Clinical Approach to Infections in Pregnancy Vineet Mishra, Madhuri Chandra
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Overview: Impact of Viral Infections on Mother and FetusCHAPTER 1

K Aparna Sharma,
Alka Kriplani
 
CASE SCENARIO
A 23-year-old primigravida presents at first 16 weeks of pregnancy for an antenatal check-up. She gives a history of fever with nonvesicular rash early in pregnancy. What would be the further course of management?
  • Consider causes of nonvesicular causes in pregnancy
    • Parvovirus B19
    • Rubella
    • Measles
  • Clinical work-up
    • Full demographic details
    • Gestation of pregnancy (date of last menstrual period)
    • Date of onset, clinical features, type and distribution of any rash illness
    • Past relevant history of infection
    • Past relevant history of antibody testing
    • Past relevant history of vaccine administration (and dates/places)
    • Any known contacts with rash illness, and dates of contact
  • Laboratory work-up
    The following scenarios can arise:
    • The laboratory tests revealed a rubella IgG positive: The patient could be rubella immune but in view of the history of rash more than 4 weeks previously, she could have become IgM negative.
    • Measuring the strength of binding of specific IgG (avidity) can be advised. IgG avidity is low soon after a primary infection, but matures over a few weeks to become more strongly binding.
    • The laboratory tests revealed a rubella IgM positive: No pregnant woman should have rubella diagnosed on the basis of a single positive rubella specific IgM alone. Results must be interpreted in relation to full clinical and epidemiological information. Unless seroconversion has been shown, further testing by alternative rubella specific IgM tests, testing an acute sample and a sample taken 10–14 days later for rubella IgG is advised.
2
 
OBJECTIVES
  • To know current prevalence rates of various viral infections in India.
  • The incidence of infection in pregnancy.
  • The effect of pregnancy on the viral infection.
  • The risk of maternal to child transmission in context of period of gestation.
  • The consequences of congenital or perinatal infection.
 
INTRODUCTION
Viral infections in pregnancy have an impact on the health of the mother and the baby. Apart from causing maternal morbidity and mortality, the baby can be affected through a transplacentally acquired infection, infection in the intrapartum period or in the neonatal period. Maternal infections in pregnancy may be transmitted to fetus, resulting in congenital malformations if the insult occurs during the period of organogenesis. The extent of damage depends on the virulence of infecting agent, whether it is a primary infection, maternal immunity status, gestational age and the route of infection.
Understanding the extent of fetal and maternal affection can be better if they are categorized as causing:
  • Predominantly fetal affection including congenital malformations [cytomegalovirus (CMV), genital herpes, varicella zoster and rubella)]
  • Both fetal and maternal affection (HIV, HBsAg, HCV)
  • Predominantly maternal affection (HEV, influenza).
An overview in terms of epidemiology in the Indian context and extent of fetal and maternal affection is the key understanding to the importance of these infections and to plan further management strategies.
 
PREDOMINANTLY FETAL/NEONATAL AFFECTION
This category covers infections such as TORCH which are essentially asymptomatic in the mother or cause a fleeting manifestation of fever with rash. They can have long-term implications on the fetus in terms of congenital infections, malformations, intrapartum or neonatal fetal affection depending on the gestational age of exposure. Classically the term TORCH infections have involved toxoplasmosis, rubella, cytomegalovirus, herpes and others. The other category includes treponema pallidum, varicella-zoster virus (VZV) and parvovirus B19.
The relative predilection to in utero affection or postnatal affection summarized in (Table 1.1).
 
Diagnosing TORCH Infections in the Pregnant Women
Paired serological tests are most helpful, when the first sample has been drawn during clinical illness. The second sample is drawn 4 weeks later and rise in titer or otherwise is used to interpret the test results and diagnosing infection (Table 1.2).3
Table 1.1   Relative predilection to in utero/postnatal affection
Pathogen
Congenital
Perinatal
Toxoplasma gondii
+++
+
Treponema pallidum
+++
+
Varicella-zoster virus
++
++
Parvovirus B19
++++
0
Human immunodeficiency virus type 1
+
+++
Rubella virus
+++
+
Cytomegalovirus
+
+++
Herpes simplex virus
+
+++
Table 1.2   Interpretation of TORCH serology
IgG Negative
IgM Negative
Unexposed/Susceptible/Unvaccinated (Rubella)
IgM positive
IgG negative
Acute infection or primary infection
IgM antibodies known to cross-react and hence false positive report can occur
Repeat serology: IgM decreasing or negative with IgG positive indicative of acute infection
IgM negative
IgG positive
Past infection
Timing of past infection can be determined by the avidity test
High avidity: Infection before 3 months
Low avidity: Infection within 3 months
Depending on the gestational age, fetal affection can be predicted
 
Common Infections
 
Genital Herpes
Prevalence: An estimated 536 million people aged 15–49 are infected with the herpes simplex virus type 2 (HSV-2) worldwide.1 Five percent of all women of childbearing age report a history of genital herpes and up to 30% women receiving obstetric care have serologic evidence of past HSV infection.
Indian data: Studies from India2 revealed a seroprevalence of HSV-2 to be 7.5–8.5%. A relatively low prevalence of HSV-2 seropositivity suggest that type specific serotesting may be better strategy for diagnosing clinically asymptomatic infections.
Maternal affection: The predominant symptom of the disease is genital lesions, but a majority of infected individuals experience no symptoms or mild ones that are often unrecognized.
Fetal affection: HSV-2 infection in pregnancy has been associated with premature delivery, low-birth weight infants, fetal malformations, and vertical transmission of the virus during childbirth.34
Transmission: While neonatal herpes occurs in less than 1% of prevalent infections, the risk of transmission increases to 25–50% among women infected during pregnancy. In addition, it is estimated that prevalent HSV-2 infection is associated with a 2- to 4-fold increased risk of HIV-1 acquisition.4
Neonatal affection: Although both HSV-1 and HSV-2 may cause neonatal herpes, HSV-2 is responsible for 70% of cases. Neonatal herpetic infection is defined as infection within 28 days of birth. About 90% of infections are perinatal transmitted in the birth canal. HSV infection acquired in this manner carries a 70% risk of dissemination. Approximately 10% of infections are congenital, usually a consequence of the mother acquiring primary HSV infection during pregnancy and the fetus acquiring the infection transplacentally.
 
Varicella-zoster
Prevalence: The incidence of varicella infection during pregnancy is estimated to be 1–5 cases per 10,000 pregnancies in the temperate areas such as Europe and United States.5
Indian data: In a study on the seroprevalence of varicella-zoster from India,6 it was found that there was a progressive increase in seroprevalence with age, 16% in 1–4 years to 72% between 15 and 24 years. This means that in tropical countries, a high proportion of pregnant women and their infants are susceptible to varicella-zoster virus (VZV).
Maternal affection: Primary varicella infection during pregnancy is associated with significant maternal and fetal morbidity and mortality. Approximately 10–20% of pregnant women who are infected with varicella will develop pneumonia, which carries a mortality rate of up to 40%.
Fetal affection: Fetal morbidity and mortality is related to the development of congenital varicella syndrome. This syndrome is characterized by limb hypoplasia, microcephaly, hydrocephaly, cataracts, intrauterine growth restriction, and mental retardation.7
Transmission: The risk of congenital varicella syndrome ranges from 0.4 to 2% with maternal varicella infection during the first 20 weeks of gestation.
Neonatal affection: Neonatal infection may occur in 10–20% of neonates whose mothers became acutely infected from 5 days before delivery to 2 days after the delivery.
 
Cytomegalovirus
Prevalence: Cytomegalovirus (CMV) is a widely prevalent infection among humans and is the most common congenital viral infection with a birth prevalence. It is the most common cause of nongenetic hearing loss in the post-rubella era and a common cause of developmental delay.5
Indian data: In different parts of India, serological survey have shown 80–90% prevalence of CMV IgG antibodies in women of childbearing age.8
Fetal affection and transmission: The risk of seroconversion in pregnancy is 2-2.5%. Primary infection more commonly is transmitted to the fetus and has a more severe fetal affection as compared to the secondary infections. The Flow chart 1.1 shows the relative risk of fetal and neonatal affection.9
 
Rubella
In adults, rubella is a self-limited disease characterized by rash. The infectious period is from 7 days before to 7 days after rash onset.
Prevalence: According to Indian data in a seroprevalence study of rubella in and around New Delhi, India, it was found that, approximately 10–15% of women reached childbearing age without developing immunity against rubella virus and were at high risk of contracting infection during pregnancy.10
Maternal affection: Although rubella is asymptomatic in 25–50% of cases, some individuals may experience mild prodromal symptoms such as low-grade fever, conjunctivitis, sore throat, coryza, headaches or malaise, and tender lymphadenopathy.
Fetal affection: Pregnancy outcomes as a result of maternal rubella infection include spontaneous abortion, fetal infection, stillbirths or fetal growth restriction and the congenital rubella syndrome (CRS) with the classical triad of sensorineural deafness, eye abnormalities such as microphthalmia cataracts and congenital heart disease—especially pulmonary artery stenosis and patent ductus arteriosus.
zoom view
Flow chart 1.1: Risk of fetal and neonatal affection in cytomegalovirus (CMV)
6Transmission: When maternal infection occurs in the first trimester, fetal infection rates are up to 50%, dropping to <1% after 12 weeks. Diagnosis of primary maternal infection should made by serologic tests. Diagnosis of fetal infection includes detection of fetal serum IgM (but not until after 22–24 weeks of gestation) or viral culture of the amniotic fluid.
Neonatal affection: About 3–10% of suspected CRS cases are ultimately proven to have confirmed CRS with the aid of laboratory tests. CRS accounts for 10–15% of pediatric cataract.
 
TORCH Infections in the Current Perspective (Table 1.3)
Various factors have influenced the epidemiology of TORCH infections in the current times.
  • Availability of vaccines: Rubella and varicella vaccines have significantly decreased the susceptible population in the reproductive age group and provide an option for primary prevention against these infections.
  • Availability of treatment for infections like toxoplasmosis and CMV have decreased the spectrum of neonatal manifestations of these diseases.
Table 1.3   Summarizing the fetal and neonatal affection in TORCH infection
Fetal affection
Neonatal affection
Diagnosing fetal/neonatal affection
1st trimester
2nd and 3rd trimester
Rubella
50% fetal affection
<1%
3–10% have confirmed CRS
AF culture
Fetal serum IgM
Varicell-zoster virus
2% fetal affection (up to 20 w) limbs, eyes and CNS
Peripartum neonatal varicella (20% affection)
Untreated mortality rate of 30%.
Chorionic villi sampling and fetal blood sampling for the detection of the viral DNA
Viral DNA can be detected in tissue samples by PCR
HSV-2
10% congenital due to primary HSV infection during pregnancy
90% perinatal transmitted in the birth canal
Neonatal affection with:
primary infection 30–50%,
recurrent infection 1–3%
Skin, eye, and mouth infection is usually detectable in 24–36 hours by viral cultures.
Encephalitis by culture of CSF or, more sensitively, by DNA detection by PCR
Cytomegalovirus
50% fetal affection following primary infection
Asymptomatic viral shedding after reactivated infection
Symptomatic: 50–60% CNS involvement
Asymptomatic: 10% eventually have CNS manifestations
Congenital disease: Culture the virus in body fluid in first 3 weeks of life
7
  • Increasing awareness, better serological and viral-based techniques are available which can diagnose the fetal and neonatal infection more accurately.
    In view of the changing dynamics, it is most important to understand when to order a TORCH test in a pregnant woman so as to justify the investigation being done and provide a possible treatment to the mother.
  • Routine TORCH screening in pregnancy should not be advised.
  • TORCH infections be suspected in:
    • Symptomatic woman with history of fever with nonvesicular rash/genital lesions.
    • Systematic manifestations
    • Fetal manifestations
      • Fetal hydrops
      • Fetal brain lesions
      • Unexplained intrauterine growth restriction (IUGR)
      • Other sonographic markers of fetal infection.
 
BOTH MATERNAL AND NEONATAL AFFECTION
 
HIV
Prevalence: India has the third largest HIV epidemic in the world.11 In 2013, HIV prevalence in India was an estimated 0.3%. India's Prevention of Parent to Child Transmission of HIV/AIDS (PPTCT) programme started in 2002. Based on 2013 WHO Guidelines,12 the program aims to initiate antiretroviral treatment for all pregnant and breastfeeding women living with HIV regardless of CD4 count or stage of HIV infection.
Maternal affection: Most infections in pregnant women are diagnosed for the first time during antenatal screening and are mostly asymptomatic. Even those women who have been diagnosed as HIV positive prior to pregnancy, should be started on cART for the prevention of mother-to-child transmission and not for their own health.
Fetal affection and transmission: HIV can be transmitted from an HIV-positive woman to her child during pregnancy, childbirth and breastfeeding. Mother-to-child transmission (MTCT) accounts for over 90% of new HIV infections among children. With no treatment, the risk of vertical transmission is as high as 25–40%, but with the implementation of universal antenatal HIV testing, counseling, maternal antiretroviral medication and neonatal postexposure prophylaxis for newborns of women with HIV, delivery by cesarean section prior to onset of labor, and discouraging breastfeeding, the mother-to-infant transmission has decreased to less than 5%. The Option B+ advocated by WHO in 2015 has been adopted by National AIDS Control Organization (NACO) where all the pregnant and breastfeeding women are advised to take lifelong triple drug therapy for prevention of maternal to child transmission even if not for their own health. Also, women on cART are counseled to breastfeed in resource limited settings where the formula feeding practices are less than ideal. Due to limited vaginal birth after 8cesarean (VBAC) and operative facilities, NACO advocates that cesarean sections be done for obstetric indications only in HIV positive women.
 
Hepatitis B
Prevalence: It is estimated that 5% of the world's population is chronically infected with hepatitis B.13 In India, the HBsAg prevalence rate among pregnant women varies between 0.9% and 11.2%.14
Maternal affection: Acute HBV infection during pregnancy usually is mild and not associated with teratogenicity or mortality. Unless the patient has acute liver failure or protracted severe hepatitis, antiviral therapy is usually unnecessary.
Fetal affection and transmission: Without immune prophylaxis, in mothers who are both HBsAg and HBeAg positive, the risk for transmission to the baby is between 70% and 90% by 6 months of age, whereas in the case of mothers who are HBsAg positive, but HBeAg negative, it is less than 10%. The transmission can be minimized by starting antiviral therapy in appropriately selected patients as shown in Flow chart 1.2.
Neonatal and future implications: The risk for development of chronic hepatitis B infection varies inversely with the age at which infection occurs, 90% of affected infants develop chronic infection as opposed to 30–50% of under-five children and 6% of children above five years of age.
zoom view
Flow chart 1.2: Overview of management of HBV in pregnancy
9Chronic hepatitis B infection acquired in childhood carries a 25% risk for development of chronic liver disease, cirrhosis or hepatocellular carcinoma.
 
Hepatitis C Virus Infection
Prevalence: The seroprevalence of hepatitis C antibodies in an antenatal population in India was found to be of 0.3%.15 The highest prevalence of infection occurs among individuals of reproductive age.
Maternal affection: Hepatitis C is mostly asymptomatic in pregnant women and they have an uneventful pregnancy outcome usually and vertical transmission is the greatest concern.
Fetal affection and transmission: The mechanism underlying vertical transmission is poorly understood. Overall the transmission rate appears to be less than 2%, however, certain conditions predispose to a higher rate of infection rate.
 
PREDOMINANTLY MATERNAL AFFECTION
 
Hepatitis E Virus
Prevalence: In India, hepatitis E is the most common cause of acute hepatitis in adults.16 Many studies17,18 have reported that HEV is responsible for 58% and 62% of cases of acute viral hepatitis in pregnant women, respectively.
Maternal affection: Mortality rates among pregnant women, especially those infected in the 3rd trimester, have ranged between 5% and 25%. A significant proportion of pregnant women with acute hepatitis E (up to 70%) progress to acute liver failure.
Fetal affection and transmission: Vertical transmission of HEV infection from mother to infant, although rare, has been reported.
Hepatitis E in pregnancy is also associated with high rates of spontaneous abortion, intrauterine death, and preterm labor.
 
Influenza
Influenza is an acute, viral respiratory infection that causes significant morbidity and mortality among high-risk groups such as pregnant women and infants.
Prevalence: Pregnant women have been observed to be at an 18-fold higher risk of hospitalization as compared to healthy nonpregnant women and the risk is greatest among women in later stages of pregnancy.19
Gunasekaran20 et al. found that a higher proportion of pregnant women were positive for both seasonal influenza (11.1% pregnant women versus 1.4% nonpregnant women) and influenza A/H1N1pdm09 (21.4% pregnant women versus 2.7% nonpregnant women).10
Maternal affection: Pregnant women with coexisting medical conditions such as asthma or diabetes are at 3–4 times greater risk of morbidity as compared to non-pregnant control subjects with similar high-risk conditions. Overall mortality among pregnant females who developed influenza-associated pneumonia can be around 25% which can exceed 50% if the affection occurs in 3rd trimester of pregnancy. In view of the extensive spectrum of morbidity and the high mortality influenza vaccination which significantly decreases the severity of affection without any adverse consequences on the fetus should be more widely propagated and availed.
Fetal affection: Influenza infection among pregnancy is also linked to adverse pregnancy and birth outcomes. Newsome and colleagues reported that among severely ill pregnant women hospitalized for pandemic influenza A (pH1N1), 63.6% delivered preterm and 43.8% delivered low-birth weight infants.21
Neonatal affection: Among young infants, influenza infection may present with fever and other nonspecific symptoms such as irritability, reduced oral intake, dyspnea, vomiting, and diarrhea.

KEY POINTS

  • Viral infections in pregnancy have an impact on the health of the mother and the baby.
  • The extent of fetal and maternal affection, depends on the virus, the term of gestation, the individual immunity.
  • Certain viruses have a mild illness in mother, but devastating consequences in the fetus, either by causing congenital malformations or neonatal affection such as CMV, genital herpes, varicella-zoster and rubella.
  • Others may cause both fetal and maternal affection, e.g. HIV, HBsAg and HCV.
  • While HEV and influenza in pregnancy, have a stormy course and are associated with significant maternal morbidity and mortality.
MULTIPLE CHOICE QUESTIONS
1. Maternal rubella >20 weeks, has no significant risk to fetus:
  1. True
  2. False
2. Neonatal herpes can be caused by:
  1. HSV 1
  2. HSV 2
  3. HSV 1 and HSV 2
3. Nearly all cases of neonatal herpes result from direct contact (during delivery) with infected maternal secretions:
  1. True
  2. False
4. Cesarean delivery can help prevent mother-to-child transmission of all except:
  1. HIV
  2. Herpes (HSV 2)
  3. Rubella
  4. HCV
115. Varicella can spread through:
  1. Contamination
  2. Droplet
  3. Sharing needle
  4. Unprotected sex
6. Serological survey in India, have shown prevalence of CMV IgG antibodies in women of child bearing age is:
  1. <50%
  2. 60%
  3. 70%
  4. >90%
7. The most common congenital viral infection is:
  1. Rubella
  2. CMV
  3. Varicella
  4. Measles
8. Malformations in congenital rubella syndrome include:
  1. Cataracts
  2. Limb deformities
  3. Mental retardation
  4. Micrognathia
9. Hepatitis with worst prognosis for mother is by:
  1. HAV
  2. HBV
  3. HCV
  4. HEV
10. Vaccination against this viral infection is recommended in pregnant women:
  1. Rubella
  2. Varicella
  3. Measles
  4. Influenza
ANSWERS
1. a
2. c
3. a
4. c
5. b
6. d
7. b
8. a
9. d
10. d
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