Congenital varicella syndrome: the evidence for secondary prevention with varicella-zoster immune globulin

The case

A 33-year-old woman who was engaged to be married presented for her initial visit with an obstetrician. Her varicella-zoster IgG antibody titer, as measured by latex agglutination, was < 0.91, which signified nonimmunity. The patient did not know if she had previously had varicella. She had not been vaccinated. Three months later, she became pregnant. She was told to avoid crowds of children and to seek vaccination after her delivery.

At 13 weeks of gestation, the patient was visited by her mother, who complained of severe pain over one side of her scalp. When the patient moved her mother’s hair to see what was causing the pain, she felt her mother’s hair to be wet to her touch and saw multiple small blisters. An immediate visit to an internal medicine specialist confirmed a diagnosis of herpes zoster infection in the patient’s mother. The patient was sent within 18 hours of her mother’s arrival and her potential exposure to zoster to her obstetrician. Varicella-zoster immune globulin (VZIG) was not given.

Three weeks later, the patient broke out in a varicella rash and was treated with acyclovir. She recovered completely. The patient then began follow-up with a maternal–fetal medicine specialist, seeking information about whether her fetus was infected with varicella and whether the fetus had congenital varicella syndrome.

Repeated sonographic examinations at 19 and 24 weeks of gestation were interpreted as showing bilateral clubfeet, with no other abnormality. Amniocentesis was not performed. At 32 weeks of gestation, ultrasonography showed intrauterine growth retardation, polyhydramnios and stippling of the fetal liver. An amniocentesis performed at that time was culture-negative for varicella virus, but results of polymerase chain reaction testing showed varicella-zoster DNA. No cytomegalovirus DNA was found in the amniotic fluid. Fetal cells showed a normal karyotype. No cause for the findings on ultrasound, other than likely congenital varicella syndrome, was found. Because of worsening intrauterine growth retardation, the baby was delivered by cesarean section at 36 weeks of gestation.

The baby was born with bilateral clubfeet, partial aplasia of the right lower extremity, microgastria, severe reflux, an absent gag reflex and profound oral aversion (i.e., refusal to feed). Over the subsequent three years, she has had repeated episodes of aspiration pneumonia and has required feeding through gastrostomy and jejunostomy tubes, a permanent tracheostomy and 24-hour oxygen therapy. She has had multiple episodes of cutaneous zoster infection and of viral and bacterial pneumonia, requiring prolonged periods on a ventilator. She has had a gastric fundoplication and surgical repair of her clubfeet. Within the last six months before time of writing, she has been found to have partial defects of both cellular and humoural immunity, with antibody responses to protein antigens but not to polysaccharide antigens, and with selective defects in cellular immunity, including subnormal cellular response to varicella-zoster virus. She continues to be unable to handle oral food or oral secretions and has experienced apneic spells, some involving loss of consciousness. She has also had episodes of cyclic vomiting, lasting hours to days, which have not been responsive to medications. The child has learned to communicate by using sign language, and she has a vocabulary of 20 words.

The patient and family launched a malpractice lawsuit, which was settled in their favour.

Congenital varicella syndrome is the result of serious infection and strikes 1%–3% of fetuses whose susceptible mothers have contracted chicken pox in pregnancy.1^,2 The greatest risk of developing congenital varicella syndrome is apparent when a nonimmune pregnant woman is infected during the thirteenth to twentieth week of pregnancy.3 Primary prevention of congenital varicella syndrome consists of effective vaccination of the mother before conception, while secondary prevention involves the use in susceptible pregnant women of varicella-zoster immune globulin, a specific IgG antibody against varicella-zoster virus, after exposure.

We systematically review the existing evidence for secondary prevention of chronic varicella syndrome by varicella-zoster immune globulin after maternal exposure to varicella-zoster virus during pregnancy.

What evidence supports prevention of congenital varicella syndrome by varicella-zoster immune globulin?

Three events must occur before a fetus contracts congenital varicella syndrome. They are clinical infection in the mother, viral infection in the fetus and development of congenital varicella syndrome in the infected fetus. We present the existing evidence synthesized into an overall estimate of the protective effect of varicella-zoster immune globulin.

What do practice guidelines recommend?

In the United States, the American College of Obstetrics and Gynecology Practice Bulletin #20, entitled “Prenatal viral and parasitic infections” and published in September 2000,17 states “If exposure does occur, prophylactic intervention with varicella-zoster immune globulin early in the incubation period can prevent or attenuate the disease manifestations of VZV in susceptible contacts at high risk from this infection.”

In the same paragraph, however, this bulletin states that “maternal administration of varicella-zoster immune globulin does not ameliorate or prevent fetal infection.” It goes further to state explicitly that “there is no protective effect.”17 In this bulletin, which contains 131 citations of the literature, there is no citation to support the assertion of lack of protective effect of varicella-zoster immune globulin. Existing evidence that prevention of clinical disease in the mother may have a protective effect on the fetus is not considered. The bulletin cites the initial Enders study3 only for the overall incidence of congenital varicella syndrome, not mentioning the protective fetal effect nor citing the later published data.5^,6

The guidelines of the Centers for Disease Control and Prevention18 include the following statement: “Because pregnant women might be at higher risk for severe varicella and complications, use of varicella-zoster immune globulin (VZIG) should be strongly considered for pregnant women without evidence of immunity who have been exposed. However, administration of VZIG to pregnant women has not been found to prevent viremia, and therefore does not prevent fetal infection, congenital varicella, or neonatal varicella. The primary indication for VZIG in pregnant women is to prevent complications in the mother rather than to protect the fetus.” Similarly, the 2008 Federal Drug Administration guidelines assert that “there is no evidence that administration of VZIG to a susceptible pregnant woman will prevent viremia, fetal infection, or congenital varicella syndrome. Therefore the primary indication for VZIG in pregnant women is to prevent complications of varicella in a susceptible adult patient rather than to prevent intrauterine infection.”19

These statements appear to contradict previous Centers for Disease Control and Prevention publications acknowledging, for at least twenty-five years, that varicella-zoster immune globulin prevents clinical symptoms in a substantial percentage of exposed patients and mitigates the disease in those in whom clinical symptoms were not entirely prevented.20

Last, the American Academy of Pediatrics has adopted the Centers for Disease Control and Prevention perspective, with similar recommendations.21

In Canada, the 2009 Practice Guidelines on Immunization in Pregnancy by the Society of Obstetricians and Gynecologists of Canada mention fetal protection by varicella-zoster immune globulin as a theoretical benefit, but do not discuss the available evidence for prevention of fetal infection.22 The guidelines state that “susceptible women should then be offered varicella-zoster immune globulin within 96 hours of exposure in an attempt to prevent the disease or reduce the severity of the infection in the mother … Although there may also be some benefit to the fetus, this remains to be investigated in a clinical trial.”21

What should clinicians do?

Prospective, randomized, double-blind, controlled studies are the gold standard in clinical science. For diseases as rare as congenital varicella syndrome, the likelihood that any such study will be sufficiently large to have the power to make absolute conclusions about the effect of varicella-zoster immune globulin is prohibitively small. Further, the available data to date on the beneficial effect of varicella-zoster immune globulin for the exposed nonimmune pregnant mother and her baby would render such a study ethically unacceptable. Given this reality, it is important for clinicians to be familiar with the available evidence, even if, on the scale of strength, it does not compare with randomized controlled trials. Although from regulatory perspectives, without appropriate clinical trials, none of the varicella immunoglobulin products can be labelled as “preventing congenital varicella syndrome,” the existing evidence should not be ignored by clinicians.

It is likely that guidelines have not made stronger statements about the effectiveness of varicella-zoster immune globulin in secondary prevention of congenital varicella syndrome because the existing evidence did not come from a randomized controlled trial. It is “off label” use, and available evidence of efficacy, effectiveness and safety should be addressed by professional societies and public health authorities.

Although the existing data on prevention of fetal infection and congenital varicella syndrome are not perfect, randomized controlled trials are unlikely to be conducted for this relatively rare medical event. The analysis presented here indicates a very high likelihood that varicella-zoster immune globulin substantially protects the fetus from congenital varicella syndrome at each of the steps in the development of final organ damage if the nonimmune mother is treated within 96 hours of exposure. Of importance, the adverse effects associated with varicella-zoster immune globulin (e.g., allergic reactions, anaphylaxis) are minimal.14

Unless guidelines are revised to reflect the inherent uncertainty in the evidence base and the fact that definitive studies are unlikely to be conducted, health care providers (and their nonimmune pregnant patients) may not appreciate the urgency of administering varicella-zoster immune globulin immediately upon reported contact with varicella. These patients and their babies may be put at avoidable risk because of assumptions regarding the ineffectiveness of varicella-zoster immune globulin in affording fetal protection.

Key points

• In 1%–2% of cases, maternal chickenpox may result in congenital varicella syndrome, which is associated with severe, lifelong disabilities.

• Evidence from prospective cohort studies suggests high rates of protection against fetal infection and congenital varicella syndrome in mothers with chicken pox who received varicella-zoster immune globulin (VZIG).

• Given advice by several major guidelines that VZIG can improve maternal morbidity but not fetal outcome, clinicians may not appreciate the urgency of giving VZIG to nonimmune pregnant patients on reported contact with varicella.

• Guidelines should be revised to reflect the available evidence on the effectiveness of VZIG in preventing congenital varicella syndrome.