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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
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
WHAT IS THE BURDEN OF TB IN PREGNANCY?
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
~500,000 died
3.5 million
WHO Global TB Report, 2017Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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
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
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
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
CENTER FOR GLOBAL HEALTH
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
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
HOW DO YOU SCREEN FOR TB IN PREGNANT WOMEN?
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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
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
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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
DOES PREGNANCY IMPACT ACTIVE TB TREATMENT?
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH
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
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)
Weill Cornell Medicine
CENTER FOR GLOBAL HEALTH