Surveillance of neonatal herpes in the British Isles 2004-2006

Ethical statement

Ethics approval for this study was granted by London MREC (reference MREC/03/2/80; PIAG/BPSU 2-10(g)/2005). Cases were notified through the normal BPSU protocols to this study between 2004 and 2006; paediatricians were not required to request patient consent for reporting, cases were pseudonomysed, and the study team had no contact with reported cases.

Data collection

This study was carried out through the BPSU’s active national surveillance scheme, established in 1986, whereby consultant paediatricians (mainly members of the Royal College of Paediatrics and Child Health) report specified rare paediatric conditions on a monthly basis. On receipt of a report the BPSU notifies the appropriate study investigator who contacts the reporting clinician for further details. Respondents make a nil return if they have no cases to report; the BPSU monitors response rates, which at the time of this study were 94%. Full details of the BPSU methodology have been described elsewhere¹¹. For this study, paediatricians were asked to report any infant under one month of age with a laboratory-confirmed diagnosis of HSV infection, or any such infant treated with antiviral drugs for suspected HSV infection, or any stillborn infant in whom HSV was suspected, born between 1 January 2004 and 31 December 2006. Respondents were then asked to complete a standard questionnaire providing demographic, clinical and laboratory details including maternal and perinatal information, presentation and treatment. Subsequently, the notifying paediatrician was asked to provide brief follow-up information on the health outcome of the surviving children, including any further treatment required, in their second or third year of life. All clinical and laboratory investigations were undertaken locally as part of the normal care of the infant.

Case definition

Infants with neonatal HSV confirmed by virus culture, polymerase chain reaction (PCR) or immunofluorescence (IF) on a sample taken within 28 days of birth, were classified as confirmed cases. HSV type was reported by the notifying paediatrician on the basis of laboratory results.

Paediatricians were asked to classify infant presentation as disease localised to the skin, eye and/or mouth (SEM), disseminated infection, with or without central nervous system (CNS) and/or SEM involvement, or CNS infection with or without SEM involvement, as described by Whitley¹, and in accord with other similar studies^4–6.

Adverse health outcomes among survivors were classified as mild, moderate or severe, based on the latest clinical findings reported to the study.

Data analysis

Data were managed in a study-specific Microsoft Access 2002 database (Microsoft Corp., Redmond, Washington, USA) and were analysed using Access and Excel.

Confirmed neonatal cases

A total of 45 boys and 40 girls, including two twin pairs, were reported with confirmed neonatal HSV over the three years. Seventy-one infants were born in England, nine in Scotland, and the remaining five in Wales, Northern Ireland or Ireland, giving a minimum estimated incidence of 3.58/100,000 live births (95% CI 2.86-4.42) in the British Isles. In almost all cases (79, 93%), the virus was typed: 34 (43%) HSV-1, and 42 (53%) HSV-2, with another three infants (4%) reported with dual infection (grouped with those with HSV-2 in this report).

Maternal and birth factors

Table 1 shows maternal and infant characteristics. Median maternal age at delivery was 25 years (range 15–45), and only 5% of mothers were reported to be of black or minority ethnic origin. Two sets of twins were delivered vaginally, at 32 and 34 weeks gestation. Just over a third of singletons (35%) were delivered by caesarean section, but in no case was this because of concerns about herpes infection in pregnancy. Median gestational age was 38.5 weeks (range 26–42); 42% of singletons were pre-term (<37 weeks). Median singleton birthweight was 2755 grams (range 948–4700) and all term infants weighed at least 2500 grams at delivery, apart from one born at 37 weeks gestation.

Clinical presentation

As shown in Table 2, 61% (52/85) of infants presented with SEM lesions, and for 24, this was the sole manifestation. Of the 61 infants with disseminated or CNS infection, 54% (33) had no SEM lesions reported. Infants with HSV-1 were more likely to have SEM lesions than those with HSV-2 infection (25/34, 74%; 23/45, 51%); CNS and disseminated infection were more common in infants with HSV-2 infection (36/45, 80%; 19/34, 56%).

Treatment

Most infants (82/85, 96%) were treated with acyclovir. Two of the three untreated infants died in the second week of life, and were only diagnosed at post-mortem with disseminated infection; the third, with localised infection only, was reported well at age 30 months. Two infants started treatment prior to presentation with clinical symptoms because their mothers were known to have had genital herpes infection in pregnancy (one diagnosed before delivery, one just after); another 23 were treated on the day of presentation with symptoms. The remaining 57 infants started treatment a median two days after presenting with clinical symptoms, 95% within six days. Two infants started treatment more than two weeks after the onset of reported clinical symptoms despite having SEM involvement, but neither had any problems reported at the last follow up. Among the 63 infants who survived the neonatal period, median duration of the initial course of treatment was 14 days, and 45% received subsequent courses of treatment.

Outcome

It is known that 23 children (27%) have died, all but one in the neonatal period (Table 3 and Figure 1); all of those who died had disseminated or CNS infection, only five also had SEM lesions, and 45% were pre-term. Of neonates with HSV-2, 15 (33%) of 45 died and six (18%) of 34 with HSV-1 (HSV type unknown for two). Two previously asymptomatic infants who died unexpectedly in their second week of life were diagnosed with disseminated HSV-1 infection at post-mortem; the other 20 neonates who died started treatment a median of one day after presentation with symptoms, 95% within five days; all but one died within 15 days of birth.

Figure 1. Flow chart.

HSV, herpes simplex virus; ms, months.

Of the 63 survivors, 13 (21%) were lost to follow up before their first birthday at a median age of five months: two showed signs of developmental delay when last seen at the ages of one and four months; the remaining 11 had no problems reported at last follow up (Figure 1).

Follow-up information was provided for the remaining 50 children at a median age of 34 months (range 12–65 months). Long-term sequelae were reported in 2/4 surviving children whose virus was not typed, 4/21 (19%) children with HSV-1 infection, and 13/25 (52%) of those with HSV-2. Severe developmental delay and major health problems including recurrent seizures, visual impairment, and quadriplegia or hemiplegia (median age at follow up 37 months, range 24–65) were reported in 13 children, including one child who died aged three years. Another six children had less severe problems reported, including speech and language delay, mild developmental delay and/or visual or hearing impairment (at median age 33 months, range 28–57). The remaining 31 children were reported well or with only minor health issues (at median 33 months, range 12–62).

Likely source of infection

For 48 infants (including a pair of twins), it was not possible to determine timing of exposure to HSV, that is, whether they had been exposed prenatally or around the time of delivery to maternal genital infection, or postnatally to an oral cold sore or whitlow. For the other 37 infants, 18 (including a pair of twins) were probably exposed to pre/perinatal maternal genital infection, and 19 to a probable postnatal source (Table 1).

Among the infants with probable pre/perinatal exposure, the risk was only identified prior to delivery in two cases: one woman, diagnosed with genital HSV during pregnancy, was treated with acyclovir for seven weeks between diagnosis and delivery by emergency caesarean section when she went into early pre-term labour. Another pregnant woman had reported a past history of genital HSV; following a pre-term vaginal delivery her baby was diagnosed with neonatal HSV and subsequently the mother was found to be shedding virus in the genital tract. Two more mothers reported a history of genital herpes prior to pregnancy after their babies were diagnosed. Another thirteen women were retrospectively found to have had symptoms compatible with current or recent genital HSV, including two with partners who were also diagnosed with genital infection.

In 19 cases, a parent or relative was reported to have a ‘cold sore’ or similar lesion around the time of delivery or infant diagnosis, or to have frequent oral cold sores; this comprised six mothers or fathers with non-genital HSV lesions, five parents who reported that they frequently had oral cold sores, and eight symptomatic visiting relatives.

Among the 35 infants with type of HSV known and a likely source of infection identified, it was more likely to be postnatal exposure (11/18, 61%) for infants with HSV-1 than for infants with HSV-2 (7/17, 41%). Median gestation was 39 weeks (range 27–42) for infants probably exposed to postnatal infection; 38 weeks (26–42) for infants whose likely exposure was unknown, and 34.5 weeks (27–41) for those with likely pre/perinatal exposure.

Underlying data

The data for this study was collected 2004–2006. At that time, approval to share raw individual patient data was not required or requested. Identifiers including maternal and infant dates of birth and other demographic characteristics were collected as essential study data and adequate anonymisation of data is not possible due to the rarity of the disease. Assurances were provided that all data would be kept securely and not shared outside the study team. Under these circumstances, data cannot be made publicly available, even in an anonymised form. If researchers wish to access these data for the purposes of further research, they may contact the corresponding study author, Dr Pat Tookey, by email (p.tookey@ucl.ac.uk), providing details of the information required and the intended use of the data, for example comparison with other similar case series, and we will do our best to facilitate this.