tuberculosis in pregnancy and postpartum - jyoti mathad.pdf · irr 1.95 postpartum tb risk of tb in...
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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
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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
CENTER FOR GLOBAL HEALTH
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WHAT IS THE BURDEN OF TB IN PREGNANCY?
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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~500,000 died
3.5 million
WHO Global TB Report, 2017Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
CENTER FOR GLOBAL HEALTH
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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
US CDC TB Report, 2016Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
US CDC TB Report, 2016Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
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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
CENTER FOR GLOBAL HEALTH
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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HOW DO YOU SCREEN FOR TB IN PREGNANT WOMEN?
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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Latent TB tests
Pai, Lancet 2004
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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;
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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DOES PREGNANCY IMPACT ACTIVE TB TREATMENT?
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
NR= not recommended; PS= potentially safe based on animal studies
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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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
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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
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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
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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
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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
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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)
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH