SEROEPIDEMIOLOGY OF TOXOPLASMA , RUBELL A , CYTOMEGALOVIRUS AND HERPES SIMPLEX VIRUS-2 IN WOMEN WITH BAD OBSTETRIC HISTORY . PART I : TOXOPLASMA AND RUBELLA INFECTIONS

Bad obstetric history (BOH) is associated with social and psychological impacts on society worldwide. The causes of BOH may be genetic, hormonal, abnormal maternal immune response, and maternal infection. In women with bad obstetric history (BOH), Toxoplasma (T) IgG high rate has been reported for Nepal (55.2%), while high (42.5%) and lowest (6.97%) active toxoplasma infections has been reported for India. In Arab countries, IgG and IgM higher and lowest seroprevalence rates were for Iraq. The higher susceptibility rates for Rubella in Arab countries excluding Iraq were reported in Morocco (83.4%), Sudan (34.7%), Qatar (25.1%), and Tunisia (20.3%). The lowest susceptibility was reported for Saudi Arabia (6.7%). In Iraq, studies indicate a high susceptibility rates in Thi Qar (98.05%), Kirkuk (91%), Baghdad (79%), and Waset (45.7%). The lowest susceptibility rates were reported for Diyala (0%) in women with previous abortion, and 3.9% in pregnant women without history of BOH.


Introduction
Bad obstetric history (BOH) implies previous unfavorable fetal outcome in terms of two or more consecutive spontaneous abortions, history of intrauterine fetal death, intrauterine growth retardation, stillbirth, early neonatal death, and/or congenital anomalies [1].The causes of BOH may be genetic, hormonal, abnormal maternal immune response, and maternal infection [2,3].

TORCH Complex:
The TORCH infections can lead to severe fetal anomalies or even fetal loss.They are a group of viral, bacterial, and protozoan infections that gain access to the fetal bloodstream transplacentally via the chorionic villi.Hematogenous transmission may occur at any time during gestation or occasionally at the time of delivery via maternal-to-fetal transfusion [4].Primary infections caused by TORCH-Toxoplasma gondii, Rubella virus, cytomegalovirus (CMV), and herpes simplex virus (HSV)-are the major causes of BOH [5].These infections usually occur before the woman realizes that she is pregnant or seeks medical attention.The primary infection is likely to have a more important effect on fetus than recurrent infection and may cause congenital anomalies, spontaneous abortion, intrauterine fetal death, intrauterine growth retardation, prematurity, stillbirth, and live born infants with the evidence of disease [6].Most of the TORCH infections cause mild maternal morbidity but have serious fetal consequences [7].The ability of the fetus to resist infectious organisms is limited and the fetal immune system is unable to prevent the dissemination of infectious organisms to various tissues [8].TORCH infections in the mother are transmissible to fetus in the womb or during the birth process and cause a cluster of symptomatic birth defects.Many sensitive and specific tests are available for serological diagnosis of TORCH complex [9]; however, ELISA test is more routinely used for its sensitivity.An attempt is being made to find out the correlation of TORCH infection during pregnancy in the Iraqi population.Toxoplasma gondii is an obligate intracellular protozoan parasite, which is linked to one of the most prevalent chronic infections affecting one third of the world's human population [10].
The infection is characterized by non-specific symptoms with the consequent formation of cysts that may remain in latent form in many organs [11].Primary infection is usually subclinical but the infection hazard is its occurrence during pregnancy.There are four groups of individuals in whom the diagnosis of toxoplasmosis is most critical: a) pregnant women who acquire their infection during gestation, b) fetuses, c) newborns who are congenitally infected, immunocompromised patients, and d) those with chorioretinitis [12][13][14].Although congenital toxoplasmosis is not a nationally reportable disease in Iraq, it represents a health care problem.Reported studies indicated an estimated 400 to 4,000 cases occur in the U.S. each year [11,15,16].The overall prevalence and incidence varies in different communities and contributes significantly to heavy morbidity [10].Congenital toxoplasmosis mainly results from a primary infection acquired during pregnancy [17], but not from the reactivation of a latent infection in immunocompetent pregnant women [18].However, it is believed that latent toxoplasmosis could reactivate and cause a congenital transmission of the parasite to infants who then become infected in utero [19].Countries with high disease prevalence have instituted successful secondary prevention programs via widespread maternal serologic screening [20], but universal maternal serologic screening for toxoplasmosis is not currently recommended in most of countries [21][22][23][24].Instead, current practice suggests maternal serological screening when abnormal fetal findings or presence of infertility problem indicate possible infection [22].ELISA methods is commonly performed in many countries to detect anti-toxoplasma antibodies [25].ELISA results are generally well accepted by clinicians because of their excellent sensitivities and specificities, the rapid availability of results, and the relatively low costs of the tests.It is important to understand that a single serologic test is not enough for the diagnosis of toxoplasmosis [26].In worldwide, commercial test kits for Toxoplasma-specific IgG and IgM antibodies are readily available.The presence of IgM antibodies is not always an indication of a recent infection since IgM maybe present for many months [27,28].Misdiagnosis of recent infections may be as a result of the presence of specific T. gondii IgM antibodies in the chronic stage of an infection, or false-positive IgM positivity [17,29].IgM test results are difficult to interpret and the reliability of test kits is largely dependent upon other factors.A negative IgM with a positive IgG result can indicate infection at least 1 year before.A positive IgM result may indicate more recent infection or may also be a false positive reaction [25].Currently worldwide, there is no systematic screening of pregnant women to detect seroconversion during gestation and most clinicians make decisions depending on result of single serum sample.This approach is not effective to detect toxoplasma infections during pregnancy, thus monthly serological screening for pregnant women is the recommended approach [30].The presence of elevated levels of Toxoplasma specific IgG antibodies indicates infection has occurred at some point, but does not distinguish between an infection acquired recently and one acquired in the distant past.In acute infection, IgG and IgM antibodies generally rise within 1 to 2 weeks of infection [31].Given the potential for false-positive results, the true value of IgM testing is in ruling out the presence of acute infection.In other words, negative IgM results are reassuring, whereas positive results should be interpreted carefully, confirmed in a toxoplasmosis reference laboratory, and followed by serial titers at least 3 weeks apart [12,28,32].There are different Toxoplasma seropositivity reports from all over the world.The population of Turkish childbearing age women has the seropositivity of T. gondii as 1.34% for IgM and 24.6% for IgG [33].In Maracaibo, Venezuela the overall prevalence of toxoplasmosis was 33%, while 18.2% were positive IgM [34].In Qatar among 823 women of childbearing age, the T. gondii IgG and IgM was 35.1% and 5.2% respectively [35].Sixty-five studies [3,33, characterizing the prevalence of maternal infections with T. gondii in developing and developed countries and fifty-nine [35, studies in Arab countries (30 studies reported for Iraq) were identified.The features and results of these studies are summarized in Tables I and II.The majority of studies had small sample sizes, between 0-4112 subjects.Most of these studies were conducted in antenatal clinics, hospitals, health care facilities or prenatal clinics.The remaining studies (3.3%) were community-based and the study setting was not specified in 7.4% of the studies.The most commonly used test was ELISA, which is the gold standard for T. gondii analysis.The median of IgG Toxoplasma prevalence was 38.5% [64] for Bangladesh.IgG high rate of detection was reported for Brazil [50] (75%, 832 pregnant women), while the lowest rate was for Thailand [38] (5.3%, 831 pregnant women).IgM lowest rate reported for China [49] (0%, 235 pregnant women) and Vietnam [59] (0%, 300 pregnant women), while the highest rate reported for Ghana [87] (76.1%, 159 pregnant women).In women with bad obstetric history (BOH), IgG high rate was reported for Nepal [62] (55.2%, 345 BOH) and the lowest one was that reported by Natu et al [74] (19.44%, 499 BOH).IgM in BOH high rate was reported for India [36] (42.5%, 200 BOH), while the highest one for India also [91] (6.97%, 86 BOH).In Arab countries, the median of IgG prevalence was 41.9% which was reported for Sudan [144].IgG highest rate of detection reported for Iraq [132] (94%, 54 pregnant women) Bahrain [137] (15.8%, 146 Pregnant women), while the corresponding values for IgM were 55.5% (Iraq, 180 pregnant women) [129] and 2.8% (Egypt, 323 pregnant women) [153] respectively.Concerning BOH, IgG ranges between 77.1% (Iraq,122 BOH) [114] and 6.84% (Iraq, 190 BOH) [130], while the range of IgM was between 58% (Iraq, 50 BOH) [127] and 0.97% (Iraq, 310 BOH) [104].

Rubella virus
Rubella is a contagious viral disease caused by a togavirus and usually goes unnoticed.However, maternal infection during pregnancy may result in fetal loss or in congenital rubella syndrome (CRS) [156,157].Infection in the first eight to ten weeks of pregnancy results in damage in up to 90% of surviving infantswhere multiple defects are common.The risk of damage declines to about 10 to 20% with infection occurring between 11 and 16 weeks gestation [158].Fetal damage is rare with infection after 16 weeks of pregnancy, with only deafness being reported following infections up to 20 weeks of pregnancy.Some infected infants may appear normal at birth but perceptive deafness may be detected later [157,158].Before the introduction of Rubella immunisation, Rubella was commonly prevalent in children, and more than 80% of adults had evidence of previous rubella infection [159].© Our Dermatol Online 4.2013 527 Rubella infection of a pregnant woman may have devastating effects on the developing fetus and once congenital infection occurred there is no availability of treatment for the foetus.Thus the mainstay of prevention is the universal immunization of all infants and identification and immunization of women at risk Fetal infection is acquired hematogenously, and the rate of transmission varies with the gestational age at which maternal infection occurs, with higher frequency in first trimester [160].
Periconceptual maternal infection does not seem to increase the risk of CRS [160].Maternal immunity, either after vaccination or naturally derived, is generally protective against intrauterine rubella infection [162,163].However, there have been cases of CRS after maternal reinfection [163].Therefore, CRS should always be considered in a fetus or neonate with a clinical picture suggestive of congenital infection [162].It should be noted that no case of CRS has been reported when maternal reinfection occurred after 12 weeks of pregnancy [164].Seven studies were with a retrospective (12.1%) study design and of the total 13 (22.4%)studies deals with women with bad obstetric history (BOH).These studies detected the presence of maternal anti-rubella IgG as a marker of past infection or immunization and mothers who did not possess these antibodies were susceptible to Rubella infection.Maternal IgM was detected in some studies as a marker of recent or current infection, which is associated with an increased risk of vertical transmission.The range of maternal susceptibility to Rubella was 2.1% to 43% in pregnant women [186,189] and 21.1% -71.04% in women with BOH [91,190].Higher susceptibility rates were reported [1,91,93,178,209,210] in Nigeria (84.8%),India (71%), Nepal (50%), Brazil (28.4%),Iran (25%), and Sri Lanka (24%).The higher susceptibility rates for Arab countries excluding Iraq were reported [35,216,220,221] in Morocco (83.4%),Sudan (34.7%),Qatar (25.1%), and Tunisia (20.3%).The lowest susceptibility was reported [217] for Saudi Arabia (6.7%).
While the lowest susceptibility rates were reported for Diyala (0%) in women with previous abortion, and 3.9% in pregnant women without history of BOH [215].The same figures was reported later by another research group in Babylon [213].

Table I . Characteristics and results of studies reporting prevalence of maternal Toxoplasma infection . Article Location, setting of study Type, Duration Population Results
[97]bik-Cavlek T, et al[96]Croatia, Hospital Cross sectional, 5 years Pregnant & non pregnant women 29.1% IgG, 0.25% IgM Goncalves MA, et al,[97]

Table I . Characteristics and results of studies reporting prevalence of maternal Toxoplasma infection (continued). Article Location, setting of study Type, duration of study Population Results
[103]i RT[103]Iraq, Al-Anbar, Hospital Cross sectional, 6 months 50 Pregnant women 50% IgM Razzak et al [104] Iraq, Duhok, Hospital Case control, 18 months 310 Women with BOH 0.97% IgM El Mansouri et al [105] Morocco, Institute National Hygiene Al-Hindi A, et al [150] Palestine, IVF centre Retrospective, 6 years 1954 Women with infertility or abortion 7.9% IgM

Table III . Characteristics and results of studies reporting prevalence of maternal rubella infection (continued). Article Location, setting of study Type, duration of study Population Results
[218]ndi A, et al[150]Palestine, IVF centre Retrospective, 6 years 1954 Women with infertility or abortion 7% IgM Nama J et al[218]Iraq, Najaf, Hospital Case control, 10 months 300 Aborted women 77% IgG, 4.66% IgM