3.4 fold)

– Low birth weight (2 fold)

– Lower Apgar scores

– Prematurity (2 fold)

– Small for gestational age (2 fold)

– Infant HIV (2 fold)

– Congenital TB (rare)

Jana Int J Gyn Obstet 1994Jana NEJM 1999Chin HC BJOG 2010

Khan AIDS 2001; Pillay Lancet ID 2000;Gupta JID 2011



Follow-up and monitoring

• Consider checking LFTs monthly1

• Breast feeding allowed if on 1st line– NOT recommended with rifabutin or

fluoroquinolones

– No evidence for other medications

• WHO, “If mother suspected of having TB, separate from infant”2

– Can resume when smear negative or infant started on TB treatment

Many DON’T follow this guideline

– Baby should get INH + BCG (if available)

1Blumberg AJRCCM 2003; 2WHO 1998

Second-line TB drugs in pregnancy

Drug FDA Guidance

Group A: Fluoroquinolones* Not recommended if pregnant or BF

Group B: Injectable agents

Amikacin/Kanamycin*/Streptomycin Causes fetal abnormalities

Capreomycin Not recommended if pregnant

Group C: Other second line agents

Ethionamide/Prothionamide* Not recommended if pregnant

Cycloserine/terizidone Not recommended if pregnant

Linezolid Not recommended if pregnant

Clofazamine* Not recommended if pregnant

Group D: Add-on agents

(D2) Bedaquiline Animal studies suggest no harm

(D2) Delaminid (EMA approved) Not yet classified but no teratogenicity

(D3) p-aminosalicyclic acid (PAS) Not recommended if pregnant

WHO MDR TB Guidelines, 2016

MDR TB in pregnancy

• Treatment similar to non-pregnant adults– Individualized treatment with at least 4 new agents

• Favor injectable after delivery

– Lactation: little to no data so often not recommended

• >57 published case reports; 4 cases with HIV• Outcomes: case series suggest treatment success possible

Gach 1999;Shin 2003; Nitta 1999;Lessnau 2003;Tabarsi 2007; Khan 2007; Palacios 2009; Toro 2011

**

*

*also on LZD, MEM

TB Treatment and Prevention Trials for Pregnant Women

Goals Study

Immunology

• Impact of pregnancy, stage of pregnancy and HIV on immune response to MTB

PRACHITi study (~85% enrolled)

Treatment

• Opportunistic PK/safety of 1st line TB drugs in pregnancy

TSHEPISO (completed)

• PK/safety of MDR TB drugs in pregnancy IMPAACT P1026s (enrolling)

• Maternal TB treatment registry IMPAACT P1026s (accrual early 2016)

Preventive Therapy

• IPT in HIV-infected pregnant women P1078 (completed)

• INH/Rifapentine x 12 weeks in HIV-infected and HIV-uninfected pregnant women

P2001 Version 1.0-50% enrolled

Summary

• Peak incidence of TB in women during reproductive age

• Immune and physiological changes may be important for diagnosis and treatment

• Best approaches of integrated TB screening and prevention are still needed

• Maternal TB associated with adverse pregnancy outcomes, maternal mortality and infant TB and mortality

• Need to include pregnant women in trials of diagnostics and drugs whenever feasible

• Several ongoing studies will help to fill in the knowledge gaps

Acknowledgements

NIAID: K23AI129854 NICHD: R01HD081929NCATS: KL2 TR00458 of the CTSC at Weill Cornell Medical CollegeFogarty: D43TW000010, CFAR 1P30AI094189 Foundations: Ujala, Wyncote, GileadIndian Dept. of Biotechnology (DBT) and Council of Medical Research (ICMR)



tuberculosis in pregnancy and postpartum - jyoti mathad.pdf · irr 1.95 postpartum tb risk of tb in...

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