MATERNAL AND PERINATAL TUBERCULOSIS

A Bekker

Department of Pediatric and Child Health, Desmond TB Tutu centreStellenbosch University,Tygerberg Children’s Hospital

MOM AND BABY S

Born by NVD at peripheral hospital (23 July 2008)

• 38 weeks - male• 2605 g (5 .7 lbs)

Respiratory distress at birth and transferred to TygerbergChildren’s Hospital (level 3)

MOM

18 yrs old , G1P1Uncomplicated pregnancyHIV - , RPR -

ARRIVAL TO NICU

GENERAL

oedematous +

pale

petchecial rash

RESP IPPV

GIT

hepatosplenomegaly

(5 cm liver; 4 cm spleen)

ascites

RADIOLOGY

ULTRASOUND

• Viseromegaly with hyperechogenic lesions in the liver

• Abundant free fluid (ascites)

CONGENITAL INFECTION

• Term baby boy

• Acutely ill

• Abnormal blood results in keeping with infection

• Septic work up

• TORCH infection

• Parvovirus screen

DETERIORATION IN FIRST WEEK

• IV Pen and Gentamycin

• Broad spectrum antibiotic cover + Acyclovir

• Optimal supportive therapy – HFOV and vasopressors

• All test results were coming back negative

…..took a week for the penny to drop…

CASE OF CONGENITAL TB

MOM’S HEALTH?

TB screening questions

• No coughing

• No night sweats

• No fever

• Weight loss (not applicable)

• No other family members or close contacts with TB

• Because of high TB incidence in our area:– CXR

– Sputum specimens for M. tuberculosis

TB symptom screening tool

TB INVESTIGATIONS

Date Type AFB M.tb culture

Mom 01/08/08 Endometriumbiopsy

- Positive 22/09/08

Date Type AFB M.tb culture

Baby 30/07/08 Trachealaspirate

+ Positive 04/09/08

30/07/08 Urine - Positive 12/09/08

01/08/08 Ascitic fluid - Positive 12/09/08

11/08/08 Bone marrow - Positive 16/10/08

OUTLINE

• Burden of TB

• Understanding maternal and perinatal TB

• Approach to the TB-exposed newborn

2015 TB CASES WORLDWIDE

TB INCIDENCE RATES HIV PREVALENCE IN TB CASES

WHO Global Report 2016

3.2 million women fell ill with TB 70% of TB/HIV cases – Africa 480 000 of women with TB died

TB CASE DETECTION AMONG WOMEN

SA - 2015 SUB-SAHARAN AFRICA

Deluca JAIDS 2009WHO Global Report 2016

IMPACT OF MATERNAL TB

Increased mortality

• 6-fold increase in perinatal deaths

• 4-fold increase in TB-exposed newborn deaths (India)

Increased prematurity and low birth weight

• twice as likely

Increased risk for HIV transmission

• Infants from TB/HIV women– 2.5-fold (95% CI, 1.05-6.02) increased odds of acquiring HIV infection*

* Gupta JID 2011

OUTLINE

• Burden of TB

• Understanding maternal and perinatal TB

• Approach to the TB-exposed newborn

MATERNAL TB PRESENTATION

• Asymptomatic

• Endometrial TB

• Typical PTB with cavities

• Primary TB disease - pleural effusions

• Disseminated TB disease (miliary TB and TBM)

Poor sensitivity (28-55% ) and specificity (84-91%) of TB symptom-screening tool was found in HIV-infected pregnant

women *

*Hoffmann PLoS One 2013*Gupta CID 2011

TYPES OF MATERNAL TB ASSOCIATED WITH PERINATAL TB

Bacillaemic phase – in utero transmissionTypical cavitating disease – post-natal transmission

Congenital TB is rare:

• transmitted in utero by haematogenous spread via the umbilical vein or ingestion/aspiration of infected amniotic fluid during birth

Postnatal infection much more common:

• which occurs by inhalation of bacilli spread by the airborne route from a mother or other close source case with infectious pulmonary TB

TERMINOLOGY

• Congenital TB + Postnatal TB = Perinatal TB

TRANSMISSION MODES FOR PERINATAL TB

POSTPARTUM PERIOD

• Postpartum women were twice as likely to develop TB than pregnant women – UK epidemiological study

“Adjusting for age, region, and socioeconomic status

the postpartum TB risk was significantly higher

than outside pregnancy

(IRR, 1.95; 95% confidence interval [CI],1.24–3.07)”

Zenner AJRCCM 2012

TB DISEASE SPECTRUM AND TREATMENT OUTCOMES AMONGST

HIV INFECTED AND -UNINFECTED PREGNANT SOUTH AFRICAN WOMEN

OVERVIEW OF MATERNAL TB CASESN=74

13 (18%)Delivered

elsewhere, but transferred in

to TBH

(N=74)Maternal TB

cases

53 (72%)HIV-infected

21 (28%)HIV-uninfected

61 (82%) Delivered at

TBH

CHARACTERISTICS OF MATERNAL TB CASES (N=74)

Age, years (mean ± SD) 30 ± 5.9

Hb, g/dL (mean ± SD) 9.8 ±1.75

Ethnicity, black, n (%) 48 (65)

HIV infection, n (%) 53 (72)

Duration of TB treatment at delivery, months (median; IQR) 1 (0-3)

Previous TB, n (%) 22 (30)

Intra- and postpartum TB diagnosis, n (%) 33 (45)

Bacteriologically status TB diagnosis, n (%) 49 (66)

Smear positive (9 AFB and 1 Xpert) 10

Culture positive 39

MDR TB, n (%) 6 (8)

Intra-uterine deaths, n (%) 4 (5)

Maternal deaths, n (%) 5* (7)

CHARACTERISTICS OF INFANTS BORN TO MATERNAL TB CASES (N=74)Gestational Age, weeks, (median; IQR) 36 (32-38)

Prematurity (<37 weeks), n (%) 47 (64)

Birth weight, grams, (median; IQR) 2197 (1453-2920)

Low birth weight (<2500 g) 42 (58)

TB treatment decision in infants

TB preventive therapy, n (%) 54 (73)

TB treatment, n (%) 4 (5)**

No TB treatment indicated, n (%) 7 (10)

Perinatal and neonatal deaths, n (%) 9 (12)

HIV status (for 53 HIV-exposed infants)

PCR HIV infected, n (%) 3 (6)

** M.tb confirmed in 2

Total Maternal TB(n=74)

HIV-infected(n=53)

HIV-uninfected(n=21)

OR, 95% CI p-value

Ethnicity, black, n (%) 42 (79) 6 (29) 9.5 (2.5 – 35.9) 0.005

Previous TB, n (%) 16 (30) 6 (29) 1.08 (0.4 – 3.3) 0.89

Intra- and postpartum TB diagnosis, n (%)

25 (47) 8 (38) 0.69 (0.21-2.16) 0.48

EPTB , n (%)* 23 (43) 4 (19) 3.26 (0.9 – 11.5) 0.05

Prematurity (<37 ), n (%) 36 (69) 11 (52) 2.05 (0.7 – 5.90 0.18

LBW (<2500 g), n (%) 30 (58) 12 (57) 1.02 (0.4 – 2.9 ) 0.97

Neonatal deaths and IUDs,n (%)

10 (19) 0 (0) - 0.03

Maternal deaths, n (%) 5 (9) 0 (0) - 0.15

* Includes combined EPTB and PTB

MATERNAL TB TREATMENT OUTCOMES*

N=74

FAVOURABLE

n=41 (55%)

Cured

9 (13%)

TB treatment completed

32(43%)

UNFAVOURABLE

n=33 (45%)

LTFU before entering TB clinic service

13 (18%)

LTFU after entering TB clinic services

13 (18%)

Treatment failure

2 (2%)

Died

5 (7%)*WHO definitions, 2013

Key findings

• High burden of TB and HIV-associated in pregnant women at referral hospital level

• HIV co-infected women presented with severe immune deficiency

• Delayed TB diagnosis

• ⅔ Premature and LBW infants

• High maternal and newborn mortality, associated with maternal HIV infection

• Poor maternal TB treatment outcomes

WHICH INFANTS ARE AT HIGH RISK TO DEVELOP TB?

• Premature babies

• LBW infants

• Growth restricted

• HIV-exposed

WHEN TO CONSIDER TB IN NEONATES?

- nonspecific symptoms but mother (or other source case) diagnosed with TB

- pneumonia not responding to broad spectrum antibiotics, especially in TB endemic settings or if the mother/primary caregiver has TB

- high lymphocyte count in CSF with no identified pathogen;

- fever and hepatosplenomegaly

- abdominal distension with ascites Schaaf Respirology 2010

CLINICAL PRESENTATION• Often acute onset of symptoms.

• Age of onset (n=29): median 24 days (range 1-84)

Signs/symptoms Number (n=55)

Respiratory distress 41 (75%)

Hepato/splenomegaly 38 (69%)

Fever 30 (55%)

Lymphadenopathy 20 (36%)

Lethargy/irritability 17 (31%)

Abdominal distension 14 (25%)

Ear discharge 9 (16%)

Skin lesions 7 (12%)

Hageman. J Perinatol 1998;18:389.

Symptoms and signs in congenital TB: combined data from 75 cases of congenital TB

Symptoms and signs Occurrence

Respiratory distress including tachypnoea

Hepatomegaly, splenomegaly

Fever (usually low grade)

Prematurity/low birth weight

Common (i.e. >40%)

Cough – may be acute or chronic

Poor feeding

Failure to thrive

Abdominal distension (including ascites)

Frequent (i.e. 25-40%)

Irritability

Peripheral lymphadenopathy

Sepsis syndrome

Infrequent (i.e. 10-25%)

Skin papular/pustular or ulcerative lesions

TB meningitis

Jaundice (obstructive)

Otorrhoea/mastoiditis

Wheeze or stridor

Apnoea or cyanosis attacks

Facial nervepalsy

Shock

Rare (i.e. <10%)

Schaaf et al. Respirology

2010;15:747-763

Comparison of CXR features in infants with culture-confirmed congenital tuberculosis versus those <3 months of age with mainly

postnatal tuberculosis

Radiographic feature Congenital TB

n = 53 (%)

TB in infants (<3 mo)

n = 27 (%)

Lymphadenopathy

(hilar/paratracheal)

4 (8) 14 (52)

Lobar/segmental opacification

(unilateral or bilateral)

18 (34) 14 (52)

Airtrapping NA 15 (56)

Large airway compression NA 13 (48)

Bronchopneumonia (bilateral) 17 (32) 5 (19)

Miliary TB 16 (30) 7 (26)

Ghon focus NA 2 (7)

Cavities or cystic lesions 4 (8) NA

Lobar collapse NA 4 (15)

Pleural effusion 1 (2) 2 (7)

Normal chest radiograph 4 (8) 1 (4)

Schaaf et al. Respirology 2010;15:747-763

OUTLINE

• Burden of TB

• Understanding maternal and perinatal TB

• Approach to the TB-exposed newborn

APPROACH TO THE TB-EXPOSED NEWBORN

Infectious mother non-infectious mother

Well baby unwell baby

WHICH MOTHERS ARE AN INFECTION RISK?

A recently diagnosed mother with TB

• Received < 2 months of TB treatment at time of delivery

OR

• Sputum smear/culture has not yet converted to negative/ results are

unknown at time of delivery

APPROACH TO THE TB-EXPOSED NEWBORN

Infectious mother non-infectious mother

Well baby unwell baby

Well baby & non-infectious mother

Observe and f/up

Unwell baby

TB-screening

Well baby & infectious mother

TB-screening

Observe and follow-up

1. Well baby and non-infectious mother

– BCG at birth

– Monthly follow-up

– Ask about TB symptoms at each visit

– Screen for TB in the presence of any TB symptoms

Well baby & non-infectious mother

Observe and f/up

Unwell baby

TB-screening

Well baby & infectious mother

TB-screening

Perform TB-screening

2. Unwell baby

TB Screening

• Gastric aspirates (x2)– Xpert and culture

• Chest radiology

• If indicated:

• Abdominal ultrasound

• CSF

• Blood culture

Well baby & non-infectious mother

Observe and f/up

Unwell baby

TB-screening

Well baby & infectious mother

TB-screening

Perform TB-screening

3. Well baby

TB Screening

• Gastric aspirates (x2)– Xpert and culture

• Chest radiology

• If indicated:

• Abdominal ultrasound

• CSF

• Blood culture

Perform TB screening

No TB TB

Prevention versus Observation Treatment

2. Unwell baby 3. Well baby with infectious mother

IPT PREVENTION

– No BCG at birth

– INH 10 mg/kg/day for 6 months -

– Monthly follow-up

– Ask about TB symptoms at each visit

– Screen for TB in the presence of any TB symptoms

– At IPT completion – BCG administration

Perform TB screening

No TB TB

Prevention Treatment

Unwell baby Well baby with infectious mother

TB - TREATMENT

Intensive phase – 2 months (3/4 drugs)

• INH

• RMP

• PZA

• EMB (ETH)

Continuation phase – 4 months (2 drugs)

• INH

• RMP

TREATMENT2009 WHO-RECOMMENDED DOSES

INH 10 (7-15) mg/kg/d

RMP 15 (10-20) mg/kg/d

PZA 25 (20-30) mg/kg/d

EMB 20 (15-25) mg/kg/d

ISONIAZID PHARMACOKINETIC STUDYIN 20 LOW BIRTH WEIGHT INFANTS,

DOSED AT 10 MG/KG

Bekker et al. AAC 2014

FUTURE DIRECTIONS

• Identifying and quantifying the burden of maternal and infant TB

• Improving integration of health care systems (maternal &child; HIV & TB)

• PK/PD information – maternal and infant

ACKNOWLEDGEMENTS

Anneke Hesseling, Simon Schaaf, Robert Gie, Mark CottonDTTC team: BCH PK unit, TBH, KDH and KBHTygerberg neonatal team Harry Crossley fundingFamilies that participated

QUESTION

Of the symptoms below, which ones are most common in congenital TB:

1. Weight loss

2. Night sweats

3. Respiratory distress

4. Jaundice