Tuberculosis and Pregnancy

Tuberculosis and pregnancy

Susanna Capone, MD, MIH University Department of Infectious Diseases and Tropical Medicine WHO Collaborating Center for TB/HIV collaborative activities and for the TB elimination Strategy University of Brescia Brescia, Italy

ESCMIDESCMID Postgraduate Education Online Course Lecture Library Infectious Diseases of Pregnant Woman, Fetus and Newborn 29th September 2016 Bertinoro Summary From the mother’s point of From the newborn’s point of view: TB and Pregnancy view: Congenital Tuberculosis 1. Epidemiology 1. Congenital and 2. How pregnancy can perinatal affect TB 2. Epidemiology 3. Diagnosis 3. Diagnosis 4. Active TB © by author4. Treatment Management 5.ESCMID Managment Online of LTBI Lecture Library 6. TB and HIV hints From the mother’s point of view: TB and Pregnancy

Tuberculosis affected an estimated 9.6 million people (3.2 million women and 1 million children) and caused 1.5 million deaths globally in 2014, including about half©‐million by author women and at least 140.000 children. ESCMID Online Lecture Library TB is one of the top killers of women worldwide

rd World Health Organization. Global tuberculosis Report 2015 (3 cause). Geneva, Switzerland: WHO, 2016. TB incidence: countries and regions

Europe 3% Americas 3% E. Mediterranean 8%

South‐East Asia Africa 28% 41% © by author

23% in India 10% each:ESCMID Indonesia & China Online Lecture Library 5% each: Nigeria & Pakistan Prevalence of active TB in pregnant and post partum women

<20 cases per 100 000 population per year in LBC

>60 cases per 100 000© population by perauthor year in HBC ESCMID Online Lecture Library

Mathad & Gupta, CID, 2012: 55 (11): 1532-1549 Prevalence of LTBI in pregnant and post partum women

Mathad & Gupta, CID, 2012: 55 (11): 1532-1549 2. Does Pregnancy influences the TB natural history?

M. tuberculosis

IRR for TB: Pregnant women 2fold vs First NON pregnant women Re-infection Infection (exogenous) Primary TB Pregnancy Latent ? TB Reactivation © by author(endogenous)

ESCMID OnlineProgressive Lecture? LibraryPost-primary TB Primary TB Does pregnancy affect the course of TB?

• Pregnancy suppresses the T‐helper 1 (Th1) response, which may mask symptoms while increasing susceptibility to new infection and reactivation of tuberculosis (i.e. M. leprae) • After delivery the Th1 suppression reverses and symptoms exacerbate as in IRIS. • Biologic changes in pregnancy© by author and postpartum ‐ influence TB progression ESCMID Online Lecture Library © by author

An upward trend immediately postpregnancy, peaking at 90 days postpartum (IRR,ESCMID 1.74; 95% CI, 0.95–3.19) Online and a gradual Lecture decrease to anLibrary IRR of 1.53 (95% CI, 0.79–2.96) and 1.19 (95% CI, 0.55–2.58) at 180 days and 270 days postpartum, respectively

Zenner D et al, Risk of tuberculosis in pregnancy: a national, primary care based cohort and selfcontrolled case series study. Am J Respir Crit Care Med 2012; 185:779–84 Risk of TB during pregnancy

• Tuberculosis during pregnancy increases the occurrence of preterm labor, low birth weight, and neonatal mortality • Late diagnosis of tuberculosis in pregnancy may increase the risk of obstetric morbidity by 4‐fold and that© ofby preterm author labor by up to 9‐ fold ESCMID Online Lecture Library 3. Diagnosis of TB during pregnancy

• Insidious onset, protean manifestation, non‐specific nature of symptoms • Loss of appetite, tiredness, fatigue, shortness of breath and sweating, can be due to pregnancy • Diagnosis is delayed because of clinicians’ concern to suggest chest X‐ray© during by authorpregnancy ESCMID Online Lecture Library 3. Diagnosis of TB during pregnancy • Bacteriological confirmation and other radiological diagnostics for extra‐pulmonary cases are more difficult to perform during pregnancy • Surgical or endoscopic biopsies for extra‐pulmonary TB may not be feasible in pregnant women because of technical difficulties such as non‐accessibility of the lesions, secondary increased risk of preterm labor and anesthetic© hazbya rdsauthor for the foetus ESCMIDWHO CLINICAL Online APPROACH LectureIN HIGH Library BURDEN HIV/TB COUNTRIES: CURRENT COUGH, FEVER, NIGHT SWEATS, WEIGHT LOSS Active TB diagnosis • In symptomatic and asymptomatic women with a recent contact with a patient with active pulmonary TB, CDC recommends a chest xray, which poses minimal risk to the foetus . If findings are abnormal, sputum samples should be sent for microscopy and culture examination. • Common extra‐pulmonary© by author sites of tuberculosis in pregnancy include lymph nodes, gastro‐intestinal tract and bones . ESCMID Online Lecture Library Additional diagnostic testing (eg, biopsy)should be pursued if clinical suspicion is high. 4. Active TB management

“Untreated tuberculosis represents a far greater hazard to a pregnant woman and her foetus than does TB treatment”

Centre for Disease Control, “Treatment of tuberculosis,” MMWR, vol. 52, no. RR‐11, pp. 1–77, 2003. When mother is smear positive • Immediate maternal treatment for TB; • If the mother has received tuberculosis treatment for <2 months before delivery or remains potentially infectious, the child should be given IPT. • In the newborn,© in byabsence author of evidence of congenital TB, isoniazide (10mg/kg/day) ESCMIDshould be commenced Online Lecture at birth and Library continued for six months When the mother is smear positive • In endemic countries, WHO recommends BCG vaccination in infants born to mothers with active tuberculosis, after completion of infant IPT, as INH seems to inhibit vaccine efficacy • BCG vaccination is not recommended in HIV‐ infected infants because of the risk of disseminated BCG© by disease author ESCMID Online Lecture Library TB and breastfeeding • The CDC encourages breastfeeding if a woman has been on first‐line ATT and is no longer infectious • There has been no documented cases of tuberculosis transmission via breast milk since the development of ATT • Women with tuberculosis mastitis should breastfeed from the unaffected© breast.by author • Small concentrations of ATT are secreted into the ESCMIDbreast milk, posing Online minimal Lecture risk to the Library infant. Active TB Treatment

Jyoti S. Mathad and Amita Gupta Tuberculosis in Pregnant and Postpartum Women: Epidemiology, Management, and Research Gaps; CID 2012;55(11):1532–49 Rifampicin • Safe: pregnancy category C • There is an increased risk of haemorrhagic disorders due to secondary hypoprothrombinaemia in the woman and in her newborn particularly in case of RIF use in late pregnancy © by author • Vitamin K should be administered to the ESCMIDmother and Onlineat birth to Lecture her infant Library • Dose: 10 mg/kg/die Isoniazid • Safe: pregnant category A • The women must be followed up because of the possibility of INH‐induced hepatotoxicity (liver function each 15 days for the 1st 2 months and then monthly). • Pyridoxine supplementation© by author is recommended for all pregnant women taking INH because of ESCMIDa higher risk Online of its deficiency Lecture during Library pregnancy. • Dose: 5 mg/kg/die Ethambutol • Safe: pregnancy category A • The retrobulbar neuritis that may complicate the use of this drug in adults, generated the fear that it may interfere with ophthalmological development when used in pregnancy but this has not been demonstrated when© by the author standard dose is used. ESCMID Online Lecture Library • Dose: 15 mg/kg/die Pyrazinamide

• Safe: pregnancy category B2 • The use of pyrazinamide in pregnancy was avoided by many physicians for a long time due to unavailability of adequate data on its teratogenicity. • Actually no report on any secondary foetal malformations. • Presently, CDC does not recommend but IUALT, WHO, QH and other organizations recommend it. • Its use is particularly ©indica byted author in women with TB meningitis, HIV coinfection, and suspected INH resistance. • If PZA/Z is not used, a nine‐month regimen containing INH ESCMIDand RIF is recommended, Online supplemented Lecture by LibraryETH until drug susceptibility results are available. • Dose: 25 mg/kg/die Streptomycin • Not recommended!!! • The drug has been proven to be potentially teratogenic throughout pregnancy. • It can cause foetal malformations and VIII nerve paralysis, with deficits ranging from mild hearing loss© to by bilateral author deafness. ESCMID Online Lecture Library Second line drugs

The management of drug‐resistant cases and the use of second‐line agents (both generally and during pregnancy) should only be considered after consultation with an expert in TB management. Teratogenicity has been described with© aminoglycosides, by author capreomycin and ethionomide and patients taking these ESCMIDagents should Online be advised Lecture to take Library measures to avoid pregnancy. Flurochinolones

• Pregnancy category: B3 (cipro, moxi, norflo). • Animal studies of ciprofloxacin suggest a risk of damage to articular cartilage , subsequent juvenile arthritis with short courses , possibility of joint damage with longer ones. • No reports on foetus abnormalities in pregnant women having taken© byflurochinolones author • Should only been used when the benefits outweigh ESCMIDthe risks Online Lecture Library Amikacin

• Pregnancy category D: not reccomended! • All aminoglycosides are potentially nephrotoxic and ototoxic to the foetus and • The use of aminoglycosides in pregnancy should be a last resort in very selected cases (i.e. XDR). © by author ESCMID Online Lecture Library Capreomycin

• Pregnancy category C • Studies in pregnant rats have shown evidence of teratogenicity. • Contra‐indicated in pregnancy !!! • Should only be used following consideration of its risks and benefits.© by author ESCMID Online Lecture Library Ethionamide and prothionamide

• Pregnancy category N/A • These drugs have been shown to be teratogenic in animal studies • Not recommended in pregnancy. © by author ESCMID Online Lecture Library Cycloserine

• Pregnancy category not listed • There is no evidence of teratogenicity in rats, but there are insufficient studies in humans to confirm its safety in pregnancy. • Consider only when the benefits outweigh the potential risks. © by author ESCMID Online Lecture Library Para‐aminosalicylic acid

• Pregnancy category N/A • Limited animal and human safety data on its use in pregnancy. • May be associated with a slightly higher incidence of limb and ear abnormalities. © by author ESCMID Online Lecture Library Amoxycillin/clavulanic acid

• Safe: pregnancy category B1 • No evidence of teratogenicity in animal studies. • Used without problems documented in late pregnancy as prophylaxis in women with prolonged rupture of membranes, but limited experience in the© 1 byst trimester. author • ESCMIDLikely to have Online a role in Lecture the treatment Library of MDR ‐ TB in pregnancy. 5.LTBI screening • In low‐burden countries, CDC recommends latent tuberculosis screening only for high‐risk women: tuberculosis contacts, injection drug use, HIV or other immunosuppression, foreign birth, and/or residence in congregate settings. • In high‐burden countries, latent tuberculosis screening is not routinely recommended (except for HIV +), though TST/IGRAs© by author screening might be useful for identifying the HIV‐infected patients most likely ESCMIDto benefit from Online isoniazid Lecture (INH) preventive Library therapy. LTBI tests thresholds They do not change during pregnancy: ‐A positive TST is induration ≥10 mm for HIV negative and ≥5 mm for HIV‐positive ‐ A positive IGRA is a difference in IFN‐γ concentration of >0.35 IU/mL (Quantiferon Test) or >6 spots (Tspot.TB© by) between author the tuberculosis antigen and negative control sample, regardless ofESCMID HIV status. Online Lecture Library LTBI treatment

© by author ESCMID Online Lecture Library LTBI managment • CDC recommends delaying treatment of latent tuberculosis until 2–3 months postpartum, unless the patient has had a recent known tuberculosis contact • Pregnant women treated with IPT had a 2.5–4 times increased risk of hepatitis compared with non pregnant women • Because symptoms© of bypregnancy author overlap with those of hepatitis, some experts recommend monitoring labs every 1–2 weeks in pregnancy for at least the first 8 weeksESCMID of therapy Online regardless Lecture of symptoms Library 6. TB during pregnancy and HIV trasmission

Maternal TB clinical disease as an important independent risk factor associated with MTCT of HIV. Maternal TB was associated with 2.5‐fold increased odds of MTCT of HIV, adjusting for maternal factors (eg, CD4 cell count, viral load, and antiretroviral use) as well as infant factors (eg, nevirapine administration and breast‐feeding duration). © by author ESCMID Online Lecture Library

Gupta et al., “Maternal tuberculosis: a risk factor for mother‐to‐child transmission of human immunodeficiency virus,” Journal of Infectious Diseases, vol. 203, no. 3, pp. 358–363, 2011 From the newborn’s point of view: Congenital Tuberculosis

• Congenital (i.e. acquired in utero) → sources of foetal infection can be hematogenous spread from placenta, or aspiration/ingestion of infected amniotic fluid. • Neonatal (i.e. acquired© by earlyauthor in life from the mother or other persons) → acquired infection afterESCMID birth from Online the untreated Lecture mother Library or other adult reservoirs in the family or surroundings. Congenital tuberculosis

• Hematogenous spread from the placenta to umbilical vein→ primary complex in the liver or in the lungs

• Ingestion and aspiration of amniotic fluid contaminated by placental© by author or genital infection →primary complex in the lungs or gastrointesnal tractESCMID Online Lecture Library 2. Epidemiology • Congenital tuberculosis is a rare disease associated with a high mortality rate of up to 44% • Less than 300 cases of congenital tuberculosis were reported worldwide before 1984 • Over 80 additional© by cases author have been reported thereafter ESCMID Online Lecture Library Histopathology section of the placenta, Ziehl‐Neelsen stain: AFB

Histopathology section of the © by authorplacenta, Ziehl ‐Neelsen stain: AFB ESCMID Online Lecture Library 3. Criteria for congenital tuberculosis Cantwell et al. proposed the revised criteria in 1994 The infant must have proved TB lesions and at least one of the following: • a lesion in the first week of life, • a primary hepatic complex or caseating hepatic granuloma, • tuberculosis infection© by of the author placenta or maternal genital tract, • ESCMIDexclusion of postnatal Online transmission Lecture by Library a thorough contact investigation. Cantwell, M.F. et al. (1994): Brief report: congenital tuberculosis. N. Engl. J. Med., 14, 330, 1051–1054 When to suspect congenital TB • Maternal TB (active or suspect) during pregnancy as a pre‐requirement • Respiratory distress • Hepatosplenomegaly with multiple focal lesions • Failure of previous© by antibiotic author treatments and exclusion of congenital viral infection/diseases • ESCMIDMiliary radiological Online pattern Lecture Library © by author ESCMID Online Lecture Library

Wansheng Peng et al Analysis of 170 Cases of Congenital TB Reported in the Literature Between 1946 and 2009 Pediatric Pulmonology 46:1215–1224 (2011) Risk factors for congenital TB

• Miliary TB • Genital TB • Untreated TB or • Smear + mother • HIV confirmed ©or suspectby author co‐infection ESCMID Online Lecture Library Differential diagnosis

• HIV • Syphilis • Cytomegalovirus infection • Congenital herpes • Atypical pneumonia© by (Mycoplasma author pneumoniae) ESCMID Online Lecture Library Investigations of newborn

Specimens for culture and microscopy include: • induced sputum or endotracheal aspirates if the baby is on mechanical ventilation, • three early morning gastric washings taken before the first feed of the day and placed in 1% sodium bicarbonate© by author buffer for transport to the laboratory • ESCMIDcerebrospinal Online fluid or Lecture blood collected Library in TB blood culture bottles 4. Treatment • The treatment of congenital or neonatal tuberculosis involves a multi‐drug anti‐tuberculosis treatment. • The therapy of isoniazid, rifampicin, and pyrazinamide with or without streptomycin lasts for 2 months, following by at least 4 months of isoniazid and rifampicin. • Ethambutol is not ©recommended by author because of potential adverse treatment effects, such as optic ESCMIDneuritis and re Onlined‐green color Lecture blindness Library In the middle of a pregnancy…

Lady M is from Marocco, she is 33 years old and she has been living in Italy for 10 years, she has 3 children and she is currently pregnant.

In the last 3 months© of by pregnancy author she suffered from a persistent cough; she has been treated unefficaciouslyESCMID withOnline steroids Lecture and brochodilators Library for a supected asmathic form. Cough, cough &cough but…

Because she was pregnant she did not perform the chest X‐ray

Little B was born on the 28 th of December; the family organized a nice new born party with friends and relatives, according to traditional habits. © by author On the new year Eve, cough and fever relapsed. Lady M was started to amoxicillin without response to treatment.ESCMID Online Lecture Library Eventually….

Lady M underwent a chest X‐ray

CHEST X‐ RAY(9/1):pulmonary © by author cavitation in the upper right lobe and in the lower left lobe ESCMID Online Lecture Library At the hospital…

Lady M was admitted at the Infectious Diseases Department of the General Hospital in Bergamo.

Smear: positive for M.tuberculosis

She started antituberculosis© by treatment author on the 14 th of January. Doctors opted to inhibit her lactation SheESCMID was then discharged Online (still Lecturesmear positive) Library Meanwhile at home…

The contact tracing started…

The children (2, 4 , 5 years old) and the husband started the prophylaxis with isoniazide, and what about the little baby? © by author TheyESCMID couldn’t find Online the syrup Lecture drug formulation Library so she didn’t receive any treatment. A month later…

Her little baby was admitted at the hospital with fever and leucocytosis. Ampicillin and gentamicin were started, followed by gastric washing sampling.

She was then tranferred© by author toESCMID the Infectious Online and Tropical Lecture Library Diseases Department in Brescia. TB or not TB?

The baby started antituberculosis treatment: Rifampicin 15 mg/kg syrup Isoniazide 10 mg /kg galenic formulation Pyrazinamide 40 mg/kg galenic formulation © by author ESCMID Online Lecture Library A month later: do you rememeber the newborn’s party? D is a 16 months old baby, born in Italy from maroccan parents. She was admitted at Treviglio hospital with peristent fever, unresponsive to amoxicilline… She was then treated with ceftriaxone but fever did not stop.. © by author ….ESCMID so she was transferredOnline Lecture Library to our Unit Fever and treatment

Rifamipicine 200 mg ev Isoniazide 100 mg ev Pyrazinamide 300 mg per os

© by author ESCMID Online Lecture Library 1° gastric 2° gestric 3° gastric washing: washing: washing: microscopy neg microscopy neg miscroscopy neg 7/03/2013 8/03/2013 9/03/2013 10/03/2013 11/03/2012 12/03/2013 13/03/2013 …ten days later

We received the result of the 1st and the 3rd gastric washing sample: M.tuberculosis

© by author ESCMID Online Lecture Library Key actions on maternal & neonatal TB (1) • TB cascade of care should be considered a key public health intervention at all stages of pregnancy, neonatal, postpartum and postnatal care. • Training on the maternal and child TB involving all the different actors : from midwives and nurses to family doctors and specialists, particularly in TB low burden countries. • Diffusion of TB screening algorithm in M&C care services, as part of the PMTCT package particularly in high HIV and TB prevalence settings!!!© by author ESCMID Online Lecture Library Key actions on maternal & neonatal TB (2) • Surveillance on TB prevalence among the M&C population • Cost‐efficacy and feasibility studies on screening methods for active TB and LTBI • Research and development of low‐cost assays able to early detect active tuberculosis, LTBI and incipient TB • Jointly international© byconsensus author and guidelines for the management of M&C TB. • AvailabilityESCMID and Online free access Lecture to TB& LT LibraryBI child friendly drug‐formulations. Suggested Readings (1):

• Asuquo B, Vellore AD, Walters G, Manney S, Mignini L, Kunst H. A case‐ control study of the risk of adverse perinatal outcomes due to tuberculosis during pregnancy. J Obstet Gynaecol. 2012 Oct;32(7):635‐8 • American Thoracic Society, CDC, Infectious Diseases Society of America: " Treatment of tuberculosis" MMWR 2003; 52: RR‐11. • Bothamley, G. (2001). Drug treatment for tuberculosis during pregnancy: safety considerations. Drug Safety, 24 (7), 553–565. • British Thoracic Society. (1998). Chemotherapy and management of tuberculosis in the United Kingdom: recommendations. Thorax, 53, 536– 548. © by author • Centers for Disease Control and Prevention. (2003). Treatment of tuberculosis. Morbidity and Mortality Weekly Report, 52 (RR‐11), 1–77. • ESCMIDCenters for Disease Online Control and Prevention. Lecture (5th Ed. Library 2011). Interactive Core Curriculum on Tuberculosis: what the clinician should know, available at http://www.cdc.gov/tb/webcourses/CoreCurr/index.htm.Fifth Suggested Readings (2):

• Enarson, D.A., Rieder, H.L., Arnadottir, T., Trébucq, A. (2000). Management of Tuberculosis: a guide for low income countries. 5th ed. Paris: International Union Against Tuberculosis and Lung Disease. • Mathad J.S., Gupta A., Tuberculosis in Pregnant and Postpartum Women: Epidemiology, Management, and Research Gaps, CID, 2012: 55 (11): 1532‐ 1549. • Migliori GB, Zellweger JP, Abubakar I, Ibraim E, Caminero JA, et al. European union standards for tuberculosis care. Eur Respir J. 2012 Apr;39(4):807‐19. • MIMS Online. (2003). Available© by from author • Ormerod, P. (2001). Tuberculosis in pregnancy and the puerperium. Thorax,ESCMID 56, 494–499. Online Lecture Library • Queensland Government (2016), Treatment of Tuberculosis in pregnant women and newborns. Guideline Version 3.1. Suggested Readings (3):

• Summers L. Understanding tuberculosis: implications for pregnancy. J Perinat Neonatal 1992; 6(2): 12‐24. • Starke JR. “Tuberculosis: an old disease but a new threat to the mother, fetus, and neonate,” Clinics in Perinatology, vol. 24,no. 1, pp. 107–127, 1997. • Taylor AW, Mosimaneotsile B, Mathebula U, Mathoma A, Moathlodi R, Theebetsile I, Samandari T. Pregnancy Outcomes in HIV‐Infected Women Receiving Long‐Term Isoniazid Prophylaxis for Tuberculosis and Antiretroviral Therapy. Infect Dis Obstet Gynecol. 2013;2013:195637. doi: 10.1155/2013/195637. Epub© 2013by Marauthor 7. • World Health Organization. (2003). Treatment of Tuberculosis: guidelines ESCMIDfor national programs. Online 3rd Ed. Geneva: Lecture WHO. Library • World Health Organization. (2014). Guidance for national tuberculosis programmes on the management of tuberculosis in children. 2nd Ed. Geneva: WHO. THANKS!!!© by author ESCMID Online Lecture Library