Congenital Intrauterine TORCH Infections Deepika Deka
INDEX
×
Chapter Notes

Save Clear

Section 1
1MATERNAL FETAL SEQUELAE2

Intrauterine Infections and Congenital TORCH SyndromesONE

Deepika Deka
Infections in the pregnant woman are an important cause of fetal and neonatal mortality and morbidity. Most respiratory or gastrointestinal infections are localized, do not infect the placenta or cause significant damage. However, some organisms not only infect the placenta, but also the fetus (transplacental route). Fetal infection can be caused by virus, bacteria and parasite. Some of these are infections with Toxoplasma gondii (Toxo), rubella, cytomegalovirus (CMV) and herpes simplex virus (HSV). They have several clinical features in common and hence given the acronym “TORCH” group of infections. This term has served to increase awareness of a class of organisms that have a relatively benign or even symptomless course in the pregnant woman, but can cause havoc in the transplacentally1–4 infected fetus in the form of fetal loss, structural anomalies and developmental defects. Although, this collective term suggests that some clinical features are not distinguishable by pathogen, the clinical syndrome caused by one pathogen generally can be distinguished from infection caused by another pathogen on a clinical basis, authenticated by specific laboratory parameters.
TORCH agents cause a varied spectrum of disease. Placental infection has been implicated in the causation of abortion, preterm labor and stillbirth in index pregnancy and seroprevalence is higher in women with previous pregnancy loss. However, they do not generally cause recurrent fetal loss.5,6 Fetal infection can occur at any time during pregnancy. “Congenital infection” commonly refers to transplacentally acquired infection from the infected mother. Neonatal infection with TORCH organisms can also be contracted during vaginal delivery, via breast milk or by exposure in the neonatal period.4
Developing countries have difficulty in collecting reliable and accurate data on perinatal infections, especially because serology is expensive. Magnitude of the problem needs to be studied, and India should prioritise perinatal problems, which may lead to avoiding focusing attention only on TORCH agents.7
 
INCIDENCE
The incidence varies geographically and socially. Fetal infection has been reported to occur in up to 10 percent of pregnancies per year.1 Perinatal infections account for 2 to 3 percent of all congenital anomalies. Collectively, TORCH infections create more neonatal morbidity and mortality than early onset group B streptococcal sepsis in USA. The incidence of maternal infection by CMV and toxoplasmosis is 2 to 10/1000 births.8 In the United States, approximately 85 percent of women of child-bearing age are susceptible to infection with T. gondii. An estimated 400 to 4000 cases of congenital toxoplasmosis occur in the US every year.9 The incidence is highest in France and Austria. In France, an estimated 44 percent of pregnant women are regularly checked for seroconversion, and between 5625 and 8850 women are treated during pregnancy every year to prevent congenital toxoplasmosis.10
The incidence of congenital CMV infection varies between 0.15 and 2.0 percent and seems to correlate with the level of pre-existing immunity in the population.11 In Japan, the annual incidence of symptomatic CMV disease is 1.6/100,000 live births.12 Prevalence of TORCH antibodies in pregnant Thai women is reported to be 15 percent for Toxoplasma gondii, 85 to 87 percent to rubella, 79 to 81 percent to herpes simplex, 100 percent to CMV.13 The risk for fetal CMV due to recurrent CMV was found to be the highest congenital infection.
The incidence of rubella decreased from 0.45/100,000 in 1990 to 0.1/100,000 in 1999, (ACOG, 2002).14 In 1989, the US established the goal to eliminate indigenous rubella and congenital rubella syndrome (CRS) by 2000. Recently, an infant with CRS was born to a mother who had immigrated to the UK, and targeted immunization has been recommended to new arrivals.15 Screening for primary rubella infection in pregnant women in China showed that 0.318 percent of women without clinical symptoms and 1.477 percent of women with clinical symptoms were infected, leading to birth of 40,000 infants with congenital rubella syndrome (CRS) every year. This is much more than the sum of patients suffering from poliomyelitis and Japanese encephalitis.16 Epidemics of rubella still occur, as in Brazil in 51999 to 2000,17 Barbados in 1996,18 Sri Lanka - 0.9/1000 live births in 1994–95 outbreak, Oman-0.5/1000 live births in 1988 and 0.7/1000 live births in 1993. Although new cases of congenital rubella are now rare, surviving victims of the epidemic of 1963–65 continue to challenge the US medical community.19
The approximate rate of neonatal HSV infection is 0.1 to 0.3/1000 live births, of which 86 percent are natal, 10 percent postnatal and only 4 percent congenitally acquired.20
In India, data are scant; TORCH infections (mental retardation + multiple congenital anomalies) were one of the top reasons for referral to genetic clinic.21 Study of a rural population showed that IHA antibodies to Toxoplasma was 18 percent; and 10 percent children before 9 years. were seropositive suggesting exposure or congenital infection22 Seropositivity was found in 77 percent women and 37 percent men in North India.23 In a study at AIIMS, 12 percent of infants suspected to have congenital infection had CMV specific IgM antibodies; and, developmental delay, hepatosplenomegaly were prominent features.24 IgM was detected in 0.6 percent of all newborns screened at AIIMS.5 One hospital study from Madurai reported 46 CRS infants with sequelae seen between 1993 and 2001.25 Data from a tertiary referral center in India demonstrated high frequency of primary TORCH infection during pregnancy.26 Another study reported that 52/342 (15.2%) infants suspected to have congenital infection from 1991–93 had CRS.27 It has been shown that Toxoplasma does not cause recurrent abortions, may be responsible for sporadic abortion.28 A study recently carried out at AIIMS by the author found that 17.8 percent adolescent girls and 20 percent pregnant women were seronegative, identifying a group of women at risk for primary rubella infection during pregnancy.
A study carried out in 300 pregnant women in Chandigarh, showed that toxoplasma IgG antibodies were detected in 46 (15.33%) cases, while 9 (3%) had positive anti Toxoplasma IgM with IgA and /low IgG avidity antibodies suggestive of acute infection during or just before pregnancy. About 85% women were susceptible to Toxoplasma infection and thus should be specifically educated about prevention of this infection during pregnancy.29
 
MATERNAL FETAL TRANSMISSION
In the viremic or parasitemic stage of maternal infection, placental infection is initiated and subsequently fetal infection occurs. Humoral immunity prevents or limits maternal and placental infection for some pathogens such as Toxoplasma and rubella, but with CMV and HSV, recurrent episodes of 6viral shedding may occur in the immunocompetent patient. In the first-half of pregnancy, the immune system of the fetus is immature, and the fetus also does not benefit from passive maternal immunity, as little or no IgG transfers across the placenta. Hence, immune response to early pregnancy infection is compromized at the critical period of ontogeny resulting in greater fetal injury, likelihood of fetal death or delivery of a symptomatic child.
 
CONGENITAL TORCH
The original TORCH complex described clinically similar congenital infections caused by Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes simplex virus, types 1 and 2. Jaundice, petechiac and hepatosplenomegaly are the classic “clinical triad” of TORCH baby. Cutaneous manifestations, including petechiae, purpura, jaundice, and dermal erythropoiesis, are commonly seen in toxoplasmosis, rubella, and cytomegalovirus infections. In herpes simplex virus infections, 80 percent of symptomatic infants show single or grouped cutaneous vesicles, oral ulcers, or conjunctivitis. Extracutaneous signs and symptoms are variable and can be severe. Significant clinical signs in congenital toxoplasmosis include diffuse intracerebral calcification, chorioretinitis, and microcephaly; congenital rubella can result in deafness, congenital heart disease, retinopathy, and brain calcification. Cytomegalic inclusion disease can include hepatomegaly, splenomegaly, periventricular calcification, and intrauterine growth retardation. Localized or disseminated congenital herpes virus infection often involves the central nervous system and the eye.31 Severity of fetal infection by TORCH agents and its resultant consequences vary, depending on the virulence of the agent, the susceptibility and gestational age of the fetus, the route of infection, the immune status of the mother (immunocompromized state or immunized to the infection) and lastly, on timely diagnosis and appropriate institution of therapy where possible. The most critical factor in causing fetal infection resulting in fetal disease of varying gravity and prognosis is the time in embryogenesis and fetal development that the fetus is insulted (Table 1.1).
Obstetricians and neonatologists need to be aware of the prominent features of each congenital infection rather than to consider them collectively.
 
APPROACH TO CLINICAL MANAGEMENT
The diagnosis of congenital intrauterine TORCH infections was earlier made only postnatally, of the symptomatic baby. Knowledge and understanding of the epidemiology, pathogenesis, transmission and sequelae, along with recent advances in ultrasonography, serology and molecular techniques have permitted state-of-the-art prenatal diagnosis and management in utero also.7
Table 1.1   Perinatal TORCH transmission and period of gestation at infection1–3,5,20,30
Transplacental
Infection
1st trim
2nd trim
3rd trim
Vaginal delivery
Toxoplasma
10–15% (severe)
20–25% (<5% severe)
60–70% (mild/symp)
—
Rubella
Primary
60% (4 wk)
<5%
—
25% (5–8 wk)
>20 wks-absent
15% (9–12 wk)
Recurrent
Rare
CMV
Primary
30–40% (10% symptomatic,
severe = 1st and early 2nd trimester)
(rare)
Recurrent
0.2–2% (<1% symptomatic)
HSV
Primary
Rare
40–60%
Recurrent
<5%
* Pregnancy within 3 months of rubella vaccine (rare—3.5%)
8
Prepregnancy presence of specific IgG antibodies excludes the risk of transplacental Toxoplasma and Parvovirus infection, diminishes the risk of CMV infection. Primary infection during pregnancy is confirmed by: 1. T oxoplasmosis (seroconversion, presence of IgA and IgM, low avidity IgG, PCR in amniotic fluid) - which indicates termination of pregnancy or antimicrobial therapy; 2. Symptomatic CMV infection (seroconversion, virual isolation from blood or urine (PCR, pp65 antigen)]; 3. PVB19 (seroconversion, IgM, PCR in blood and amniotic fluid) which indicates serial ultrasonographic evaluation for fetal anemia or fetal hydrops, and treatment by intrauterine transfusion
  1. Identification and screening of women at high risk of contracting infection during pregnancy. The most frustrating aspect of prevention of congenital TORCH is the inability to diagnose maternal infection clinically, since in immunocompetent women it is usually mild or asymptomatic; and specific serologic tests are required for screening. At present, in India, perhaps screening protocols should not be done outside research trials to study magnitude of the problem and cost effectiveness. Attention may be focussed on the high risk group of women, those with clinical signs and symptoms of suspected TORCH infections, and complications in pregnancy (Table 1.2) by specific laboratory tests to be dealt with in details in subsequent chapters.
    Currently in India, pregnant women are routinely screened in the first trimester booking only for syphilis. Some countries include rubella, hepatitis B, HIV and group B Streptococcus screen, while in countries like France, Austria where Toxoplasma is rife, routine monthly screening of non-immune women for Toxoplasma are mandatory by law. In the US and UK, screening for acute toxoplasmosis is not offered routinely because of the low frequency of maternal infection and low chance of fetal infection, and is not cost-effective.32
    Table 1.2   Indications for maternal TORCH screen during pregnancy
    1.
    Fever, fever with skin rash, exposure/contact.
    2.
    Lymphadenopathy, unexplained hematological dyscrasias, other signs/symptoms.
    3.
    Ultrasound evidence of markers for congenital TORCH.
    4.
    ? IUGR, oligohydramnios, polyhydramnios.
    5.
    Screening (routine/targeted in high risk group), preconceptional, early first trimester booking/HSV in third trimester/labor (? In India, data lacking. Not done in UK, USA).
    9
    A Norwegian study concluded that the screening TORCH panel as used at present creates a lot of work and anxiety, but yields little information.33 Many pregnancies with IUGR are screened for TORCH infections, the yield and cost of such a practice is not justified.34
  2. Diagnosis of maternal TORCH infection. Serologic tests are used to diagnose acute infection in pregnant woman and fetus, but false-positive tests occur frequently, therefore, serologic tests must be confirmed at a reference laboratory before abortion or treatment with potentially toxic drugs. In general, IgM production is the acute reaction, followed by IgG in 1 to 3 weeks. Diagnosis of acute maternal infection is made by seroconversion (IgG – ve mother, now IgG +ve), a four-fold increase in IgG serial titer over 2–3 weeks, or the demonstration of pathogen specific IgM; most labs use ELISA-IgG and IgM.1–3,35,36 In India, rarely a woman's serologic status is known before pregnancy. Also, it is rare that serum can be kept, for paired two samples to be run. Obviously, most important is the ability to pinpoint accurate timing of maternal infection to the exact period of gestation. This is extremely perplexing and sometimes impossible. If accomplished, risk of fetal infection and disease can be approximated so that the couple can be counseled on the need for prenatal diagnosis. Use of less expensive and more accurate serologic tests, reliability and validity studies are lacking.
  3. Prenatal diagnosis In the case of positive maternal serology, invasive testing for fetal infection and non-invasive ultrasonography are mandatory. It is extremely desirable that these tests are sensitive, specific and accurate; as, not only are the invasive tests of fetal diagnosis associated with slight procedural risks, false abnormal test may lead to abortion of a healthy fetus. An affected fetus may be sought to be treated, which again brings the question of how effective is fetal/neonatal therapy for congenital infections. An abnormal test result is best confirmed in a research, referral laboratory. Thus, interpretation of laboratory results is not just science, it is also an art. Prenatal diagnosis is now possible with use of ultrasonography (U/S) and ultrasound-guided procedures of amniocentesis, chorionic villus sampling and cord blood sampling for accurate diagnosis of fetal infection present or absent by sophisticated laboratory testing.37,38 However, by the time structural anomalies are visible on U/S, fetal organ damage is considerable and this is an important factor in decision making. Real-time polymerase chain reaction (PCR) analysis of amniotic fluid in 261 of 377 patients identified by prenatal screening for the prenatal diagnosis of congenital Toxoplasma infection significantly improves detection of fetal infection to decide on appropriate treatment 10and surveillance, and was accurate except for four false negative results, hence postnatal follow-up is very important in the first year of life to exclude infection in these children. Overall sensitivity and negative predictive value were 92.2% (95% confidence interval [CI] 81–98%) and 98.1% (95% CI 95–99.5%), respectively; specificity and positive predictive values were 100%.39
  4. Fetal therapy Strategy for specific management of each case needs to be planned, and parental counseling has to be done taking into consideration extent of fetal damage, options for therapy and anticipated prognosis. Rapid progress has recently been encountered in pharmacologically treating the unborn baby.40 Unique pharmacokinetic features of pregnancy, the placenta and the fetus govern maternal-to-fetal drug transfer. Ethically, it is important that the mother and family are appropriately informed about the evidence in favor of specific fetal therapy, risks and alternatives. Serious infections such as toxoplasmosis highlight the need for controlled randomised studies. Medical termination of pregnancy is still a very important management option in documented fetal infection especially with ultrasound evidence of organic disease.41 Absence of effect of prenatal treatment is due to transmission before the start of therapy. In the first and second trimester pregnancies with acute fetal Toxoplasma infection, if repeated fetal ultrasound is normal and antiparastic treatment is given, termination of pregnancy need not be done. Protocol of monitoring and treatment in toxoplasmosis: spiramycine 9 m UI dail y— the basic preventive treatment when seroconversion occurs. Antenatal diagnosis is made by ultrasound starting from 18th weeks of pregnancy, repeated every 4 weeks; and amniocentesis/cordocentesis. Pyrimethamine-sulfamide drug treatment should be started in case of positive diagnosis. A therapeutic pregnancy termination is considered if fetus is infected, more specifically when toxoplasma related malformations are detected on ultrasound. In the newborn, drug treatment is recommended for 15–18 months with spiramycine and pyrimethamine + sulfadoxine. Of 163 pregnancies treated in utero there were 3 intrauterine deaths; in 27 liveborn infants, there was proven congenital toxoplasmosis, 10 had one or more clinical signs, 5 had isolated or multiple intracranial calcifications, 7 had peripheral chorioretinitis and 2 had moderate ventricular dilatation. All 27 were free from symptoms and had normal neurologic development at 15 to 71 months of age.41 Prenatal antibiotic therapy significantly reduces the rate of sequelae among infected infants if started early.42–46 Deciding the 11mode of delivery for pregnancy with active or suspected maternal HSV infection is crucial and cesarean section improves prognosis significantly.47 Suppressive acyclovir therapy reduces need for cesarean for recurrent herpes in women whose first episode genital herpes occurs during pregnancy (none of 21 treated versus 9/25 on placebo).48 No specific therapy for congenital rubella or CMV infection has been established, so treatment is primarily supportive.
    A 20 years prospective study (1985–2005) of all mothers who received spiramycin, alone or associated with pyrimethamine-sulfadoxine, and underwent amniocentesis and monthly ultrasound screening, showed that of 666 liveborn children (676 mothers), 112 (17%) had congenital toxoplasmosis. The infected children were followed every 3–6 months, and of these, 107 were followed up for 12–250 months. Asymptomatic children were 79 (74%), while chorioretinitis developed in 28 (26%), and occurred mainly before the age of 5 years and almost always before the age of 10 years. Only one child had a serious neurological involvement. Outcome appeared consistently good, and visual impairment was usually not severe. Ocular and neurological monitoring is recommended.49
  5. Neonatal management Despite advances in prenatal diagnosis and therapy, a large number of congenitally infected babies are born worldwide. Prompt diagnosis and institution of therapy for herpes disease, Toxoplasma and CMV disease is very crucial. However, neonatal morbidity and mortality is high and most symptomatic babies have grave consequences— neurological, organic and developmental problems, requiring rehabilitative measures.1–3 Toxoplasmosis requires from 6 (in asymptomatic children) to 12 months (in symptomatic infection) treatment with pyrimethamine and sulfadiazine with supplementation of folinic acid. In symptomatic CMV infection and in asymptomatic infection with massive viral replication, 6 weeks treatment with ganciclovir is recommended to decreases viruria and the risk of hearing impairment.
  6. Prevention Prevention of maternal infection especially in high risk group is most appropriate especially as management options are yet suboptimal. Health education and counseling may have profound impact as seen in France, where toxoplasmosis prevention strategies by application of simple hygienic measures during pregnancy have drastically reduced congenital toxoplasmosis by 60 percent.50,51 Women of childbearing age and pregnant women should be educated to avoid eating raw or undercooked meat, to avoid cross-contamination of other foods with raw or 12undercooked meat, and to use proper cat-litter and soil-related hygiene. Vaccines need to be developed, the rubella vaccine has shown how CRS could be significantly controlled.38,52 Data indicate that preexisting immunity to CMV infection in the mother does not mitigate the outcome of congenital infection. Moreover, live vaccines may bear serious risk when transmittable to the fetus.11 Appropriate preconception health care improves pregnancy outcomes. Immunizations against hepatitis B, rubella and varicella should be completed if needed. Women should be counseled on ways to prevent TORCH infections.53
Lastly, knowledge, attitudes and practices of obstetricians and neonatologists on TORCH infections is important in reducing the burden of congenital infection.54 Survey of American College of Obstetricians and Gynaecologists (ACOG) representative group known as the Collaborative Ambulatory Research Network-(CARN) and randomly sampled fellows in the USA, about toxoplasmosis, showed that although the incidence of toxoplasmosis is low in US, up to 6000 congenital cases occur annually, 7 percent (CARN 10%, random 5%) had diagnosed one or more cases of acute toxoplasmosis in past year. Respondents were well informed about how to prevent toxoplasmosis. Most (CARN 70%, random 50%) were opposed to universal screening. However, only 12 percent (CARN 11%, random 12%) indicated that IgM test might be false-positive, and only 11 percent (CARN 14%, random 9%) were aware that FDA sent an advisory to all ACOG members that some Toxo-IgM kits have high false-positive rates.55
Since 1984, the World Health Organization (WHO) European Region has had targets for reducing the burden of a number of communicable diseases. The cultural and economic diversity of the region, as in India, present a number of challenges that must be overcome before the regional targets are met. These include social factors, political will, economic costs associated with supplementary campaigns, and more effective communications with health professionals and the public, on the benefits and risks associated with immunizations. Vaccines where available, should be affordable, and effective prevention guidelines should be workable in poorer nations.7,56 India needs to collect reliable and accurate data of perinatal infections, prioritise and tackle those that have serious public health problems and socioeconomic impact.
 
IMPORTANT POINTS
  1. Maternal TORCH infection may be symptomatic; but is usually mild or symptomless.13
  2. Maternal infection may not always result in fetal infection. Congenital fetal infection may be of varying severity and extent of organs affected. Seriousness of fetal damage depends on : period of gestation at attack, more severe in early pregnancy (T,R,C), early pregnancy and labor (H), severity/load of maternal infection, immune status of mother and early institution of maternal/fetal/neonatal therapy
  3. TORCH panel should not be done to investigate recurrent fetal loss, or recurrent malformations. May be done to evaluate one fetal loss or malformation probably due to primary acute infection.
  4. TORCH serologic screen should be done for targeted high risk group only. Routine screening for TORCH infection in India is not justified (data on prevalence of primary infection during pregnancy and cost effectiveness lacking). Not done in UK, USA.
    1. Protocol in France/Austria for Toxo:
      • Preconception or early first trimester booking serology
      • If seronegative, repeat for seroconversion monthly
    2. No use for first screen at late second/third trimester of pregnancy.
  5. IgM antibody is a feature of acute infective reaction followed by IgG in 1 to 3 weeks. Acute maternal infection is present when there is seroconversion, four-fold rise of IgG over serial titers 2 to 4 weeks apart, presence of IgM antibody.
  6. Serological methods should be confirmed at referral laboratory because IgM kits may be false positive. Interpretation needs expertise to pinpoint time of maternal infection. IgG positive means woman has earlier had the infection or has been vaccinated. She is not at risk for toxo or rubella, but reactivation/recurrence of CMV and HSV may occur. Congenital infection after recurrent or reactivated maternal infection (CMV, HSV) is usually low and not severe or symptomatic.
  7. Counseling and prenatal diagnosis for in utero fetal infection can be done by ultrasonography for infection markers, amniocentesis, chorionic villus sampling, cord blood sampling.
  8. Severity of fetal infection is difficult to predict, but early pregnancy infection, heavy viral load and presence of ultrasound abnormality, augurs poor prognosis, and termination of pregnancy should be considered.
  9. There is no therapy for fetal rubella, CMV. Early diagnosis and treatment of toxoplasmosis, and HSV (third trimester/labor) in mother and newborn improves prognosis.14
  10. Cesarean section is very effective in prevention of neonatal HSV in presence of active herpes simplex; it is not indicated for CMV.
  11. Vaccination for rubella should be given to all females at 18 months and booster at 12 years; if non-immune, 3 months before planning conception, or if yet non-immune, postpartum.
  12. Knowledge, awareness and practices of perinatologists are very important in reducing burden of TORCH infections. Political will and more effective communications with health professionals and the public on preventive and immunization programs are needed in India. Data are needed on: congenital infections during pregnancy/labor and in newborn/children (to prioritise and tackle those that have public health problems and cause socioeconomic loss) and on cost effective-ness of screening, prenatal diagnosis and therapy.
REFERENCES
  1. Stegmann BJ, Carey JC. TORCH infections. Toxoplasmosis, other (syphilis, varicella zoster, parvovirus B19), rubella, cytomegalovirus (CMV), and herpes infections. Curr Womens Health Rep. 2002;2:253–58.
  1. Arias F. Congenital Infections. In Practical guide to high-risk pregnancy and delivery. Pub. Harcourt Pvt. Ltd.  (2nd ed):2002;354–84.
  1. Yankowitz J, Pastorek II JG. Maternal and fetal viral infections including listerosis and toxoplasmosis. In James and Gonik (Ed): High Risk Pregnancy Management Options. 2000;525–38.
  1. Deorari AK. Incidence, clinical spectrum and outcome of intrauterine infections in neonates. J. Trop. Pediatr. 2000;46:155.
  1. Capuzzo E, Spinillo A. Genital infections as a cause of abortion in the first trimester of pregnancy. Review of the literature. Minerva Ginecol. 1995;47:557–60.
  1. Sharma P, Gupta I, Ganguly NK, Mahajan RC, Malla N. Increasing Toxoplasma seropositivity in women with bad obstetric history and in newborns. Natl. Med J India 1997;10:65–6.
  1. Ho NK. Perinatal infections-problems in developing countries. Singapore Med J. 1998;39;266–70.
  1. Newton ER. Diagnosis of perinatal TORCH infections. Clin-Obstet-Gynecol. 1999;42:59–70.
  1. Jones JL, Lopez A, Wilson M, Schulkin J, Gibbs R. Congenital toxoplasmosis: A review. Obstet Gynecol Surv. 2001;56:296–305.
  1. Wallon M, Liou C, Garner P, Peyron F. Congenital toxoplasmosis: systemic review of evidence of efficacy of treatment in pregnancy. BMJ. 1999;318:1511–14.
  1. Gaytant MA, Steegers EA, Semmekrot BA, Merkus HM, Galama JM. Congenital cytomegalovirus infection review of the epidemiology and outcome. Obstet Gynecol Surv. 2002;57:245–56.
  1. Morita M, Morishima T, Yamazaki T, Chiba S, Kawana T. Clinical survey of congenital cytomegalovirus infection in Japan. Acta Paediatr Jpn. 1998;40:432–36.
  1. 15 Taechowisan T, Sutthent R, Louisirirotchanakul S, Puthavathana P, WC. Immune status in congenital infections by TORCH agents in pregnant Thais. Asian Pac J Allergy Immunol. 1997;15:93–97.
  1. American College of Obstetricians and Gynecologists. ACOG committee opinion: number 281, December 2002. Rubella vaccination. Obstet Gynecol. 2002;100:1417.
  1. Sheridan E, Aitken C, Jeffries D, Hird M, Thayalasekaran P. Congenital rubella syndrome: A risk in immigrant populations. Lancet. 2002;359:674–75.
  1. Dai B. Study on the frequency of primary rubella infection among early pregnant women. Zhonghua Yu Fang Yi Xue Za Zhi. 1992;26:197–99.
  1. Lanzieri TM, Segatto TC, Siqueira MM, de Oliviera Santos EC, Jin L, Prevots DR. Burden of congenital rubella syndrome after a community-wide rubella outbreak, Rio Branco, Acre, Brazil, 2000 to 2001. Pediatr Infect Dis J. 2003;22:323–29.
  1. St John MA, Benjamin S. An epidemic of congenital rubella in Barbados. Ann Trop Paediatr. 2000;20:231–35.
  1. Givens KT, Lee DA, Jones T, Ilstrup DM. Congenital rubella syndrome: Ophthalmic manifestations and associated systemic disorders. Br. J Ophthalmol. 1993;77:358–63.
  1. Brown ZA, Selke S, Zch J, et al. The acquisition of herpes simplex virus during pregnancy. N Engl. J Med. 1997;337:509–15.
  1. Verma IC. Burden of genetic disorder in India. Indian J Pediatr. 2000;67:893–898.
  1. Dubey JP. Toxoplasmosis in India. In Perspect Parasitol. CBS Pub. 1988;2:131–5.
  1. Singh S, Nautiyal BL. Seroprevalence of toxoplasmosis in Kumaon region of India. Indian J Med Res. 1991;93:247–49.
  1. Broor S, et al. Prevalence of rubella virus and cytomegalovirus infection in suspected cases of congenital infection. Indian J Pediatr. 1991;58:75.
  1. Vijayalakshmi P, Kakker G, Samprathi A, Banushree R. Ocular manifestations of congenital rubella syndrome in a developing country. Indian J Ophthalmol. 2002;50:307–11.
  1. Kaur R, Gupta N, Nair D, Kakkar M, Mathur MD. Screening for TORCH infections in pregnant women: A report from Delhi. Southeast Asian J Trop Med Public Health. 1999;30:284–86.
  1. Ballal M, Shivananda PG. Prevalence of rubella virus in suspected cases of congenital infections. Indian J Pediatr. 1997;64:231–35.
  1. Mahajan RC, Gupta I, Chhabra MB, et al. Toxoplasmosis : Its role in abortion. Ind. J. Med. Res 1976;64:797–800.
  1. Khurana S, Bagga R, Aggarwal A, Lyngdoh V, Shivapriya, Diddi K, Malla N. Serological screening for antenatal Toxoplasma infection in India. Indian J Med Microbiol. 2010;28:143–6.
  1. Wong SY. Remington JS. Toxoplasmosis in pregnancy. Clin Infect Dis. 1994;11:853–61.
  1. Eppes RE, Pittelkow MR, Su WP, TORCH syndrome. Semin Dermatol. 1995;14:179–86.
  1. Royal College of Obstetricians and Gynecologists. Prenatal screening for toxoplasmosis in the UK. Report of a multidisciplinary working group. RCOG.  London.  1992.
  1. 16 Holtmon LW, Hansen TW, Holter E. The TORCH study. A revaluation. Tidsskr Nor Laegeforen. 1994;114:311–12.
  1. Khan NA, Kazzi SN. Yield and costs of screening growth - retarded infant for TORCH Infections. Am J Perinatol. 2000;17:131–35.
  1. Hill D, Dubey JP. Toxoplasma gondii: Transmission, diagnosis and prevention. Clin Microbiol Infect. 2002;8:634–40.
  1. Avelino MM, Campos D, de Parada Jdo C, de Castro AM. Pregnancy as a risk factor for acute toxoplasmosis seroconversion. Eur J Obstet Gynecol Reprod Biol. 2003;1(108):19–24.
  1. Isada NB, Paar DP, Grossman JH 3rd, Straus SE. TORCH infections. Diagnosis in the molecular age. J Reprod Med. 1992;37:499–507.
  1. Signore C. Rubella. Prim. Care Update Obs Gynae. 2001;8:33–137.
  1. Wallon M, Franck J, Thulliez P, Huissoud C, Peyron F, Garcia-Meric P, Kieffer F. Accuracy of real-time polymerase chain reaction for Toxoplasma gondii in amniotic fluid. Obstet Gynecol. 2010;115:727–33.
  1. Koren G, Klinger G, Ohlsson A. Fetal Pharmacotherapy. Drugs. 2002;62:757–73.
  1. Berrebi A. Termination of pregnancy for maternal toxoplasmosis. Lancet. 1994;344:36–39.
  1. Foulon W. Treatment of toxoplasmosis during pregnancy: A multicenter study of impact on fetal transmission and children's sequelae at age 1 year. Am J Obstet Gynecol. 1999;180:410–15.
  1. Severe JL, Ellemberg JH, Ley AC, et al. Toxoplasmosis: Maternal and pediatric findings in 23,000 pregnancies. Pediatrics. 1988;82:181–92.
  1. Roizen N, Serisher CN, Stein MA, et al. Neurologic and developmental outcome in untreated congenital toxoplasmosis. Pediatrics. 1995;95:11–20.
  1. Koppe JG, Loewer-Siegen DH, Re Roever-Bonnet H. Results of 20-year follow-up of congenital toxoplasmosis. Lancet. 1986;1:254–56.
  1. Daffos F, Forestier F, Capalla-Pavlovsky M, et al. Prenatal management of 764 pregnancies at risk for congenital toxoplasmosis. New Engl. Jour. Of Med 1988;318:271.
  1. Brown ZA, Beneditti, Ashley R. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at time of labour. N Engl. J Med. 1991;324:1247–52.
  1. Scott L, Sanchez J, Jackson L, et al. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 1996;87:69–73.
  1. Berrébi A, Assouline C, Bessières MH, Lathière M, Cassaing S, Minville V, Ayoubi JM. Long-term outcome of children with congenital toxoplasmosis. Am J Obstet Gynecol. 2010, Jul 14. [Epub].
  1. Ambroise-Thomas P, Schweitzer M, Pinon JM, et al. Prevention of congenital toxoplasmosis in France. Risk assessment. Results and perspectives of prenatal screening and newborn follow up. Bull Acad Natl Med. 2001;185:665–83.
  1. Couvreur J. Problems of congenital toxoplasmosis. Evolution over four decades. Presse Med 1999;28:753–57.
  1. Reef SE, Frey TK, Theall K, Abernathy E, Burnett CL, Icenogle J, McCauley MM, Wharton M. The changing epidemiology of rubella in the 1990s: On the verge of 17elimination and new challenges for control and prevention. JAMA. 2002;30;287:464–72.
  1. Brundage SC. Preconception health care. Am Fam Physician. 2002;65:2507–14.
  1. Schrag SJ, Fiore AE, Gonik B, et al. Vaccination and perinatal infection prevention practices among obstetrician-gynecologists. Obstet Gynecol. 2003;101:704–10.
  1. Jones JL, Dietz VJ, Power M, Lopez A, Wilson M, Navin TR, Gibbs R, Schulkin J. Survey of obstetrician-gynecologists in the United States about toxoplasmosis. Infect Dis Obstet Gynecol. 2001;9:23–31.
  1. Spika JS, Wassilak S, Pebody R, Lipskaya G, Deshvoi S, Guris D, Emiroglu N. Measles and rubella in the World Health Organization Europe region: Diversity creates challenges. J Infect Dis. 2003;15; 187(Suppl)1:S191–197.