Can Group B Strep Cause Hsv 1 in Babies

N Engl J Med. Author manuscript; available in PMC 2010 Apr 1.

Published in terminal edited form every bit:

PMCID: PMC2780322

NIHMSID: NIHMS155533

Maternal and Neonatal HSV Infections

Lawrence Corey

ⁱ Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle

² Department of Medicine, Academy of Washington, Seattle

³ Department of Laboratory Medicine, University of Washington, Seattle

Anna Wald

¹ Vaccine and Infectious Illness Establish, Fred Hutchinson Cancer Research Center, Seattle

^two Department of Medicine, University of Washington, Seattle

³ Section of Laboratory Medicine, University of Washington, Seattle

⁴ Department of Epidemiology, Academy of Washington, Seattle

Epidemiology

An estimated 30 to 65 per centum of pregnant women in the U.Due south. accept genital infection with herpes simplex virus (HSV)-1 or -2.¹ Neonatal HSV, defined as infection in a newborn inside 28 days of birth, is an especially devastating issue of the genital herpes epidemic. Untreated neonatal HSV has only a 40 pct survival rate and even the early initiation of high-dose intravenous acyclovir therapy results in significant inability amongst survivors. The frequency of neonatal HSV infection varies by patient population; between 1 in 1,700 (60 per 100,000) and 1 in eight,200 (12 per 100,000) live births in the U.S. may be complicated by neonatal HSV infection (Tabular array 1). A retrospective report in California reported rates of 12.two per 100,000 births from 1995 to 2003.^two Data from 30 U.S. wellness plans including 17 million enrollees showed a charge per unit of 60 per 100,000 births.³ Prospective, single center studies in the U.Due south. take shown neonatal HSV rates as loftier as 31.ii per 100,000 (1 in 3,200) births.⁴ These incidence data for neonatal HSV are similar to those of perinatal human immunodeficiency virus (HIV) infection earlier the advent of routine antiretroviral utilize in pregnancy and are higher than those of congenital syphilis, toxoplasmosis, and congenital rubella in endemic years (Table 1).ⁱⁱ ^, ⁵ ^– ⁹

Table 1

Incidence of neonatal HSV and other built infections in Due north America

	Location	Dates	Rate (per 100,000 live births)	Source
	National or Country Surveillance System
Neonatal Herpes	Canada⁴¹	2000–2003	v.nine	Active surveillance of all Canadian pediatricians
	Washington State	2000–2004	two.v	Washington State Dept. of Health
	Ohio	1997–2001	2.vi	Ohio State Dept. of Health
	Hospital Discharge Information
	Washington State³¹	1987–2002	viii.4	Hospital belch data
	New York City⁴⁸	1994–2003	13.4	Hospital discharge information
	California²	1995–2003	12.ii	Hospital discharge information
	California	1985–1995	11.5	Hospital discharge data
	Integrated Wellness Care Information Services National Managed Intendance Benchmark Database³	1997–2002	60	Hospital belch information from30 health plans covering 7 The states census regions
	Prospective Cohort Studies
	Washington State⁴	1982–1999	31.two	Prospective cohort study of pregnant women
Syphilis ^*	Washington Country	1996–2004	0.8	Jo Hofmann, DOH epidemiologist
Syphilis ^*	The states	1995–2005	xiv.3	CDC
Toxoplasmosis ^†	Ohio	1997–2003	<1.0	Ohio State Dept. of Wellness
Group B Strep ^‡	5–7 US metropolitan areas	1997–2003	55.3	ABC group (CDC)
Group B Strep ^‡	Ohio	1997–2001	43	Ohio Land Dept. of Wellness
Rubella ^§	U.s.a.	1970	2.1	CDC
Rubella ^§	United states	1995–2005	<0.1	CDC
HIV ^¶	Washington Country	1997–2005	1.v	Washington Country Dept. of Wellness
	Michigan⁴⁹	1993–2000	five.iv	Michigan Department of Community Health
	Usa⁹	2002	four.5	CDC

Pathophysiology

Nigh neonatal infection results from exposure to HSV in the genital tract during delivery, although in utero and postnatal infections tin occasionally occur.¹⁰ While most clinical management guidelines for HSV infections concentrate on women with long established disease, the hazard of manual is significantly greater amongst women who acquire genital infection with HSV-1 or HSV-2 during pregnancy (take a chance of 25 to 50 percent) than among those who have longstanding HSV-ii infection and subsequently reactivate virus in the genital tract at term (gamble of <1 percent) (Effigy 1, Table two). Thus, while the number of infants born to women with newly caused HSV at the end of pregnancy is much smaller than the number of infants born to women with established HSV-2, the much greater efficiency of HSV manual during newly acquired genital HSV accounts for the fact that 50 to lxxx per centum of neonatal HSV cases consequence from women who acquire genital HSV-1 or HSV-2 infection near term.^ten ^, ¹¹ Near genital HSV conquering in women occurs without signs or symptoms of disease and is associated with cervical viral shedding.

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Pathogenesis of Neonatal Canker

Table 2

Common misperceptions about neonatal herpes

Misperception	Evidence
1. Most infants with neonatal HSV are born to women with a by history of genital herpes.	Virtually maternal-fetal manual comes from women with undiagnosed genital herpes, many of whom accept acquired HSV-1 or -2 for the outset time near-term.
ii. HSV-1 infection usually is acquired from non-maternal sources.	Neonatal HSV-1 infection accounts for 30–50% of all reported HSV-1. More than than three-fourths of cases are from recently acquired genital HSV-1 in the female parent, with subsequent transmission to the baby during delivery.
3. Suppressive antiviral therapy at the finish of pregnancy eliminates the risk of neonatal HSV infection.	Suppressive acyclovir reduces the frequency of genital lesions near-term and the frequency of cesarean delivery. At that place are no data to suggest it reduces the risk of neonatal herpes.
4. Almost infants with neonatal herpes nowadays with vesicular lesions.	Neonatal HSV infection oft presents with a sepsis-like syndrome or with new onset of seizures. Skin or mucosal lesions may not announced until tardily in the disease course, or not at all.
5. Cutaneous HSV infection in the babe tin exist treated with topical or oral antivirals.	All cases of presumptive neonatal HSV should be treated with intravenous acyclovir. Confirmed cases of SEM disease should be treated with sixty mg/kg/solar day for fourteen days and for CNS or disseminated disease for 21 days^eleven.
6. IgM antibodies are useful for the diagnosis of neonatal herpes.	IgM assays are not reliable. HSV DNA detection is the optimal method for diagnosis²¹.

Approximately 2 percent of HSV-2 seropositive women by civilisation and 8 to 15 percent by polymerase chain reaction (PCR) have HSV-2 detected in genital secretions at term.¹² ^, ¹³ Almost none of this shedding is accompanied by clinically detectable genital lesions. Despite the frequent exposure to HSV during birth, <1 percentage of infants delivered vaginally to women shedding HSV-ii at term develop neonatal herpes.¹⁰ ^, ¹¹ ^, ¹⁴ The discrepancy between the high shedding charge per unit among women with established HSV-ii infection and the low neonatal transmission rate suggests a role for transplacental antibody to countervail the hazard of infection. This departure in transmission risk to the neonate between the initial acquisition of HSV during pregnancy versus reactivation of prior infection contributes to the divergent patient direction and public health strategies suggested to impact neonatal HSV.

Diagnosis

Genital HSV infections are often subclinical and, fifty-fifty if symptomatic, lack specificity in their signs and symptoms. Case series take shown that nearly primary genital herpes infections in pregnant women are non diagnosed accurately by clinicians.¹⁵ Women who present in pregnancy with HSV infection should accept both a type-specific serological assay equally well as a exam of the virus to identify and type their HSV infection.¹² This approach allows the clinician to objectively categorize the infant at highest risk of infection. Laboratory tests include viral isolation in culture or direct fluorescent antibiotic (DFA) studies to detect viral protein from genital lesions,, or PCR to exam for presence of viral Dna.¹² PCR assessment is the most sensitive and unremarkably most rapid measure.¹⁶ Accurate type-specific serological assays are based on the departure in epitope specific immune responses to the HSV glycoprotein G molecule of HSV-1 v. HSV-ii; occasionally tests based on whole antigen response are reported inaccurately equally type-specific by diagnostic laboratories. Similarly, commercial IgM assays to HSV-one and HSV-2 are non validated in pregnancy or in infants. Antibodies to gG1 or gG2 tend to develop reasonably late in the course of infection—ii to 12 weeks; hence, detection of virus in a seronegative woman or discordance between the type of viral isolate and antibody status, for example, HSV-2 isolate in a mother with only type specific HSV-one antibodies, identifies women with recently acquired infection.

Manifestations

Congenital HSV infection is rare, shares clinical features with other congenital infections, including microcephaly, hydrocephalus, and chorioretinitis, and usually presents with clinical abnormalities at nascence. Postal service-natal acquisition is almost e'er due to HSV-1 and is associated with contact with hospital personnel or family members who are shedding HSV-one¹⁷. Ritual circumcision that involves suctioning of the wound with the mouth also has been associated with neonatal HSV-1.¹⁸

Well-nigh neonatal infection results from exposure to HSV during delivery. The clinical presentation has been divided into iii categories, each associated with different outcomes and clinical manifestations. Neonates with infection confined to skin, optics and mucosa (SEM), which comprise well-nigh 45% of virtually instance serial, oftentimes present with vesicular lesions on the skin, eye or mouth and, by definition, accept no central nervous system (CNS) or visceral organ involvement (normal CSF indices; normal neurological and CT findings; and no bear witness of pneumonitis, hepatitis, coagulation issues, etc.). Systemic therapy is required; otherwise, further progression may occur. However, with high-dose intravenous acyclovir, the long-term developmental outcome of this form of neonatal herpes is good. Children with SEM herpes often accept recurrent cutaneous herpes outbreaks during early babyhood. Suppressive antiviral therapy reduces the frequency of these cutaneous recurrences, but breakthrough infections may still occur. CNS-associated infection, which comprises 30% of near large case serial, is associated with lethargy, poor feeding, or seizures, with or without cutaneous lesions. CSF pleocytosis is usually present, HSV Deoxyribonucleic acid in cognitive spinal fluid is the most sensitive laboratory test to confirm the diagnosis, and samples obtained early in the course of the disease may exist falsely negative. Morbidity of CNS HSV in infants is higher with HSV-2 than HSV-1, and may include developmental filibuster, epilepsy, blindness and cerebral disabilities. Prompt initiation of therapy influences outcome; unfortunately, non-specific presentation may filibuster diagnosis. Acyclovir therapy has essentially improved survival (Table 3); withal, neonates with CNS HSV-two infection still have high rates of developmental issues at one yr and over 50 per centum have moderate to severe neurological abnormalities.¹⁹ ^, ²⁰ Moreover, relapses of CNS infection may occur, further increasing morbidity. The highest fatality rate for neonatal HSV is associated with disseminated infection (25% of case series) involving multiple organs (such as lung, liver and encephalon) and appearing clinically indistinguishable from bacterial sepsis.¹⁷ ^, ¹⁹ ^, ²⁰ The risk of death from disseminated neonatal HSV is still high (30 pct), even with antiviral therapy. ¹⁹ ^, ²⁰. Any vesicular rash in a neonate should be evaluated for HSV. As up to 50 percent of neonatal HSV infection presents without skin rash, all infants younger than 4 weeks with CNS infection or sepsis syndromes should accept a laboratory evaluation, preferably with PCR, performed for HSV infection, including plasma/blood sample for HSV Deoxyribonucleic acid.²¹ ^, ²² CSF HSV PCR assay is considered cost-constructive in febrile newborns with pleocytosis.²³

Table iii

Upshot of neonatal herpes by category of disease

Category of disease	Mortality		Normal result
	Without therapy^fifty	With IV antiviral therapy¹⁹	Without therapy⁵⁰	With 4 antiviral therapy^nineteen
Disseminated disease	85%	31%	rare	83%
Cardinal Nervous System illness	50%	6%	rare	31%
Skin, eye and mucosa	0%^*	0%	62%	100%

Treatment of Neonatal Canker

Antiviral therapy with intravenous acyclovir reduces bloodshed to xxx percent in infants with disseminated illness and to 6 percent for those with CNS disease (Tabular array 3). Recommended doses are acyclovir twenty mg/kg torso weight intravenous every eight hours for 21 days for disseminated and CNS disease²¹ and for 14 days for disease limited to the pare and mucous membranes. Many experts too recommend the 14 twenty-four hour period regimen for asymptomatic infants born to women who acquired HSV near term. Acyclovir is superior to vidarabine, the only other antiviral that has been systematically evaluated for neonatal HSV. Transient neutropenia has been noted in near twenty% of infants treated with these high doses of acyclovir, simply has non been reported to consequence in clinically pregnant agin outcomes.^twenty Rare cases of acyclovir-resistant neonatal HSV have been reported.

Prevention

Neonatal HSV is as astringent a illness as other neonatal infections for which prevention strategies have been implemented and remains ane of the most serious neonatal infections (Table three). Recent reports in the medical and popular printing document an ongoing controversy about best management for the prevention of neonatal HSV infection, with various and sometimes opposite conclusions.²⁴ ^– ²⁸ Every bit this is an surface area of mutual misunderstanding, nosotros volition review these issues.

Preventing Neonatal HSV past Reducing Acquisition of HSV-1 or -2 in Late Pregnancy

Development of a vaccine that prevents acquisition of HSV-1 and HSV-ii infection would be the nearly effective strategy to reduce neonatal herpes. However, at nowadays such a vaccine is not available. Protective immunity confronting HSV is incompletely understood, and the commonly used animal models – mice and guinea pigs – reflect simply sure aspects of human HSV infections accurately. This has limited development of candidate HSV vaccines. Prior investigational vaccines have lacked efficacy against HSV-2 infection in clinical trials; a single-antigen recombinant vaccine showed partial efficacy confronting HSV-2 disease but demonstrated only marginal efficiency in reducing HSV-ii acquisition amidst seronegative women. An additional Phase 3 trial with this production is underway. An constructive HSV-2 vaccine for significant women would need to prevent subclinical reactivation of HSV at the time of delivery to impact neonatal herpes.

Non vaccine proposed strategies to reduce acquiring HSV during pregnancy include (ane) counseling all women to avert unprotected sexual intercourse and unprotected oral-genital contact in late pregnancy, (2) HSV serological testing of women to identify those at risk of conquering and (3) HSV serological testing of women and partners to place those with discordant serological status. These strategies rely on sexual behavior modify by pregnant women at hazard. Advocates of abstinence in tardily pregnancy emphasize its universal applicability and low cost. However, this does non address women with prior HSV-ii infection which constitute from 30 to 60 percent of most obstetrical practices. Moreover, abstinence is an approach that alone is untested, and studies of abstinence in other situations shed dubiety on its effectiveness.²⁹ ^, ³⁰

Identification of women equally high-risk for manual of HSV to the neonate on the basis of demographic or clinical characteristics is a potentially toll-effective strategy; this approach is initially adopted for hepatitis B, HIV and Group B Strep testing in pregnancy. A recent population-based case control study using Washington State information on neonatal HSV infection indicated that demographic or clinical characteristics could non differentiate women at high gamble of transmitting HSV to their infants, suggesting such an arroyo is not likely to be constructive.³¹ Similarly, universal testing is at present recommended for hepatitis B, HIV and Group B strep in pregnancy.

Type-specific HSV serological testing to place women at adventure of acquiring genital canker near term also has been advocated as a potential prevention strategy. Cognition of HSV status in women at special risk of acquiring infection near term may allow more constructive counseling of take chances reduction behavior, such every bit abstinence or protected coitus in the terminal trimester in combination with no oral-genital contact (cunnilingus). Surveys show that women are interested in testing for HSV during pregnancy, and psychosocial distress resulting from unexpectedly testing HSV-2 seropositive is small and transient.³² ^, ³³ Serologic identification of infection condition is widely advocated and has been successful for HIV prevention in the U.S. and Africa.³⁴ ^, ³⁵ Disquisitional to the knowledge of serologic status is the effectiveness of strategies that target pregnant women identified as HSV-2 seronegative. Condoms appear to be 50 pct effective in reducing the take a chance of HSV transmission from men to women, and from women to men.³⁶ Valacyclovir therapy of those with HSV-2 also has reduced the run a risk of sexual transmission to the susceptible partner by 48 per centum.³⁷ Even so, pregnancy may increase susceptibility to acquisition of HSV infection; information technology is unknown whether the utilize of condoms or antiviral therapy of the sexual partner with HSV-2 will have similar effects in HSV-two seronegative significant women.³⁸

Serological testing of both the meaning woman and her partner has also been suggested. This strategy allows identification of 12 to 20 percent of situations in which the partner is HSV seropositive and the pregnant woman is seronegative (and at run a risk for infection).³⁹ ^, ⁴⁰ This approach may be expensive and not applicable when there is considerable partner change during pregnancy. Yet, the advantage of such an approach is that it targets the high-risk couples for intensive behavioral strategies, including consequent condom use. It besides is the approach most acquiescent to the use of antiviral therapy in the HSV-2 infected male partner. There are no clinical trials to define if identification of discordant couples by serologic testing will reduce incident maternal HSV infection, and such trials are needed.

The aforementioned approaches address reducing incident HSV-2 infection. As neonatal HSV-1 infection comprises 30 to 50 percent of neonatal herpes,⁴¹ attention to the role genital HSV-1 plays in neonatal infection seems prudent, especially as commercial assays for defining antibiotic status are bachelor for both HSV-1 and HSV-two. We are unaware of any studies that take examined prevention strategies for genital HSV-i.

Reducing Neonatal Herpes in the HSV-ii Seropositive Woman

Blazon-specific HSV-2 serological testing during pregnancy can identify women who are HSV-2 seropositive but who accept unrecognized genital herpes. Knowledge of HSV-ii may touch on obstetrical management to reduce the risk of transmission of infection, such equally decreasing the utilise of invasive monitoring devices (Figure 2); a public health reward of such an approach is less clear. Diagnosis of newly recognized genital herpes and explanation of attendant risks during pregnancy (every bit well as the take a chance of transmission to sexual partners) crave considerable attempt. Approximately xx to 25 percent of patients would crave counseling about a new disease. For a practitioner who sees neonatal HSV rarely (1 in v,000 to 10,000 deliveries), this approach may be viewed as impractical. Moreover, the optimal strategy to manage women with newly identified, established genital HSV-2 in pregnancy is unclear.

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Risk of Neonatal HSV Among xl,023 Women with Genital Cultures for HSV at Delivery

The information are adapted from Brown et al.^four

Electric current guidelines recommend cesarean deliveries for women with clinical recurrent genital herpes at term (Figure 2).¹² Several small studies take shown that daily antivirals at the end of pregnancy tin reduce genital HSV recurrences and shedding at term, as well equally the need for subsequent cesarean deliveries,⁴² but take non provided insight on the potential to reduce neonatal herpes. Transmission to the neonate from women who are HSV-2 seropositive is rare; as such, one would expose a large number of mothers and neonates to antiviral therapy to forestall each example of neonatal HSV. The levels of acyclovir reached in amniotic fluid tin can be similar to those seen in infants treated with systemic acyclovir, of which upwards to xx percent develop neutropenia.²⁰ While a pharmacologic arroyo may offer potential benefit for reducing morbidity from HSV-related cesarean deliveries, widespread exposure of neonates to acyclovir has not been tested and could consequence in unnecessary toxicity. As such, routine use of antivirals in late pregnancy in HSV-2 seropositive women, especially the majority of those without a history of genital canker, should require bear witness of efficacy in reducing neonatal herpes and minimal toxicity to the infant.

Because of the morbidity to the mother, many authorities recommend that recently caused genital HSV infections in significant women should be treated with antiviral medications.¹² Acyclovir is not teratogenic and may be administered either orally to pregnant women with first episode genital herpes or intravenously to significant women with severe HSV infection. A common regimen for pregnant women with get-go episode genital canker is acyclovir 400 mg orally three times a 24-hour interval or valacyclovir 500 mg BID for 7 to 10 days. No data are available whether such therapy reduces the infection rate in the infant.

Identifying the Baby at Adventure

The isolation of HSV from the maternal genital tract at delivery is associated with >300-fold hazard of neonatal herpes.^four Other risk factors associated with conquering include fetal scalp monitors and cervical HSV infection (Figure two). Identifying HSV-exposed infants allows resources to exist focused on those at highest risk and defines a strategy that could be applied to infants born to mothers with beginning or recurrent HSV episodes. Once exposure is identified, one could initiate antiviral prophylaxis (or early expectant therapy). This arroyo requires (one) a rapid, authentic analysis to define HSV shedding at delivery, (ii) initiation of early antiviral therapy for those at risk, and (iii) conclusion of the effectiveness of the intervention to reduce acquisition of HSV or to better the upshot of infected infants (Table iii).

Rapid PCR assays have been developed for many diseases, implemented in field hospitals and used for testing samples from women in labor.⁴³ ^, ⁴⁴ In add-on, indicate-of care tests to place HSV-2 specific antibodies have been adult and are commercially available, assuasive clinicians to define the risk of neonatal infections as high (seronegative female parent) or depression (seropositive female parent)—a factor that many authorities use in determining if systemic acyclovir prophylaxis should be administered.⁴⁵ At present, piddling data exist to guide optimal intervention for managing infants exposed to HSV at nativity. Employ of antiviral prophylaxis has been quite effective in preventing HSV-ane or HSV-2 infection in neonatal animal models.⁴⁶ One recommendation for infants built-in to mothers shedding HSV-two at term is to follow them with sequential sampling for virus in urine and on the mucosa in conjunction with close clinical follow-up for sign of disease and to initiate systemic therapy if HSV infection is present.²¹ This approach could upshot in early initiation of therapy for those with neonatal HSV, which is a major determinant of favorable outcome.¹⁹ ^, ²⁰ ^, ⁴⁷ Thus, the identification and observation of exposed infants would at to the lowest degree provide "best practices" monitoring. Alternatively, antiviral therapy could exist initiated at nascence in infants whose mothers lacked HSV antibody, as their risk of invasive disease is high. Infants born to women with antibodies to the viral blazon detected could exist closely followed. These approaches, while potentially attractive, need to be empirically evaluated.

In summary, whether acquired by HSV-1 or HSV-2, neonatal HSV infection is astringent and persistent in the U.S., exceeding in incidence other infectious diseases for which nationwide prevention strategies exist. The tools to devise better prevention strategies have been developed, and several strategies to conceptually reduce infection have been outlined. Current guidelines by the American College of Obstetrics and Gynecology provide useful patient management tools merely are not directed at neonatal HSV prevention and announced not to have altered the epidemiology of neonatal HSV in the U.S. in the concluding decade.¹² A concentrated effort to conduct studies that may provide guidance to effectively reduce neonatal canker is needed and will require an brotherhood between practitioners and academicians.

Acknowledgments

Grant Acknowledgement and Contributions

Supported past grants PO1 AI-30731, R37 AI-42528, and CA-15704. LC and AW discussed the content of the Tables, Figures and text. LC wrote the first typhoon of the newspaper, which was then critically revised by both authors.

Footnotes

Conflict of Interest

Dr. Corey is director of the University of Washington Virology Division, which has received grant back up from GlaxoSmithKline, a company that make antiviral drugs for the handling of HSV-2. Dr. Corey receives no salary support from these studies. He is a consultant for Aicuris, which is developing a drug for treating HSV infection. Dr. Corey is a co-inventor on several patents describing antigens/epitopes to which T cell responses to HSV-2 are directed. These proteins have the potential to exist utilized in candidate HSV vaccines.

Dr. Wald has received grant support from the National Institutes of Wellness, GlaxoSmithKline, Antigenics and Astellas. She has been a consultant for Aicuris and Medigene, likewise every bit a speaker for Merck Vaccines. No other potential conflict of interest relevant to this article is reported.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780322/