Diagnosis and Treatment of Tuberculosis in Pregnancy

August 4, 2011

young woman with tuberculosis should become pregnant to improve her outcome!!

young woman with tuberculosis should become pregnant to improve her outcome!!


 

Historical perspective…

1850 - 1920s


 Tuberculosis was  harmful  during pregnancy, and termination of pregnancy - recommended


 

Global burden of TB


• 2 billion infected, i.e. 1 in 3 of global population
• 9.4 million (139/lakh) new cases in 2008, 80% in 22 high-burden countries
• 4 m new sm+ve PTB (61/lakh) casesin 2008
• Global incidence of TB has peaked in 2004 and is declining.
• 1.77m deaths in 2007, 98% in low-income countries
•  MDR-TB -prevalence in new cases around 3.6%


 

WHO
10 facts about tuberculosis
23 March 2009


 

Fact 1


• Tuberculosis (TB) is contagious and spreads through the air.
•  If not treated, each person with active TB can infect on average 10 to 15 people a year.


 

Fact 2


• > 2billion people, equal to 1/3 of the world’s total population, are infected.
• 1 out of 10 of those people will become sick with active TB in his or her lifetime.
• People living with HIV are at a much greater risk


 

Fact 3


• 1.77 million died from TB in 2007 (including 456 000 people with HIV), equal to about 4800 deaths a day.
• disease of poverty, affecting mostly young adults in their most productive years.
• vast majority of TB deaths are in the developing world, with more than half occurring in Asia.


 

Fact 4


• TB is a leading killer among people living with HIV, who have weakened immune systems.

 

Fact 5


• There were 9.27 million new TB cases in 2007, of which 80% were in just 22 countries. Per capita, the global TB incidence rate is falling, but the rate of decline is very slow - less than 1%.


 

Fact 6


• TB is a worldwide pandemic. Among the 15 countries with the highest estimated TB incidence rates, 13 are in Africa, while half of all new cases are in six Asian countries (Bangladesh, China, India, Indonesia, Pakistan and the Philippines).  


 

Fact 7


• Multidrug-resistant TB (MDR-TB) is a form of TB that does not respond to the standard treatments using first-line drugs.
• MDR-TB is present in virtually all countries surveyed by WHO and its partners.


 

Fact 8 Tony Moll


• estimated 511 000 new MDR-TB cases in 2007 with three countries accounting for 56% of all cases globally: China, India and the Russian Federation.
• Extensively drug-resistant TB (XDR-TB) occurs when resistance to 2nd -line drugs develops.
•  It is extremely difficult to treat and cases have been confirmed in more than 50 countries.


 

Fact 9


• WHO’s Stop TB Strategy aims to reach all pts
• MDG: target - reduce by 2015 the prevalence of & deaths due to TB by 50% relative to 1990 and reverse the trend in incidence.
• The strategy emphasizes the need for proper health systems and the importance of effective primary health care to address the TB epidemic.


 

Fact 10


• The Global Plan to Stop TB 2006-2015, launched January 2006, aims to achieve the MDG target with an investment of US$ 67 billion. This represents more than a ¾ increase in investment from 2005. The estimated funding gap is US$ 40 billion.


 

Problem of TB in India


• Estimated incidence 
• 1.96 million new cases annually
• 0.8 million new smear positive cases annually
• 75 new smear positive PTB cases/1lakh population per year
• Estimated prevalence of TB disease
• 3.8 million bacillary cases in 2000
• 1.7 million new smear positive cases in 2000
• Estimated mortality
• 330,000 deaths due to TB each year
• Over 1000 deaths a day
• 2 deaths every 3 minutes

 


 

Problem of TB in India (contd)


• Prevalence of TB infection
• 40% (~400m) infected with

M. tuberculosis

(with a 10% lifetime risk of TB disease in the absence of HIV)
• Estimated Multi-drug resistant TB
• < 3% in new cases
• 12% in re-treatment cases
• TB-HIV
• ~2.31 million people living with HIV (PLWHA)
• 10-15% annual risk (60% lifetime risk) of developing active TB disease in PLWHA
• Estimated ~ 5% of TB patients are HIV infected

 

 


 


 

Tuberculosis


• Chronic granulomatous infection caused by mycobacterium tuberculosis.
• Well recognized health hazard in India and developing countries.
• Kills more adults in India as compared to any other infectious disease.
• India constitutes 1/5th of the global burden (2/3rd cases in SEAR). Every year approx. 1.8 million people develop TB, 0.8 million new smear +ve highly infectious, 0.37 million die every year. 


 

Tuberculosis


• Annual risk of becoming infected 1.5% and once infected 10% life time risk of developing TB.
• India’s DOTS programme (March 1997) against TB has covered the whole country by 2006. > 7.3 million are on DOTS and 1.4 million additional live have been saved.  Death rate under RNTCP have been cut 7-folds from 29% to 4% in smear +ve patients.


 

 

Effects


Effect of disease on pregnancy


• ↑ risk of reactivation but the disease does not affect the outcome of therapy.
• No evidence that tuberculosis complicates pregnancy or mode of delivery.
• Advance disease – premature labour
• Spontaneous abortion – No substantial evidence.


 

Maternal outcome       


• Depends on site & timing of diagnosis
•  
• Late diagnosis – morbidity increase 4 fold
•  
• Early diagnosis – outcome similar to non pregnant women


 

Therapeutic abortion


• Tuberculosis during pregnancy -rarely  an indication for a therapeutic abortion But
•    pregnant woman with MDRTB, should be offered abortion counseling medications used  are known to cause fetal abnormalities

 

 

Effects


Of pregnancy on TB


• No development or progression of disease.
• Thought to improve the outcome of disease – enlarging uterus ® Pressure on lungs, collapse open cavities.
• However, untreated active TB – Significant risk to mother.


 

Effects


Effect on fetus


• Late diagnosis incidence of prematurity and LBW
•  
• Early diagnosis outcome similar to non pregnant woman

 


• ­ perinatal mortality.
• ­ incidence of babies with SGA, LBW.
•  Congenital tuberculosis – rare complication.

 

 


 

Antenatal management


ANC same as routine


Screening test of Recommended  individual


Diagnosis of TB


H/O


Examination


Tests to confirm


Treatment of TB


 

Screening test


Screening Criteria


Recent exposure


HIV positive


Other immunocompromised state


Recommended screening test include


tuberculin skin testing,


chest radiography if MT +ve,


interferon

g

blood test.


 

TB Screening During Pregnancy?


• Studies indicate that routine skin test screening of all pregnant women is appropriate.
•  The goal is to discover dormant infection and asymptomatic disease and
• to lower the incidence of congenital or infantile TB


 


 


 

Tuberculin skin test (TST):Mantoux tuberculin test (MT)


• most commonly used.
• Delayed hypersensitivity test.
• Test antigen used PPD-RT-23 and PPD-S.
• WHO recommended 1 TU for standard MT in India because of great prevalence,as well as typical mycobacteria infections. This leads to high sensitivity but low specificity.


 
• Not detrimental to the fetus or mother
• no evidence that the immunosuppression found in preg leads to false-negative results.
• Prior vaccination with BCG can complicate the interpretation of the Mantoux test.
• most recent guidelines from the CDC – MT not influenced by the effect of the BCG vaccine as it  wears off at a variable rate. despite being immunized, these persons are still at risk for active TB.


 

Chest X-Ray Film


•  
•  
• when PPD test is positive
• asymptomatic pt, the chest radiograph done after 12th week of gestation.  Routine screening with radiography is not indicated

 

 
• (a) AFB smear report per RNTCP guidelines:
•          Negative: no AFB/100 oil immersion fields.
•          Positive scanty: 1-9 AFB/100 oil immersion fields.
•         1+ : 10-99 AFB/100 oil immersion fields.
•         2+ : 1-10 AFB/oil immersion field.
•         3+ : > 10 AFB/oil immersion field.
•  
•  
•          To detect 1-3 organism in 300 oil immersion fields, the conc. Of organism 5000-10000/ml.


 

Diagnosing tuberculosis in pregnancy…



• Contrary to popular belief, the Heaf and Mantoux skin tests are probably as reliable as in non-pregnant women.


 


 

CDC classification of tuberculin reaction


• > 5 mm considered +ve in
• HIV +ve person
• Recent contacts of TB case
• Persons with nodular or fibrotic changes on CxR consistent with old healed TB
• Pts with organ transplants & other immunosuppressed pts.

 

 
• > 10 mm +ve in
• Recent arrivals (from high prevent countries).
• Injectable drug users.
• Residents & employees of high-risk congregate settings
• Mycobacteriology lab personnel
• Children <  4 yrs of age, or children and adolescents exposed to adults in high-risk categories.
• > 15 mm +ve in
• Persons with no known risk factors for TB.


 

Chemo prophylaxis  for Latent TB


•  
•          Criteria -
• Recent convertors (+ tuberculin test).
• Close contacts.
• Immunocompromised (HIV)
• Neonates of tubercular mother.

 

 

Recent convertors (+ tuberculin test) – INH for  6 mon postpartum.


recent exposure - INH 6 mon after  Ist trimester


MDR-TB no current chemoprophylaxis regimen.

CDC –EMB+ PZA or fluoroquinolone 6 to 12 months

PZA? Controversial!


Rifampicin + pyrazinamide (2 months) for HIV infected individuals.


 

Diagnosis OF Active TB


History


• Predisposing factors
• Signs and symptoms
• Complications


 

Pregnancy and TB Symptoms


• with active TB often have few typical TB symptoms.
• 20% - 67% pts with pul TB are unaware of their disease and have no significant symptoms
• Even mothers of children born with congenital TB often have unremarkable symptoms

 

 
• Diagnosis of TB not easy. :
• CULTURE  -

Gold standard -


• Serological test do not offer accurate sensitivity and should not be pursued.
• Molecular test hold promise in diagnosis, but lack sensitivity in paucibacillary states.


 

Diagnosis of active TB


 Identifying the organism gold standard.


24 hrs sputum collection justified.


Sputum (sputum or laryngeal swab or bronchial lavage or gastric aspirate) - microscopic examination and culture


 


 


 


 


 


 


 


 


 


 


 


 

Effect Anti-tuberculous therapy
on fetus


no ↑

in congenital malformations or fetal damage when rifampicin, isoniazid and ethambutol are used in combination
•  
• pyrazinamide is also safe


 


 


 


 


 


 


 

Side effect


• Thrombocytopenia: RMP
• Neuropathy: INH
• Vertigo: STM
• Hepatitis: PZA, RMP, INH
• Rash: PZA, RMP, EMB


 

International guidelines


• BTS, IUATLD, WHO - use first-line drug regimens
• CDC endorse pyrazinamide probably be used safely.

First line drug


• Isoniazid (preg category A) recommended for use.
•             - Hepatotoxicity (LFTs)                         - QTCC recommends Pyridoxine supplementation

 

 
• Rifampicin (pregcategory C) recommended along with vit K to both mother & infant postpartum if use in last few days (Bothamely, 2001), bleeding (hypoprothrombinemia).
• Ethambutol (pregnancy category A)
• Pyrazinamide (pregnancy category n/a)
•             - CDC guidelines do not endorses.                         - supported by IUATLD and BTS due to   lack sufficient data.


 

Second line drug


 


• Streptomycin (pregnancy category n/a) not recommended.
• Fluoroquinolones (pregnancy category B3)
• Amoxycilin/Clavulanic Acid (Pregnancy category B1).
•             - Used in late pregnancy in PROM.
•             - Minor role in M/N MDR-TB (Bothamley 2001).
• Para-Aminosalicylic Acid (PAS) (pregnancy category n/a) (Bothamley, 2001)
•             - Limb and ear abnormality.


 

Second line drug


• Amikacin (Preg category D) (WHO 2003)
•             - nephrotoxic and ototoxic.
• Capreomycin (Pregcategory C)
• Ethionamide and Prothionamide (Preg Category n/a)
•           (Ormerod 2009)
• Cycloserine (Pregnancy category n/a) (MIMS 2003)

 

 

Summary of Multidrug therapy in pregnancy


• with active TB –
• INH & RMP with EMB in resistant cases.
• PZA is not routinely recommended
• Therapy continue for 9 mon.
• complicated by highly resistant organisms and/or AIDS
• combinations of 4 or 5 drugs may be necessary, including drugs such as SM


 


 

Congenital tuberculosis


Cantewell Criteria


Lesion in the first week


Primary hepatic complex or caseating granuloma


Documented TB of placenta or endometrium


Exclusion of TB infection by carrrier

 

 

TB in Neonates


• potentially serious, with morbidity and mortality 50%
• Signs and symptoms
• nonspecific - respiratory distress, fever, hepatosplenomegaly, lethargy, lymphadenopathy, and irritability.
• Other signs include abdominal distention, ear discharge, and skin lesions
• An abnormal chest radiograph is not a consistent finding, and a positive PPD test result is even less common.


 

Isolation


• Child should not be isolated
• Isolation - born to a PPD+ve mother, mother infected with multidrug- resistant organisms or a contagious family member known to be noncompliant with treatment.
• BCG vaccination of the infant if  no isolation


 

Breast feeding


• safe when the mother is taking standard anti-tuberculous medication
• If mother is taking isoniazid, pyridoxine supplementation to child as a small amount of isoniazid is present in breast milk
• Toxicity not reported.
• Conc. of ATT drugs ineffective for TB T/t in nursing infants.


 

Breast feeding…


•  

It is usually unnecessary for the child to receive treatment unless the mother is diagnosed with open (infectious) at the time of delivery


                                    OR


contact tracing (which should be performed promptly) reveals that the child has had contact with another infectious member of the family

.


 

Breast feeding…

 
• Mother with open Tuberculosis
• Breast feeding can be done with
•  
• INAH prophylaxis
• mother can use a mask


 

Neonate….


• INAH prophylaxis is given for 3 months
•  
• Check Mantoux
•  
• Mantoux Negative need BCG vaccination


 

Contraception


 oral contracepives:effectiveness is reduced


 

MDR-TB and XDR-TB


• MDR TB - resistance to INH and rifampicin ± resistance to other anti TB drugs.
• XDR TB - resistance to at least H and R plus resistance to any of the fluoroquinolones and any one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin).


 


 

Management


• National guidelines and plans for m/m of MDR-TB have been under RNTCP. RNTCP DOTS services are being expanded.
• Diagnosis based on history of prior t/t (t/t failure, cat II failure), exposure confirmed drug-resistant TB.
• Diagnosis further done by culture and drug susceptibility testing.
• Other method of testing includes: DNA sequencing, line probe assay, PCR based assay, single strand conformation polymorphism, mocybacteriophage assay.

 

 

 
• Treatment regimen : [6(9) Km Ofx Eto Cs ZE/18 Ofx Eto Cs E] as per national DOTS guidelines if resistant to 2nd line Anti-TB drug +nt individualized regimen recommended.
• Duration of tx: 6 mon IP extended to 9 mon (+ve culture result - 4 months), 18 mon CP following IP:
• Smear examination monthly during IP and quarterly during CP.
• Culture at 4, 6, 12, 18 and 24 months of treatment. 


 

Prevention


• Implementation of a good quality DOTS.
• Improve quality and reach of DOTS services.
• Proportion of TB patients treated outside DOTS to be minimized.
• ISTC need to be used by RNTCP and professional medical associations.

 

 

Prevention


• BCG vaccination in childhood.
• Isolation of open cases and their prompt treatment
• Screening of close contacts.
• Nutritious diet
• Use of face mask.


 

References


• Bothamley G (2001) Drug Treatment for Tuberculosis during Pregnancy: Safety Considerations Drug Safety 24(7):553-65.
• British Thoracic Society (1998) Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998 Thorax 53:536-48.
• Centers for Disease Control (2003) Treatment of Tuberculosis MMWR 52(RR-11):1-77.
• MIMS (2003) acessed electronically via http://ckn.health.gld.gov.au in January 2006.
• World Health Organization (2003) “Treatment of Tuberculosis: Guideliens for National Program” WHO, Geneva 3rd Ed.
• Miller KS, Miller JM. Tuberculosis in pregnancy: interactions, diagnosis, and management. Clin Obstet Gynaecol, 1996;39:120-142.


 

References


• Centers for Disease Control and Prevention. Tuberculosis morbidity – United States, 1995, MMWR. 1996;45:365-370.
• American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med. 1994;149:1359-1374.
• Mehta B: Pregnancy and tuberculosis. Dis Chest 39:505-11, 1981.
• Centers for Disease Control and Prevention: Initial therapy for tuberculosis in the era of multidrug resistance: Recommendations of the advisory council for the elimination of tuberculosis. MMWR 42(RR-7):1-8, 1993.
• International Standards for Tuberculosis Care (ISTC). Tuberculosis Coalition for Technicasl Assistance, The Hauge, Holland (2006).
• Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis caser. Lancet Infect. Dis. 6(11), 710-725 (2006).
• Fidelma B. Rigb: Tuberculosis and Pregnancy: Update on an Old Nemesis: Posted: 04/01/2000; © Medscape Ob/Gyn& Women health