Int

Varicella or chickenpox is an infectious disease caused by Varicella Zoster Virus (VZV), which commonly affects the children. It is a mild, self-limiting disease and rarely complicate to serious conditions except in adults. Decreasing incidence of chickenpox among children, probably owing to improved living conditions ,prevention and health care, is worrisome as growing number of adults are being infected. This creates disturbing concerns in many parties as women at childbearing age might get infected and not only are them at a great risk of serious complications, but also their unborn fetus or their newborn babies.

Case scenario

Case 1

A 35-year-old primigravida at 12 weeks of gestation claims that she has recently been exposed to a colleague with chickenpox and she could not recall having chickenpox before. This is her first pregnancy after 10 years of marriage. She is worried about her unborn baby and wonders if she could have vaccination to prevent the infection.

Case 2

A 27-year-old gravida 3 para 2 has been in contact with someone who is contracting chickenpox at 28 weeks of gestation. She seeks medical consultation 2 days after the exposure as she is worried of the effect on her pregnancy.

Case 3

A 25-year-old gravida 2 para 1, at 37 weeks of gestation presents with increasing frequency and intensity of uterine contractions. She is diagnosed to have chicken pox 24 hours earlier due to an eruption of generalized macular rashes following fever and cold symptoms. This is her first episode of having such infection.

Varicella or more commonly known as ‘chickenpox’ is one of the commonest infectious diseases affecting children. It is caused by the virus called Varicella Zoster Virus (VZV) or Human Herpes Virus 3 (HHV3). It is highly contagious and easily spread by air droplets and touch.

Primary infection is characterized by fever, malaise and characteristic pruritic rash that develop from papules, vesicles, pustules then crust over before healing. Generally, it is a benign self-limiting disease affecting the children, however, serious complications for instance superimposed bacterial infection, generalized encephalitis and aseptic meningitis may occur especially in adults¹. Morbidity and mortality rates are also higher in adults compared to children. Generally, the infection confers lifelong immunity; however, the virus may become dormant in the dorsal root ganglia and be reactivated decades later, when the immune system is suppressed, leading to the development of herpes zoster or shingles.

It has been reported that in most temperate climates, more than 90% of the population were infected with chickenpox before they reach adulthood²and according to Pastuszak AL et al., more than 80% of children have had chickenpox by the age of 10³. Thus most of them are immunized and protected against the infection when they reach adulthood. Of women who claimed never had chickenpox, more than 85% of them were seropositive for VZV antibodies. However, small portions of them were seronegative and therefore not protected. When they became pregnant, they were at risk of developing primary infection. About 0.07% of pregnancies had been reported to be complicated by chickenpox. Unfortunately, we do not have local figures quoted in Malaysia

When a pregnant mother is infected with chickenpox, both the mother and fetus are at risk of its complications. The maternal effects range from mild self-limiting disease to severe life threatening complications. The effects on the fetus generally differ based on the gestational period when infection occurs. The fetal effects are greatest if the infection occur during the first 20 weeks of gestation.

DIAGNOSIS

Chickenpox is usually diagnosed clinically; based on the characteristic symptoms and rashes². Prodromal symptoms include fever, malaise, headache and anorexia. The fever is usually of low grade but can reach up to 41°C⁴. The rashes initially appear on the face and trunk and progressively involve the peripheries. It begins as red macules developing into vesicles, pustules and finally crusted within 10 to 12 days. The skin lesions can be present in all stages of development concurrently. Besides these, history of recent exposure to chickenpox also helps in establishing the diagnosis.

Laboratory tests for chickenpox are rarely done and only recommended if the patient presents with atypical or complicated features and to establish immune status of high-risk individuals⁵. The virus can be detected by culture, antigen, and genome or antibody detection. Direct antigen detection by immunofluorescence or genome detection by polymerase chain reaction can be done to confirm presence of infection. Whereas, in determining the immune status, VZV IgG can be measured.

Effects of chickenpox on pregnancy

Although chickenpox is generally a benign, self-limiting viral infection, it is associated with greater morbidity in adults¹. Women who acquire chickenpox during pregnancy are at greater risks to severe complications of the infection⁶. It is shown that it is five times more prone to be fatal⁷. In studies conducted by Parvani SG and Arvin AM, approximately 21% of 43 pregnant women infected with varicella experienced serious complications⁸. The severity of the complications appears to be increasing proportionately to the period of gestation⁷.

A study conducted by Balducci J. et al. revealed that 7.5% of pregnant women infected with chickenpox during the first trimester had spontaneous miscarriage⁹ even though another study by Byrne BMP et al. reported that women infected with chickenpox during the first trimester were not at increased risk of spontaneous miscarriage⁷. It has remained controversial as to whether Varicella infection could be a direct cause of early trimester miscarriage.

On the other hand, women who contract with varicella infection during the third trimester are said to be at great risk of varicella pneumonia¹⁰. The mortality rate reported was as high as 36%. Other studies supported the conclusion that about 10 to 20% of women with chickenpox during pregnancy had varicella pneumonia and the mortality rate reached 40%¹¹.

Apart from these, research has also shown that pregnant women with chickenpox are also at risk of premature uterine contraction and premature delivery⁸. Almost 10% and 5% of 43 pregnant women infected with chickenpox had premature uterine contraction and premature delivery respectively. A study conducted by Fiqueroa DR and Arredondo GJL has found that pregnant women infected with chickenpox during the first 20 weeks of gestation had higher risk of premature labour¹².

It is recognized that fetuses to mother infected with chickenpox are at risk of congenital anomalies. This is especially of concern if the mother contracted the infection before 20 weeks of gestation^{8, 13, 14,
15}. A number of studies have shown that the fetuses are at risk of congenital varicella syndrome or also known as varicella embryopathy. This is characterized by skin scarring, eye defects; microphthalmia, chorioretinitis, cataracts, limb hypoplasia and neurological abnormalities; including cerebral atrophy, mental retardation and bowel and bladder sphincters dysfunction^{7,
11}. However, the risk is very low that most babies born to women infected with chickenpox during pregnancy are normal¹⁶. In a prospective cohort study conducted by Harger JH et al., only 1 case of infants of 347 pregnant women infected with chickenpox during pregnancy had definite congenital varicella syndrome. Of the remaining fetuses of the 346 women, one had intrauterine death at 20 weeks and one had hydrops fetalis at 17 weeks of gestation. Other study performed reported incidence of fetal omphalocoele in 1 of 36 infants following maternal varicella infection⁹.

Fetuses of mothers infected with chickenpox after 20 to 36 weeks of pregnancy are said not to be at risk of congenital anomalies⁷. However, they may develop herpes zoster or shingles after birth or later in life. Several studies supported this. In contrast, Narkeviciute I. reported that 2 of 4 infants of mothers infected with varicella during second and third trimester had developed neonatal varicella¹⁷. (See Table 1)

Neonatal Varicella is usually developed by newborns whose mothers were infected by varicella after 36 weeks of pregnancy, nearly delivery; within 5 days before or 2 days after delivery^{7, 11}. Neonatal varicella may cause fatality as high as 30%¹¹. One study showed that mortality rate of infants whose mothers had been infected with chickenpox within 5 days antepartum to 2 days postpartum was nearly 20% of the affected cases¹⁸. Transplacentally transmited varicella infection causes development of chickenpox during the first 10 to 12 days of the infants’ life. The earlier the development of the infection, the milder the disease seemed to be, whereas infection occurring after 5 and 10 to 12 days of life caused fatality as high as 23% of the affected cases.

Early trimester complications

Late trimester complications

Maternal

Spontaneous miscarriage

Varicella pneumonia

Premature deliveries

Fetal

Varicella embryopathy ie:

skin scarring, eye defects (microphthalmia,chorioretinitis, cataracts) , limb hypoplasia and neurological abnormalities

Hydrop fetalis

Neonatal varicella

Herpes zoster/shingle in newborn

Management of chickenpox during pregnancy

Pregnant women who are not immunized to VZV but exposed to the infection are advised to seek urgent treatment as it might pose great risk to both the mother and the unborn child.

Both conservative and medical treatments are important as to prevent scarring, provide as much comfort to the patient and most importantly to prevent or at least reduce severity of complications.

Regular bathing and cool compresses may be advised as it helps reduce the itchiness. Some recommended oatmeal bath to reduce the itchiness¹⁹. Patients might also need to be reminded not to scratch as this may lead to scarring of the skin. Patients are also encouraged to drink sufficiently to maintain good hydration.

Acetaminophen can be prescribed to relieve symptom of fever. Other medical treatment includes the use of zoster immunoglobulin (ZIG) and acyclovir; an antiviral agent.

Administration of ZIG should be considered in pregnant women who are exposed to the infection without prior history of chickenpox²⁰. Its use is more effective as prophylaxis rather than to treat. It is recognized to reduce the severity¹⁹ or even prevent the infection if given within 72 hours or up to 96 hours of exposure²¹. Once the infection has set its course, ZIG is ineffective. Nevertheless, ZIG does not reduce the risk of congenital anomaly, thus detailed ultrasound scan must be done to detect early fetal congenital defects²². Counseling to the pregnant mother with chickenpox regarding the risks of fetal defects is also as important.

Once the infection is established, oral acyclovir can be given to prevent further development of the disease²¹. It has to be administered within 24 hours of the onset of the rash. It is also used as a prophylaxis for pregnant women with underlying risk factors; such as chronic lung disease, on systemic corticosteroid treatment, immunocompromised or cigarette smoker²². At any stage of pregnancy, if the women developed complications as a result of the infection, intravenous acyclovir should be given. Acyclovir is believed to shorten the duration of the illness due to chickenpox.

As have been mentioned earlier, pregnant women infected with chickenpox at later stages of pregnancy; after 36 weeks of gestation, are at risk of having babies with neonatal varicella¹¹.

The timing of maternal infection in relation to delivery determines the risk to the newborn babies²². If the mother is infected with chickenpox more than 7 days before the delivery, there might be adequate passage of specific VZV antibody transplacentally and thus confers some protection to the infants. Thus the resulting neonatal varicella might not be as severe as if the onset of the infection is less than 7 days before the delivery or 2 days after delivery.

ZIG is recommended to be given to the newborns of mothers who contracted the infection within 7 days before or 28 days after delivery. It should be given immediately after delivery or within 72 hours of exposure. This may help to prevent or suppress development of the infection. Intravenous acyclovir should be administered to infants with chickenpox, who are unwell, regardless whether they had received ZIG, any newborns with underlying risk factors whom has not received ZIG or received the prophylaxis after 24 hours exposure and to immunocompromised newborns who developed chickenpox. (See Table 2)

Drugs	Indications
Acetaminophen	Relieve symptom ie: fever
Zoster immunoglobulin (ZIG)	Prophylaxis for women who have had exposure within 72 – 96 hours to the infection Prophylaxis to newborn immediately after delivery up to 72 hours
Acyclovir	Treating infection by shortening the duration of the illness and prophylaxis to severe complications in mothers. Treating unwell newborns due to chickenpox Newborns with risk factors but did not receive ZIG on time Immunocompromised newborns who are infected.

Mothers or babies with active disease should be separated from the others to prevent spread of infection, but the infected mothers need not be separated from their own baby in fact they should be encouraged to breastfeed them.

Effects of anti-viral therapy on pregnancy

Acyclovir; an antiviral drug is usually used in the treatment of chickenpox among adolescents and adults as the infection is more severe in these groups compared to young children. In addition, acyclovir is also recommended to be given to neonates, immunocompromised and pregnant women, as varicella infection may be life threatening among these individuals²³. Prompt administration of acyclovir is believed to limit the spread of the virus to visceral organs²⁴.

However, it is known that acyclovir crosses placenta²⁵, therefore, there were some concerns regarding the use of acyclovir in pregnant women as it may cause fetal defects. Some believe the adverse effects of acyclovir on the growing fetus thus do not recommend the use of this drug in pregnant women²⁶.

However, no studies have reported such incidence²². Spangler JG et al. reported no increased risk of adverse effects of acyclovir in pregnant women with varicella pneumonia²⁵. Research conducted using pregnant rabbits and rats also proven that acyclovir was not teratogenic in the laboratory animals.

Moreover, it is important to treat severe systemic maternal varicella and varicella pneumonia with acyclovir as this contribute to a significant number of maternal mortality²⁸although it is not certain if acyclovir therapy prevents congenital varicella syndrome in newborns of maternal varicella²⁷,

Prevention with vaccination (Zoster Immunoglobulin)

Chickenpox may be prevented by the administration of varicella vaccine or varicella zoster immunoglobulin (ZIG).

ZIG is a life-attenuated vaccine, which has been proven effective in 70 to 100% of cases²⁹. It confers life-long protection against chickenpox. It is safe and the only associated undesirable effects are mild pain and redness at the injection site¹¹. It is recommended to be given to all women planning to become pregnant and proven to be seronegative.

Varicella ZIG is a blood product that contains high levels of chickenpox antibodies. It causes the infection to be less severe and in some cases, it might help preventing the infection. Though it is not proven if it confers protection to the fetus against intrauterine varicella infection, it is safe to be used in pregnant women, as it is not teratogenic.

Varicella ZIG is recommended as post exposure prophylaxis in high- risk individuals; including pregnant women, immunosuppressed individuals and to newborns of mothers who contracted chickenpox within 5 days before or 2 days after delivery²⁴(See Table 2). It is effective if administered within 72 hours or up to 96 hours of exposure²². One study has shown that of 97 pregnant women who had maternal varicella infection, none of them had babies with congenital varicella syndrome after the administration of varicella ZIG³⁰.

CONCLUSION

It is well recognized that adults infected with chickenpox are subjected to a significant number of morbidity and mortality compared to children. Chickenpox during pregnancy should trigger overwhelming concerns to the patients and healthcare providers due to its implications on the fetus ie: congenital defects. Therefore, pregnant women who are exposed to the infection especially for the first time should receive appropriate attention and care for early treatment and surveillance to prevent serious complications that may lead to fatality. Time of infection in relation to the period of gestation and time of delivery are the factors that determine the severity of the infection to the mother and the fetus. Although many studies showed that only small percentage of fetuses of infected mothers had congenital anomalies, it is important not to overlook the possibilities of severe complications in either of them. With great awareness and proper health care, significant morbidity as well as mortality can be prevented.

Key points

REFERENCES

1. Stride PJO, Coulter C, Campher MJJ, Duhig EE, Geary JM. Adult chickenpox complicated by fatal necrotising pneumonia. The Medical Journal of Australia. 2004; 181 (3): 160-1

3. Pastuszak AL, Levy M, Schick B, Zuber C, Feldkamp M, Gladstone J, Levy FB, Jackson E, Donnenfeld A, Mecschino W, Koren G. Outcome After Maternal Varicella Infection In The First 20 Weeks Of Pregnancy. The New England Journal of Medicine. 1994; Vol 330: 901-905]

4. Lissauer T, Claydem G. Infection and immunity. Illustrated Textbook of Paediatrics, 2^nd Edi. Mosby; 191-3

5. Dwyer DE, Cunningham AL. Herpes simplex and varicella–zoster virus infections. The Medical Journal of Australia. 2002; 177 (5): 267-273

6. Bull DT. Chickenpox, pregnancy and the newborn. MedScape Today. 2005; 43(9): 69-72

7. Byrne BMP, Crowley PA, Carrington D. Chickenpox In Pregnancy. Royal College of Obstetricians and Gynaecologists; Guideline No.13, Revised 2001

8. Parvani SG, Arvin AM. Intrauterine infection with varicella zoster virus after maternal varicella. The New England Journal of Medicine. 1986; 314(24): 1542-6

9. Balducci J, Rodis JF, Rosengren S, Vintzileos AM, Spivey G, Vosseller C. Pregnancy outcome following first trimester varicella infection. Obstetric Gynaecology. 1992; 79(1): 5-6

10. Koren G. Congenital varicella syndrome in the third trimester. The Lancet. 2005; 366:1591-92

11. Seidman DS, Stevenson DK, Arvin AM. Varicella vaccine in pregnancy. British Medical Journal. 1996; 313: 701-2

12. Fiqueroa DR, Arredondo GJL. Perinatal outcome of pregnancies complicated with varicella infection during the first 20 weeks of gestation. American Journal of Perinatology. 1997; 14(7): 411-4

13. Schulze OF, Roth B, Enders G, Grosser R. Congenital varicella syndrome- Is it infectious? Birth Aid Neonates. 2004; 208(1):25-28

14. Sauerbrei A. Varicella zoster virus infections in pregnancy. Intervirology. 1998; 41(4-5): 191-6

15. Huang YC, Lin TY, Wong KS, Chiu CH. Congenital anomalies following maternal varicella infection during early pregnancy. Journal of Formos Med Association. 1996; 95(5): 393-5

16. Harger JH, Ernest JM, Thurnau GR, Moawad A, Thom E, Landon MB, Paul R, Miodovnik M, Dombrowski M, Sibai B, Van Dorsten P, McNellis D. Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women. Obstetric Gynaecology. 2002; 100(2): 260-5

17. Narkeviciute I. Consequences of varicella in pregnancy: A report of 4 cases. Acta Paediatrica. 2007; 96 (7): 1099-1100

18. Sauerbrei A, Wutzler P. Neonatal Varicella. Journal of Perinatology. 2001; 21(8): 545-9

19. Parmet S, Lynm C, Glass RM. Chickenpox. The Journal of the American Medical Association. 2005; 294 (7): 866

20. Gilbert GL. Infections in pregnant women. The Medical Journal of Australia. 2002; 176(5): 229-36

21. Mohsen AH, McKendrick M. Varicella Penumonia in Adults. European Respiraory Journal. 2003; 21: 886891

22. Heuchan AM, Isaacs D. The management of varicella zoster virus exposure and infection in pregnancy and the newborn period. The Medical Journal of Australia. 2001; 174: 288-292

23. Balfour HH. Antiviral drugs. The New England Journal of Medicine. 1999; 340: 1255-68

24. Prober CG, Kirk LE, Keeney RE. Acyclovir therapy of chickenpox in immunosuppressed children -- a collaborative study. The Journal of Paediatrics. 1982; 101: 622-5

25. Spangler JG, Kirk JK, Knudson MP. Uses and safety of acyclovir in pregnancy. Journal of Family Practice. 1994

26. Gilbert GL. Infections in pregnant women. The Medical Journal of Australia. 2002; 176(5): 229-36

27. Fox GN, Strangarity JW. Varicella-zoster virus infections in pregnancy. Am Fam Physician 1989; 39: 89-98

28. Prober CG, Gershon AA, Grose C, McCracken GH, Nelson JD. Consensus: varicella-zoster infections in pregnancy and the perinatal period. Journal of Pediatric Infectious Disease. 1990; 9: 865-9

29. Chartan FB. Chickenpox vaccine gets approval in US. British Medical Journal. 1995; 310: 824

30. Enders G, Miller E, Cradock-Watson J, Bolley J, Ridehalgh M. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994; 343 (8912): 1548-51

ABSTRACT