Maternal screening for and Congenital

Tendesayi Kufa-Chakezha, MBChB, PhD Centre for HIV and STIs National Institute for Communicable Diseases Outline

• Overview of vertically transmitted infections • Burden of vertically transmitted infections • Overview of vertically transmitted infections

• Maternal syphilis • Background and epidemiology • MTCTs- prevention, screening, treatment • • Challenges and opportunities for elimination Vertically transmitted infections

• Many infections can be passed from mother to child either in utero (congenital) or during the perinatal period

• Viral – HIV, HPV, HSV, CMV, Rubella, Measles, Zika

• Bacterial – Treponema pallidum, Listeria monocytogenes, Chlamydia trachomatis , Neisseria gonorrohoeae , Group B strep,

• Protozoan – Plasmodium malariae, Toxoplasma gondi, Trypanosoma cruzi

• Fungi –

• Can cause morbidity and or mortality in both mother and Vertically transmitted infections

• Acronym that can be used “CHEAPTORCHES”** • and shingles • , C, (D), E • Enteroviruses- Coxsackie A, B, ECHO viruses • AIDS (HIV ) • Parvovirus B19 • • Other (Group B Streptococcus, Listeria, Candida, Lyme disease) • Rubella • • Herpes simplex

• Everything else sexually transmitted (,Chlamydia infection, Ureaplasma urealyticum, HPV) • Syphilis ** Proposed by Ford-Jones and Kellner in 1995 Vertically transmitted infections

• South Africa has singled out a few infections for the public sectors • HIV • Syphilis • Tuberculosis • Malaria • Hepatitis B • • Zika Burden of vertically transmitted infections

• Global# • Infections thought to cause 15.6% of NNDs globally • Congenital malformations 10.5% • Prematurity/ Low birth weight (LBW) 35.7% of NND • Infections contribute

• Sub-Saharan Africa $ • Alliance for Maternal and New-born Health Improvement (AMANHI) network • Population based study of women of reproductive age • Identification of pregnancies, follow up of pregnant women up to 6 weeks post partum • In SSA (DRC, Ghana, Kenya, Tanzania, Zambia) • < 28 weeks = 1.6% ; Stillbirths = 1.8% , rate = 17.1 per 1000 live births; NMR = 20.1 per 1000 live births • Infections accounted for 50% of and 34-39% of NNDs

#Madrid L et al 2016; $AMANHI Mortality study group Burden of vertically transmitted infections

• South Africa • CHAMPS study (neonatal deaths)# • Minimally invasive tissue sampling of infant deaths at CHBAH • 153/236 (64.8) neonatal deaths had specimens analysed • 52.9% deaths were due to complications due to prematurity • Most vertically transmitted infections cause prematurity/ LBW

• CHAMPS study (stillbirths) ## • Minimally invasive tissue sampling of stillbirths at CHBAH • Causes were identifiable for 117 of 129 (90.7%) stillbirths • Immediate foetal causes identified in 79.1% of stillbirths • 37.2% of immediate foetal causes were due to infection

# Madhi S.A et al CID 2019;69(S4):S351–60; ## Madhi S.A et al CID 2019;69(S4):S342–50 Viral infections

Infection Burden Timing of MTCT Effects on the foetus/ Maternal Screening Management infant HIV Prevalence 30% in Intrauterine LBW, prematurity HIV test at booking ART SA PMTCT CI pregnant women Intrapartum Infection visit and every ANC Viral load monitoring guidelines, 2019 Goga et al Untreated 10- 40% of Post partum (BF) visit Infant prophylaxis DHB HIV+ mother transmitted PMTCT – 0.9% at birth , 1.3% at 10 weeks in 2016/17 CMV Maternal prevalence Intrauterine /HSM PCR on saliva, urine, Avoiding exposure Madrid L et al 50- 85% in developed Petechiae blood, CSF after Maternal treatment 2016 Marsico C et al countries Microcephaly and CNS birth with antivirals 2017 0.6- 0.7% of all live involvement Serology- IgM CMV HIG births have MTCT of Hearing loss Antigenaemia CMV Facilitates HIV Not routine in RSA 5% of stillbirths at transmission CHBAH had CMV identified HBV 3.6% of people Intrauterine Small for gestational age Maternal screening Vaccination at birth SA PMTCT CI chronically infected Intrapartum (SGA), prematurity, LBW, HBSAg for born to guidelines, 2019 Mokaya J et al , Post partum (BF) congenital anomalies, HBeAg/ HBV VL if positive mothers 2019 and neonatal jaundice positive HBIg Congenital infection- Antivirals if becomes chronic symptomatic Bacterial infections

Infection Burden Transmission Timing Effects on the foetus/ Maternal Treatment/ of MTCT infant Screening management

TB Unknown? Throughout pregnancy LBW, prematurity TB symptom TB treatment for SA PMTCT CI 216 000 pregnant Haematogenous Congenital infection screening at all mother guidelines, 2019 Sugarman J at al , 2014 women had TB in spread via placenta (rare). Might be missed contact Maternal TBT if Wolf B, et al, 2019 2014, 50% in SSA Amniotic fluid resulting in high Xpert MTB/Rif for eligible ingestion mortality all pregnant TBT for the infant Contact with genital women TB treatment foe lesions neonate

GBS 10-40% Intrauterine Stillbirths (3rd Swab and testing Treatment Madhi S.A et al , 2019 colonisation of the Intrapartum trimester) Not routine in RSA ? Vaccine Seale A.C et al , 2017 genital tract Preterm births 2% of all stillbirths Neonatal invasive globally , 4% in SSA, disease (sepsis, 3.1% in SA , meningitis, encephalopathy) Listeria Sporadic cases Intrauterine Stillbirths None. Index of Antibiotics SA PMTCT CI 0.17/1 000 live Haematogenous Prematurity suspicion guidelines, 2019 births at Tygerburg spread via placenta Invasive disease – hospital meningitis/ sepsis Outbreaks Protozoal

Infection Burden Transmission Effects on the foetus/ Maternal Screening Treatment/ Timing of MTCT infant management

Malaria 30 million women Intrapartum Abortion, Stillbirth , No screening Intermittent preventive Kakuru A, 2019 at risk annually Placental and prematurity, LBW , recommended therapy (IPTp) with Bauseman M et al, 2019 transplacental Malaria in infancy Parasitological/ Rapid sulphadoxine- infection Tests where malaria in pyremethamine (SP) at pregnancy is each ANC visit (DOT for suspected at least 4 visits) Insecticide treated Prompt diagnosis and case management

Toxoplasmosis 190 000 Intrapartum Chorioretinitis with IgM and IgG Pyrimethamine, Bissati K.E et al, 2018 (179300- 206300) Acute maternal blindness antibodies Sulfadiazine De Oliveira Azavedo CT et al, 2016 per annum infection Meningoencephalitis- Amniotic fluid PCR for Folinic acid throughout Hydrocephalus foetal diagnosis pregnancy Convulsions Syphilis

• Transmission is mostly via vaginal, anogenital or orogenital sexual contact – i.e. contact with infected lesions, mucosal membranes

• Trans-placental transmission from infected mother to fetus also occurs • Commonest cause of pregnancy loss in the developing world

• Transmission through blood transfusion or organ donation also possible

• Relatively infectious mostly in the primary and secondary stages • 10- 30% per sexual contact (O’Bryne P et al 2019) , 10-64% of sexual contacts develop syphilis (Stolcey J et al 2018)

• Underlying/ basic pathology at all stages is vasculitis Epidemiology: prevalence, incidence and new cases in South Africa, 2017

Source: Kularatne R, et al 2018 Epidemiology: Syphilis prevalence and incidence trends 1990- 2017 South Africa

Source: Kularatne R, et al 2018 Epidemiology: Syphilis prevalence among pregnant women in SA

Source: 2015 ANC HIV prevalence survey report Mother-to-child-transmission of syphilis (congenital syphilis)

• Preventable public health problem

• Occurs when syphilis in a pregnant woman remains undetected, untreated or inadequately treated

• Can result in pregnancy loss, still births, preterm or low birthweight babies and congenital infection in neonates and infants

• Maternal syphilis known to double the risk of MTCT-HIV AOR 2.1, 95% CI 1.3-3.4, with 88% of HIV infections acquired in-utero in HPTN 040 study (Yaganeh N, 2015, Adachi C, 2018)

• In 2016, the global prevalence of maternal syphilis was 0.69% - this means almost 7 per 1000 pregnant women had syphilis infection

• In the same year there were 355 000 adverse birth outcomes due to syphilis – 143 000 foetal deaths and still births, 61 000 neonatal deaths, 41 000 preterm/ low birth weight and 109 000 infants with CS

15 There is a global plan for the elimination of congenital syphilis South African strategy for PMTCs Prevention

Levels of prevention Interventions

Pre-primary/ Interventions address structural drivers that increase vulnerability to syphilis and structural other STIs at population level - Education , Poor socio-economic conditions, promoting gender equality, gay rights, decriminalising sex work etc

Primary Interventions to prevent acquisition of infection from an infected partner to an uninfected partner - Behavioural change and communication interventions- reduce # partners - Condom use - Medical male circumcision [ 42% ↓ in males& 59% ↓ females- Pintye et al, 2014] - New tools ? Vaccinations ?Antibiotic prophylaxis – Doxycycline post-exposure prophylaxis , other drugs considered AZ, benzathine penicillin

Secondary Interventions targeted at those who are infected to improve screening, early detection and treatment in order to reduce infectiousness and prevent complications - Screening high risk groups / key populations- pregnant women, syphilis exposed infants, MSM, FSWs - Partner notification and treatment

Tertiary Interventions to manage complications or sequelae of such - Treatment and management of complications due to syphilis – ocular, neuro- syphilis , care of infants with congenital syphilis Screening for maternal syphilis

• Syphilis screening and treatment part of the ANC package since the 1980s in South Africa

• Meant to take place during the first booking visit. No recent studies of coverage of syphilis testing in the country. • 84 to 100% in studies from 2000- 2013 (Rotchford K, 2000; Myer L, 2003; Deperthes B.D, 2004; Chueu MP, 2005; Dihn T.H, 2013) • Coverage estimated to be 95.6% in the 2017 ANC survey • Routine surveillance for coverage only conducted at 270 sentinel sites, data incomplete • Attempts at using laboratory data to estimate coverage limited by lack of pregnancy markers in CDW, lack of unique identifiers to deal with duplicate testing

• Traditionally comprised collection of a blood specimen for rapid plasma reagin (RPR) testing and confirmatory testing of positive ones with TPPA/TPHA/ FTA/TPAb in the laboratory (traditional algorithm)

• Reverse testing algorithm implemented since 2013 and POC tests being evaluated Treatment of maternal syphilis

Source: STI Treatment guidelines, 2015 Congenital syphilis

• Category 2 Notifiable medical condition • All health care providers required to report case within 7 days of diagnosis • Case definition largely clinical but includes laboratory component

Congenital syphilis cases notified in South Africa 120 105 100

78 80 73 67

60

40 40 Data : NICD, NMC programme 28 27 29

20

0 Q4 17 Q1 18 Q2 18 Q3 18 Q4 18 Q1 19 Q2 19 Q3 19 WHO surveillance case definition

Source case definition: Global guidance on criteria and processes for validation: Elimination of mother-to-child transmission of HIV and syphilis.2nd Edition 2017 Challenges in elimination of MTCTs

• Don’t have a good handle on new cases, incidence and risk factors in our settings

• We are not winning the war against syphilis and STIs in general • Better understanding of transmission dynamics, infectiousness of the latent and tertiary phases, correlates of protection/ immunity. Required for development of vaccines , new diagnostics • Role of HIV in transmission of syphilis –Are higher rates in HIV positives due to confounding by behaviour or there is a biological basis. Role/mechanism of HIV infection in repeat syphilis infections? What is the effect of ART • How to scale up interventions that are known to work in preventing syphilis, improving partner notification and treatment • How to develop and adapt interventions to the digital era we are in – use of social media, big data analytics and artificial intelligence in prevention Challenges in elimination of MTCTs

• Screening and diagnosis • Syndromic management vs aetiological testing • Most genital ulcers due to HSV • Screening high risk groups and treating secondary/ early latent infections

• Efficiency in screening services • POC testing – dual vs single , with HIV or without test

• Treatment • Alternative treatments when BP is not feasible • Management of individuals who remain sero- fast after treatment Challenges in elimination of MTCTs

• Health education • Transmission and its prevention, symptoms and signs, diagnosis and treatment, complications • Where to access treatment

• Sexual health services • Youth, male, MSM and FSW friendly , non-judgemental services • Accessible – opening hours • Confidential – counselling, partner notification • Integrated ? – HIV, Contraceptive services etc Conclusions

• Prevention and control of maternal and congenital syphilis remains a public health challenge

• Despite effective screening methods and treatment and no emergence of resistance • Increasing cases in the western world • Cases of congenital syphilis still occur • No good surveillance system

• Opportunities exists: • In prevention- MMC, ? prophylaxis for high risk groups, use of digital technologies for contact tracing, testing etc. • Improving care and treatment of the infected • Surveillance – NMC platform and CDW Acknowledgements

• Mobore Morifi and the NMC team • Ranmini Kularatne, Frans Radebe, Venessa Maseko and the STI reference laboratory team

Thank you!!!