1. Management of a pregnant woman with HSV Clinical Case Study 1 Raj Patel and Rohilla Maarij University of Southampton Marrakech 30 th May 2014

2. Why is herpes in pregnancy important ? Common cause of anxiety to patient and practitioner Responsible for some possibly preventable adverse outcomes 90% are undiagnosed 2% women acquire HSV-2 in pregnancy BUT Neonatal herpes (the main driver of anxiety and interventions) is rare outside North America –USA 20-50 / 100 000 deliveries –Unnecessary or ineffective interventions may cause anxiety, give false hope and waste resources

3. Neonatal Herpes in outside North America Very little good data Reporting unlikely to be comprehensive Good reporting in the Netherlands/ some Scandinavian countries and possibly in the UK Rates in very low risk countries appear to be rising (both the Netherlands 1:30,000 and UK 1:60,000) have seen a rise in the last 6 years Average European rate is 1:12-15,000 (similar to Australia)

4. Neonatal Herpes- what do we know? A minority of cases due to transplacental infection –Predominantly associated with primary acquisition disease but rarely also seen in recurrent infection (occasional case report) –Baby ill at term – scars, small, choioretinitis, microcephaly, hydranencephaly, microphthalmia- diagnose by finding virus – 20% die, severe complications with neurological damage –Only a minority of mothers have history or symptoms of an acquisition episode –There appears to be little that can be done to prevent this rare complication Hutto C, Arvin A, Jacobs R, Steele R, Stagno S, Lyrene R, Willett L, Powell D, Andersen R, Werthammer J, et al. Intrauterine herpes simplex virus infections. J Pediatr. 110:97-101, 1987

5. Neonatal Herpes- what do we know? Majority of cases due to infection close to term Greatest risk in those women that acquire HSV late and do not have a good antibody response – 30-80% risk of transmission if they are shedding virus at term –High likelihood of viral shedding (upto 50% of days in first few weeks) –High titre of virus –Baby will have little or no passive immunity Typically present once baby is at home (rarely before day 5) 3 classical presentations

6. Neonatal Herpes- what do we know? May be due to nosocomial infection -25%

7. Neonatal Herpes- what do we know? May be due to nosocomial infection

8. Neonatal Herpes- what do we know? HSV-1 worse then HSV-2 – more often associated with neurological problems HSV-1 now accounts for nearly 50% of cases Less then 20% have symptoms suggestive of HSV in pregnancy In primary disease in third trimester Caesarean section is protective Needs to be done electively but even if performed after membranes rupture there is benefit It is unlikely that current strategies will prevent the bulk of cases that we see

9. Neonatal Herpes- what do we know? Low unpredictable risk in those with recurrence at term – < 3% in those with recurrence and shedding at term (< 1:50 risk) In the UK very few cases in those with a history of recurrent genital herpes Risk in the order of 1:12000 (12% x 2% x 3%) Suppressive antivirals from 36 weeks keeps everybody calm and prevents LSCS

10. Treatment with ACV from 36/40 ACV placebo Lesions at delivery5%14% HSV by PCR2%34% LSCS for HSV4%10% ACV significantly reduces but does not eliminate HSV lesions and detection in pregnancy Suppression does not control short shedding (<6h) and controls only 85% of shedding

11. Neonatal Herpes- what do we know? Low unpredictable risk in those with recurrence at term – < 3% in those with recurrence and shedding at term (< 1:50 risk) In the UK very few cases in those with a history of recurrent genital herpes Risk in the order of 1:12000 (12% x 2% x 3%) Suppressive antivirals from 36 weeks keeps everybody calm and prevents LSCS No evidence that it prevents transmission Aciclovir 400mg tds used Other drugs also used Advice on what to do if a lesion is present at term is controversial

12. Managing RGH at term Most lesions are not visible The risk appears low Conservative approaches in the Netherlands was not associated with a rise in numbers of neonatal cases (initially) Other interventions may also add risk (scalp electrodes/ forceps / ventoux cup) (Brown metanalysis shows increased risk but does not separate between primary and recurrent episodes)

13. Case Study -Miss KH January / February 2016 24 year old in her second pregnancy Managed in Southampton mixed care

14. Case Study -Miss KH Developed vulval soreness in January 11 th 2016 (30/40)- 2 weeks after sex- self medicated with pseudocream Attended General Practitioner – complaining of dysuria and genital soreness 18-2.16 Not examined but given co-trimazole pessary and cream Self examined with mirrors -claims vulva was swollen, red on both sides- noticed no ulceration herself Initial symptoms and swelling eased with canesten but noted that this did not feel like Candida infection – throughout itching was minimal Attended GP again 2 nd feb 2016 (33/40) – symptoms of soreness persisting – discomfort sitting examined and left labial lesion noted referred to GUM

15. Case Study -Miss KH Examined in GUM – single ulcer right labia, clean not indurated, on erythematous base, superficial and painful on swabbing no palpable lymph nodes Probable HSV – looks mild ? Recurrence Tests ordered – HSV/ syphilis PCR, full STI screen, Herpes serology from week 16/40 banked sample

16. Case Study -Miss KH Examined in GUM – single ulcer right labia, clean not indurated, on erythematous base, superficial and painful on swabbing no palpable lymph nodes Probable HSV – looks mild ? Recurrence Tests ordered – HSV/ syphilis PCR, full STI screen, Herpes serology from week 16/40 banked sample

17. Case Study -Miss KH Past History –No history of cold sores or recurrent genital rashes or ulcers –X 1 episode of candida in the past –3 sexual partners ever –Current partner for 8 years –Previous sexual partner 2 years ago –Last sex 2 weeks before start of dysuria symptoms (December 2015) –Partner has no history of genital sores – x1 previous pregnancy – Full Term Vaginal Delivery - forceps

18. Case Study -Miss KH Reviewed 1 week later -Lesion has healed Results: –HSV PCR – in house POSITIVE HSV-2 –Syphilis PCR – negative –Chlmydia/GC NAATS VVS- negative Serology Week 16 : weakly positive for HSV-1 and HSV- 2 OD 92.3 (Focus) 1% above cutoff Week 33: positive for HSV-2 alone OD110

19. Case Study -Miss KH Summary –25 year old women with first episode genital HSV diagnosed at week 34/40 –single ulcer –Long period of genital symptoms prior to diagnosis (3 weeks) –Weak positive serology on week 13/40 banked bloods on Focus serology –Positive serology at week 34/40

20. What would you do? Recurrent/ acquisition? –Test partner for antibodies –Plan for vaginal delivery –Offer suppressive acyclovir to term, –Arrange caesarean section at 39/40

21. Considerations Sexual history surely must be a recurrence? –Been with partner for 8 years /PSP 2 years –Last SI 5 weeks before ulcer –Serology

22. Considerations Reliability of Clinical Features –Only 1/3 acquisitions of HSV are symptomatic (prospective transmission studies) and even many of these are not classical –Many will be unilateral, single and mild –CAN NOT EXCLUDE RECENT ACQUISITION

23. Considerations Reliability of Serology –Can you Trust the booking in serology? –False positives to HSV-2 typically occur in those with HSV-1, certain ethnic groups, when Low titres of antibody are found, having cross reacting JA fragment antibodies –About 4% of the uninfected population may have false positive antibodies –1 in 12 patients with HSV-2 and 1:3 with HSV-1 loose their antibodies –This patient would not meet criteria for many research studies which require a x3 above cut off inclusion –Positive at 34/40 must mean established infection? –She has protective antibodies now so is she safe to deliver vaginally?

24. What does a positive antibody result at 36/40 mean? Patients with Primary Infection at time of presentation (Western Blot) 18% -30% with both IgG and IgM antibodies Type Specific Antibodies to HSV 1 and 2: Review of Methodology. Herpes 1998:5 33-38 Ashley R.L Some evidence that full seroconversion associated with lower risk of transmission but data confused

25. Differential diagnosis Recurrent lesion in third trimester in a previously undiagnosed women with some evidence of previous infection (Trust the serology from week 13/40 and note mild episode)- ? Precipitated by Candida Acquisition episode of HSV in third trimester- (first features started 2 weeks after si), ignore serology from 13/40 as weak, antibodies can form early in infection). Manage as recent acquisition

26. What did we do? Started KH on acyclovir 400mg tds to term Discussed with obstetrician, midwife and PATIENT Explained uncertainty Planed C/S at 39/40

27. Why did we do this? Southampton has 15-20,000 deliveries per year In the last 6 months we have had 3 cases of neonatal HSV 2 deaths and 1 survived All women were undiagnosed with HSV or in unrecognised serodiscordant relationships Is there such a thing as a low risk country?