Screening for Infectious Diseases During Pregnancy: Which Test and Which Situation

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1 158 Current Women s Health Reviews, 2012, 8, Screening for Infectious Diseases During Pregnancy: Which Test and Which Situation Marisa Márcia Mussi-Pinhata 1, * and Silvana Maria Quintana 2 1 Department of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, SP, Brazil; 2 Department of Obstetrics and Gynecology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, SP, Brazil Abstract: The purpose of this article is to review the current knowledge, and recommendations for screening infectious diseases during pregnancy to improve maternal, fetal and newborn health. We examined studies and public health policies published in English language to identify which tests and in which situations recommendations are being made. Universal prenatal screening with at least one test for syphilis, human immunodeficiency virus, and asymptomatic bacteriuria is largely recommended. Approaches for maternal screening for preventing perinatal transmission of the Hepatitis B virus are not uniform and early vaccination of newborns irrespective of maternal screening is frequently adopted in resourcelimited countries. Screening for maternal Hepatitis C infection can be considered for high-risk women. Routine screening for Cytomegalovirus is not usually recommended by public health authorities but is being debated among experts. Universal screening for Group B Streptococcus at weeks gestation is the preferred approach for preventing neonatal disease. Selective early gestation Chlamydia trachomatis and Neisseria gonorrhea screening of pregnant women based on risk factors is performed in developed countries. Although prenatal testing for Toxoplasma gondii is routinely offered in some countries, no consensus exists about the benefits, diagnostic tests or the most effective screening strategy to prevent congenital toxoplasmosis. Keywords: Diagnostic tests, infection, infectious pregnancy complications, pregnancy, prenatal screening, screening tests. INTRODUCTION A major goal of prenatal care is to improve maternal, fetal and newborn health. To achieve this purpose it is essential that situations that may increase the risk of unfavorable outcomes be early identified. Infectious diseases can occur during pregnancy and puerperal period favoring adverse outcomes such as prematurity and low birth weight with the consequent increasing rates of morbidity and mortality [1]. Further, the possibility of mother to child transmission of the infectious agent during gestation, at delivery or during breastfeeding is a major concern. It must be considered that the epidemiology of the disease in the population is essential to define which screening test to offer, since the occurrence and characteristics of infections vary in different populations. Understanding the true burden of disease is important in making decisions and implementing potentially effective preventive strategies [2]. Ideally, the decision for screening an infectious disease during pregnancy should follow the precepts of population screening for diseases such as a 1) a high prevalence of the disease; 2) limited clinical diagnosis; 3) existence of a highly sensitive test of low cost; 4) the existence of an intervention that ameliorates the disease. This review aimed to search the literature with respect to screening for infectious diseases during pregnancy taking *Address correspondence to this author at the Departamento de Puericultura e Pediatria da FMRP-USP, Avenida Bandeirantes 3900, Ribeirão Preto, SP, Brasil; Tel: ; Fax: ; s: mmmpinha@fmrp.usp.br, mussi.pinhata@pq.cnpq.br into account the published international guidelines, and policies. Table 1 summarizes these reccomendations. 1. Syphilis Treponema pallidum, the etiological agent of syphilis, can be transmitted through the placenta from the infected mother to the fetus. The risk of transmission is higher at earlier stages of maternal infection. In up to 80% of pregnancies adverse outcomes can result from transmission of infection. Examples of adverse outcomes are hydramnios, miscarriage, spontaneous abortion, fetal hydrops stillbirth, congenital syphilis, low birth weight and serious infection in the newborn which can result in perinatal death. Congenital syphilis can cause significant harm to child health, including mental retardation [3]. Congenital syphilis can be effectively prevented by testing and treatment of pregnant women. Not only the fetus and the mother can be benefited but also potential partners can be offered treatment [4]. Estimates of the World Health Organization indicate that among 340 million cases of curable sexually transmitted infections (STI) that occur every year worldwide, 12 million are cases of syphilis. About 2 million pregnant women get infected by T. pallidum infection every year while around 1 million of babies are affected with congenital syphilis [5]. In large parts of the world and particularly Sub-Saharan Africa and Asia congenital syphilis is an important public health problem [6, 7]. In addition, it is re-emerging in the developed world such as Europe [8], and Canada [9]. The leading cause for the continued high incidence of congenital syphilis despite the availability of viable, cost effective interventions /12 $ Bentham Science Publishers

2 Screening for Infectious Diseases During Pregnancy Current Women s Health Reviews, 2012, Vol. 8, No Table 1. Recommendations for Screening of Infectious Diseases During Pregnancy Condition Screening Preferred Test (s) for Screening Preferred Test (s) for Confirmation Syphilis Universal 1 st prenatal visit and before delivery RPR or VDRL FTA-ABS or TPHA-TPPA HIV Universal 1 st prenatal visit and before delivery Conventional or rapid EIA Conventional EIA and Western Blot Hepatitis B Universal in developed countries [1 st prenatal visit and selectively for women with risk factors before delivery] Non mandatory according to WHO guidelines AgHBs serology AgHBe serology (optional) Hepatitis C Selectively for women with risk factors Anti-HCV antibody screening test (immunoassays) Recombinant immunoblot assay or a nucleic acid test Asymptomatic Bacteriuria Universal, at 12 to 16 weeks' gestation or at the 1 st prenatal visit Urine culture of a midstream clean-catch specimen Urine culture Cytomegalovirus Routine screening not recommended Selective screening for women with risk factors CMV IgG and IgM antibodies CMV IgG avidity N/A Group B Streptococcus (GBS) Universal for detection of rectovaginal GBS colonization at weeks gestation or risk factor approach GBS culture in selective culture media as Todd-Hewitt with gentamicin and nalidixic acid N/A Chlamydia trachomatis Selective screening for < 24 years old women and those with risk factors at 1 st prenatal visit repeating at 3 rd trimester in those with risk factors Nucleic acid amplification test (NAATs) in urine or vaginal secretions Culture on Thayer-Martin media Neisseria gonorrhea Selective screening for < 24 years old women and those with risk factors at 1 st prenatal visit repeating at 3 rd trimester in those with risk factors Nucleic acid amplification test (NAATs) in urine or vaginal secretions Culture on Thayer-Martin media Toxoplasma gondii No consensus exist First prenatal visit repeating monthly or every 3 months for the seronegative ones Enzyme immunoassays for IgG and IgM. Enzyme immunoassays for documenting seroconversion. Avidity index and a panel of tests for detecting recent infection for those with IgM positive in the first test. N/A non applicable. to detect, treat, and monitor this infection is the deficiency of adequate antenatal care [10]. It has been clearly shown that serology screening of pregnant women with treatment of those with reactive tests is a cost-effective, inexpensive and achievable intervention for the prevention of congenital syphilis and improvement of child health. Even in developed countries which prevalence rates are < 1%, screening pregnant women for syphilis has been shown to be cost-saving [11]. Public health policies for prevention of congenital syphilis are based on increasing access to and quality of maternal and newborn health services; screening and treating all pregnant women and partners; and establishing surveillance, monitoring, and evaluation [12]. Identification of pregnant women with syphilis can only be performed with serological tests since most are asymptomatic. Universal (all women) prenatal syphilis screening is recommended by virtually all Public Health guidelines and professional organizations around the world [6, 13, 14]. The World Health Organization recommends that all pregnant women should be tested at their first antenatal visit within the first trimester, preferably before 16 weeks of gestation, and again in late pregnancy during the third trimester. At delivery, women who for some reason do not have test results should be tested. Women testing positive should be treated and informed of the importance of being tested for HIV infection. Their partners should also be treated and plans should be made to treat their infants at birth [12]. Differently, recommendations for countries with lower prevalence of syphilis usually only cogitate repeating testing in third trimester pregnancy and/or at delivery for women in high-risk groups, those who live in areas with a high prevalence of syphilis, have not been previously tested, or have had a positive test result for syphilis during the first trimester [14, 15]. Which Tests Should be Used? Nontreponemal tests normally used for initial screening are the Venereal Disease Research Laboratory (VDRL) or

3 160 Current Women s Health Reviews, 2012, Vol. 8, No. 2 Mussi-Pinhata and Quintana Rapid Plasma Reagin (RPR) which are sensitive, easy to perform, can be semi-quantitative and are broadly available. However, as many as 28% of positive RPR results may be false positives (low titers) in pregnant women as well as false negative results can occur when there is excess of antibody (prozone phenomenon) [16]. Consequently, preferably, a positive test should be confirmed by the fluorescent treponemal antibody absorbed test (FTA-ABS), T. pallidum haemagglutination assay (TPHA) or the T. pallidum particle agglutination (TPPA) assay. When access to treponemal tests is limited, especially in high prevalence areas, a non-treponemal titer >8 should be taken as indicative of active disease and treatment be quickly initiated [11]. RPR reagents that are stable at room temperature have become commercially available. Rapid testing allows antenatal screening in resource limited settings increasing the number of women diagnosed. Several rapid tests that use whole blood; require minimal training, no equipment or special storage conditions, and have sensitivities of 85-98% and specificities of 92-98% compared with standard treponemal assays are now obtainable [17]. 2. Human Immunodeficiency Virus Human Immunodeficiency Virus (HIV) infection of pregnant women threatens their own lives and those of their babies. Mother-to-child transmission of this virus can occur during pregnancy, the birth process or through breast milk. Mother-to-child transmission of HIV infection can be substantially reduced from 15-30% without interventions to less than 2% with the use of antiretroviral therapy during pregnancy, during labor and in the neonatal period, with an elective caesarean section delivery in selected cases and refraining from breastfeeding [18]. Although the HIV epidemic appears to have stabilized in most regions, prevalence continues to increase in Eastern Europe and Central Asia and in other parts of Asia due to a high rate of new HIV infections. Sub-Saharan Africa accounted for 71% of all new HIV infections in 2008 remaining the most heavily affected area [19]. Women denote half of the 33.4 million people infected with the HIV worldwide according to current WHO estimates. In 2008, 2.3 million adults were newly infected and an estimated new HIV infections occurred among children under the age of 15. Most of these new infections in children likely result from maternal to child transmission and the great majority could have been prevented [19]. HIV counseling and testing for certain groups of pregnant women with high risk behavior were first recommended 25 years ago [20]. Since then significant advances in knowledge with respect to testing, treatment and prevention of HIV infection has internationally changed the guidelines for HIV screening during pregnancy. Especially, the possibility of effective prevention of perinatal transmission [21] highlighted the benefits for HIV testing of pregnant women. Universal screening is the only means by which all infected women may be identified because they have no recognized risk factors other than heterosexual intercourse. In several developed countries, for more than a decade it has been recommended that all pregnant women be tested for HIV as part of the routine prenatal care as early as possible [22, 23]. However, prenatal HIV testing is still lacking in most Sub-Saharan African countries where only approximately 10% of pregnant women know their HIV infection status, although general guidelines are available in most African countries [24]. There is evidence showing that the existence of a universal policy increases the likelihood that a physician will offer the test [25, 26]. In addition, if it is offered, most women accept screening for HIV during their pregnancy [27]. Until recently, the primary mode of HIV testing recommended by the World Health Organization [28] and in the US [22] was the known as voluntary counseling and testing in which pretest counseling and consent was required. Though, it is now known that an opt-out policy toward prenatal HIV testing achieves the highest rates of screening [29, 30] and has been universally guided by the Joint United Nations Programmme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) to be implemented [31]. An opt-out or right of refusal policy considers HIV screening as a routine prenatal screening test; to a pregnant woman is given a simplified pre-test information that testing will be done, but consent is implied unless she specifically refuses. Provider-initiated HIV testing and counseling has already been implemented in a range of prenatal settings in parts of Canada, Thailand, the United Kingdom, and the United States [32]. Acute HIV infection during pregnancy could result in high rates of perinatal HIV transmission [33]. HIV test early in pregnancy can miss acute infection during gestation averting women of receiving prophylactic interventions. Therefore recommendations for repeating HIV testing during the third trimester, usually before 36 weeks gestation, for certain groups of HIV-negative women in epidemic settings has been made by some organizations [32, 34]. If the women still arrives at labor and delivery without an HIV test result they should be tested using rapid tests [35]. It has been also recommended to test the newborn infant when the mother missed testing during gestation or at delivery and is not available for testing [32] Which Tests Should be Used? Commercially available HIV tests are accurate, fast, and acceptable. The conventional enzyme immunoassays (EIA) begin to detect HIV antibodies 2-6 weeks after infection [36]. A repeatedly positive HIV antibody screening test result, ideally performed in two different samples collected at different time points, should be confirmed with an indirect immunofluorescent antibody (IFA) or Western blot (WB) assay. However, WB and IFA tests used for confirmation are less sensitive in early HIV infection than some of the newer screening tests, increasing the potential for negative, indeterminate or inconclusive results with some specimens from HIV-infected persons. Nucleic acid amplification tests for direct detection of HIV-RNA, which may present before antibodies develop is an alternative for these situations [33]. Reactive tests that are false positive can

4 Screening for Infectious Diseases During Pregnancy Current Women s Health Reviews, 2012, Vol. 8, No also occur, especially in populations with lower prevalence rates. When urgent results are needed to make decisions, such as in pregnant women who present at labor with unknown HIV serostatus, rapid (< 30 min) HIV EIA tests can be used. Rapid tests need minimal laboratory infrastructure and can be performed by health workers with minimal training and are applicable in different settings [37, 38]. Rapid HIV testing done in oral fluid or whole blood is highly accurate compared with conventional tests [36]. A systematic review of studies performed worldwide [39] indicated that sensitivity estimates (75%-100%) were generally lower than specificity estimates (86.4%-100%). To improve diagnostic accuracy and to reduce false-positive results, it may be necessary to use two rapid tests during labor and delivery. Algorithms for confirmation of a rapid test usually apply two EIA or EIA and WB. 3. Hepatitis B HBV infection is a worldwide health problem mostly prevalent in Asia, Africa, Southern Europe and Latin America. In these regions the overall prevalence of hepatitis B surface antigen (HBsAg) carriers ranges from 2 to 20% [40]. Chronic Hepatitis B Virus (HBV) infections increase long-term morbidity and mortality by predisposing infected persons to cirrhosis of the liver and liver cancer. Although HBV can be transmitted from the mother to the child during intrauterine life, it is widely accepted that the vast majority (80-95%) of infections are transmitted after exposure to cervical secretions and maternal blood at or near the time of birth [41]. The age at which HBV infection occurs is an important factor affecting the outcome. The earlier the infection occurs, the higher is the risk for chronicity [42]. Of the estimated 350 million individuals chronically infected with hepatitis B virus (HBV) worldwide, it is commonly accepted that at least 50% acquired their infections either perinatally or in early childhood. This is especially true in countries where HBV has intermediate (2-8%) to high prevalence (>8%) [43]. This fact emphasizes the relevance of the prevention of the vertical transmission of VHB during the neonatal period for both improving the child health and avoiding virus dissemination in the community. Post exposure immunoprophylaxis is safe and highly effective for prevention of mother-to-infant transmission of HBV, avoiding the majority of perinatally-acquired infections. Neonate vaccination after birth (i.e. within 12 hours) followed by two or three additional doses over months can prevent about 72% (60-80%) of vertical transmission of HBV [44]. The addition of hepatitis B immunoglobulin given within 12 hours of birth at a different injection site further increases the protective efficacy of the prophylactic regimen in infants born to women who are positive for both HBsAg and HBeAg to 92% (83-97%) when compared with vaccination alone [45]. However, in full-term neonates born to mothers who are HBsAg-positive but HBeAg-negative, protection against perinatally acquired infection achieved by immediate vaccination against HBV (given within 24 hours) may not be significantly improved by the addition of HBIG [46]. It has long been recognized that prevention of perinatal transmission is a high priority in the attempt to decrease the global burden of chronic HBV [41]. According to the Expanded Program on Immunization (EPI) of the World Health Organization (WHO) the basis for prevention of mother to child transmission of HBV is vaccinating all infants against hepatitis B vaccine as soon as possible after birth (within 24 hours), irrespective of maternal HBV status and even in countries with high HBV endemicity [47]. In newborn infants whose mothers are HBsAg-positive, particularly if they are also HBeAg positive, the HBIG prophylaxis in conjunction with HBV vaccination may be of additional benefit [46]. Thus, to enhance the chance of identifying pregnant women chronically infected with HBV and maximizing the protective efficacy of postexposure prophylaxis regimen by combining HBIG to the HBV vaccine, testing for HBsAg should be routinely recommended for every pregnant woman, regardless of assessed risk and previous testing, as has been routinely done in the US [48]. However, maternal screening is costly and is usually not feasible in developing countries with high prevalence of disease. Consequently, most policies have focused in the strategy of universal vaccination at birth. Decreasing incidences of maternally-acquired HBV infection after implementation of universal vaccination at birth have already been documented in several countries [49]. Differently, some European countries have chosen not to implement the universal immunization at birth and instead use HBsAg screening of pregnant women [50] to guide the need for neonatal immunization. A diverse approach from the universal maternal screening during pregnancy is the selective risk-based strategy (e.g. i.v. drug use, promiscuous heterosexuals, commercial sex workers, sex partners of HBsAg-positive persons) to determine whom to screen. However, difficulties in implementation and up to 50% losses of the VHB carriers have been reported [49, 51]. Which Test (s) to Use? The serological detection by enzyme Immunoassays of the surface antigen of HBV (HBsAg) which is identified in serum days following infection and persist for widely variable periods of time in persons with chronic infection is the preferred method because denotes HBV carriage. Considering that an important proportion (7-40%) of individuals who are HBsAg-positive may also carry the hepatitis B e-antigen (HBeAg), which is associated with high infectivity, to evaluate neonate infection risk and plan follow up some countries also perform HBeAg serology [40]. 4. Hepatitis C Hepatitis C virus (HCV) infection is a widespread health problem. Most of the 130 million infected people are chronically infected. The estimated global prevalence of HCV infection is 2.2% [52]. HCV and the hepatitis B virus are the leading causes of chronic viral hepatitis and hepatocelular carcinoma worldwide. The most efficient transmission of HCV is through large or repeated direct percutaneous exposures to blood such as in transfusions, transplantations, and injecting drug use. HCV transmission

5 162 Current Women s Health Reviews, 2012, Vol. 8, No. 2 Mussi-Pinhata and Quintana can also occur by means of accidental needlesticks or mucosal exposures to blood or body fluids (mother-to-child or sexual), although less efficiently than direct exposure to blood. The prevalence of HCV infection among women of child-bearing age shows geographic and temporal variation. In different countries it ranges from 0.6 to 6.0% [53, 54] with increased proportions among pregnant women with specific risk factors such as a history of injecting-drug use, blood transfusion or organ transplantation before donors had been screened for this virus [55]. HCV can be transmitted from the mother to the child in both intrauterine and intrapartum periods, although the exact mechanism of vertical transmission is not known. Overall, it occurs in 3-10% of pregnancies [56]. Studies indicate that this transmission occurs in women with detectable HCV RNA and is rare in pregnant woman without HCV viremia [55]. HVC RNA levels have been confirmed to be the main risk factor for vertical transmission of this virus [57, 58]. However, likely as a result of the fluctuation of these levels, there is no safe viremia level under which perinatal transmission of HCV may not occur during pregnancy [59]. It has been extensively demonstrated that coinfection with HIV in mothers not receiving antiretrovirals is associated with an increased risk (to as much as 44%) of perinatal transmission of HCV [60-64]. Although few policies concerning practices and counseling has been produced by international societies or groups of experts, routine screening of pregnant women for chronic HCV infection is not recommended for asymptomatic women without risk factors [54, 65]. Universal screening has not shown to be useful in a costeffective analysis [66]. This fact is a consequence of low prevalence and low rate of vertical transmission in general populations, and the absence of current prenatal or postnatal pharmacologic or immunologic measures that are proven to prevent vertical transmission of the virus [56, 67]. Additionally, a potential role of interferon during gestation as an anti-hcv therapy which could decrease maternal HCV viremia and possibly interfere with vertical transmission warrants further study [54]. Screening for HCV infection is generally recommended for the subset of pregnant women with risk factors for HCV exposure, considering the higher prevalence in these selected groups and the benefits for mother and infant to be identified and followed up [65, 67, 68]. Testing should be performed at the first prenatal visit. Women at high risk include those with history of injecting illegal drugs (even once); recipients of previously unscreened blood, blood products and organs (blood transfusion or solid organ transplant before 1992, coagulation factor concentrates before 1987) or from a blood donor who later tested positive for HCV infection; chronic (long-term) hemodialysis; persistently abnormal alanine aminotransferase levels without other evidence of liver disease; HIV-infection; occupational percutaneous or mucosal exposure to HCV-positive blood; long-term sex partner of an HCV-infected individual, born to an infected mother, administrating or receiving acupuncture and/or tattooing with unsterile medical devices [15, 69, 70]. Which Test (s) to Use? Detection of antibodies against HCV (anti-hcv) by an antibody screening assay (immunoassay, EIA, or enhanced chemiluminescence assay) followed by more specific supplemental assays (e.g., the recombinant immunoblot assay-riba or a nucleic acid test) is required for identifying and confirming persons with HCV infection. Interpretation of different tests can be found elsewhere [71]. 5. Asymptomatic Bacteriuria Urinary tract infection comprises the most common infection during pregnancy. Recent studies have shown that the prevalence of asymptomatic bacteriuria (ASB) in pregnant women, as defined by the presence of significant bacteriuria without symptoms of an acute urinary tract infection (UTI), varies from 2 to 15% with Escherichia coli being the etiologic agent in more than 80% of the cases [72, 73]. The physiological changes of the maternal organism occurring in genito-urinary system facilitate bacterial growth. These changes include progesterone-induced dilatation of the uretheres and renal pelvis, displacement of the urinary bladder from the pelvis into the abdomen, urinary stasis due to decreased uretheral and bladder tones, changes in urinary ph and osmolality, glycosuria and aminoaciduria [74]. Previous history of urinary tract infection and low socioeconomic status have also been identified as risk factors for urinary tract infection [75]. Asymptomatic bacteriuria is associated with adverse outcomes for both mother and neonate increasing the risk of labor and preterm delivery, premature rupture of membranes, neonatal sepsis and low birth weight [76]. Additionally, maternal risk for progression to pyelonephritis is high [77]. Convincing evidence indicates that detection and treatment of asymptomatic bacteriuria with antibiotics significantly reduces the incidence of symptomatic maternal urinary tract infections [78, 79]. Antibiotic treatment of asymptomatic bacteriuria is also associated with a decrease in the incidence of preterm delivery or low birth weight, but the methodological quality of the studies means that any conclusion about the strength of this association needs to be drawn cautiously [80, 81]. The need for universal screening pregnant women for asymptomatic bacteriuria has been reaffirmed by several guidelines. [78, 79, 82-84]. All of them recommend testing at least once during pregnancy. Most recommend a single urine culture at 12 to 16 weeks' gestation or at the first prenatal visit if later. Others indicate repeating testing around the 30th gestational week. Further, some authors have suggested that urine should be cultured in each trimester of pregnancy to improve the detection of asymptomatic bacteriuria, once up to half of the cases may be missed with just a single culture [85, 86] especially in high risk women. The best approach remains to be defined and many questions still remain unanswered.

6 Screening for Infectious Diseases During Pregnancy Current Women s Health Reviews, 2012, Vol. 8, No Which Test (s) to Use? An ideal screening test should be simple, rapid, sensitive, specific and not too expensive so that it can be implemented in all settings. The decision about the test to screen ASB in pregnancy is a balance between the performance of the test and cost of screening [87]. The gold standard diagnostic test is the urine culture. The presence of at least 10 5 colony-forming units of a single uropathogen per milliliter of urine from a midstream cleancatch specimen is considered a positive test result with a 95% probability that the pregnant woman has true bacteriuria [88]. However, there are limitations such as high cost, the need for microbiology laboratory with trained and experienced team and also the processing is labor-intensive and requires at least 24 hours, ideally 48 hours for results to be available. Consequently, it is usually not feasible for urine culture to be a universal screening test in resource-limited settings [89]. Many screening tests for ASB are available including urine Gram stain, microscopic urinalysis, urine dipsticks, dipslide urine cultures, bioluminescence assay, among others. The screening tests commonly used in the primary care setting (dipstick analysis and direct microscopy) have poor positive and negative predictive values for detecting bacteriuria in asymptomatic persons. However, no currently available tests have a high enough sensitivity and negative predictive value in pregnant women to replace urine culture as the preferred screening test [78, 80]. Further research is needed to develop a screening test that could reduce the use of urine culture. 6. Cytomegalovirus Human cytomegalovirus (CMV) is a member of the herpes virus family which is spread through contact with infected bodily fluids, such as urine, saliva or genital tract secretions. During the latency period after the primary infection which is typically asymptomatic, reactivation or reinfection with a different CMV strain can occur even in immunocompetent persons [90]. In general, the prevalence of CMV is lowest in developed countries and in high socioeconomic classes and high in poor countries and people with a low socioeconomic status. CMV is a major cause of human congenital infection in all regions of the world [91] and an important cause of neurological disease and sensorineural deafness in children [92]. Congenital infections are the result of transplacental transmission of CMV. Differently from other congenital infections, transmission and disease may occur as a consequence of both primary and recurrent maternal infection. However, the risk of vertical transmission of CMV is higher for mothers with primary (40%) than in those with non-primary (1%) infection during gestation [93]. Worldwide, birth prevalence estimates of congenital CMV infection ranges from 0.4% to 2.9% with higher rates being consistently demonstrated in populations with higher CMV seroprevalence [94]. Studies which identified infected newborns through universal screening showed that 12.7% of the infected infants have CMV-specific symptoms at birth, and 40-58% of them will have permanent sequel such as sensorineural hearing loss [95] and neurologic disease while the percentage of infants without symptoms at birth who developed permanent sequels was estimated to be 13.5% [96]. Although routine serologic screening of pregnant women or newborns has not been recommended by public health authorities, the need for a systematic screening for Cytomegalovirus infection during gestation has been debated raising several controversies [97]. Differently from those who recommend routine prenatal screening to prevent congenital infection [98], experts against it base their decision in the absence of recognized prenatal prophylaxis or treatment, or reliable infant prognosis markers in addition to difficulties for establishing reliable serological diagnosis of maternal primary infection or properly identifying secondary infection in a previously seropositive women [99-101]. These authors emphasized iatrogenic concerns resulting from screening such as parental anxiety, invasive prenatal testing, and, terminations of pregnancies for unaffected fetuses that could be more frequent than disorders related to congenital CMV infection. More recent developments have introduced the possibility for diagnosing maternal primary CMV by using avidity testing [ ]. Additionally, Nigro et al., [106] published a non-randomized or blinded study that suggested the ability to prevent and treat congenital CMV with maternal CMV intravenous immunoglobulin administered to mothers with primary infection. A cost-effective modeling analysis have indicated that universal screening for primary maternal cytomegalovirus at 20 weeks of gestation using IgG, IgM and avidity testing would be cost effective for reducing the burden of congenital CMV infection if treatment with cytomegalovirus-intravenous immune globulin achieved at least a 47% reduction in clinical disease [107]. However, in view of the lack of confirmation of the protective efficacy and the high cost and limited availability of the CMV-IVIG, the best approach to this issue is still controversial [108]. Further controlled trials with CMV- IVIG are needed. In populations with low or intermediate seroprevalence among women of reproductive age, and consequently a significant proportion of susceptible women, a selective screening strategy has been recommended by a single medical society (Society of Obstetricians and Gynaecologists of Canada) as follows: Serologic testing for CMV may be considered for women who develop influenza-like illness during pregnancy or following detection of sonographic findings suggestive of CMV infection. Seronegative health care and child care workers may be offered serologic monitoring during pregnancy. Monitoring may also be considered for seronegative pregnant women who have a young child in day care [109]. Other authors also suggest to include immunosuppressed patients and those who have clearly documented exposure to someone with active CMV infection [102]. With respect to populations with high seroprevalence rates such as those from developing countries in which most

7 164 Current Women s Health Reviews, 2012, Vol. 8, No. 2 Mussi-Pinhata and Quintana congenital infections area a result of secondary maternal infection [110], no real benefit of routine prenatal screening can be anticipated. With or without prenatal serologic screening, hygienic measures for prevention of congenital CMV infection should be taught to all pregnant women at the beginning of the gestation given it has shown to be protective [111]. Which Test (s) to Use? Conventional antibody testing with an immunoassay for CMV IgG and IgM is useful to identify seronegative women. Diagnosis of primary maternal cytomegalovirus (CMV) infection in pregnancy should be based on seroconversion, i.e. appearance of virus-specific IgG in the serum of a pregnant woman who was previously seronegative. When conventional tests show detection of IgM and IgG suggesting an acute infection, confirmatory immunoblot test for IgM should be performed along with IgG avidity. In addition to seroconversion, the presence of IgM and low avidity (<25%) can be used as a presumptive diagnosis of primary infection [112]. Virologic maternal tests are not enough to diagnose a recent primary maternal CMV infection and the detection or quantification of CMV in maternal blood does not seem to be associated with a higher risk for fetal infection [113]. 7. Group B Streptococcus (GBS) Group B Streptococci (including Streptococcus agalactiae) are gram-positive bacteria which are part of the normal vaginal microbiota. The source of vaginal GBS colonization is the maternal gastrointestinal tract. During pregnancy, GBS has been found to be present in the rectovaginal compartment of 6-45% of asymptomatic pregnant women [ ]. GBS can be transmitted to the fetus during gestation, passage through the birth canal or after delivery. Approximately 50-65% of infants born to colonized mothers are colonized in the skin, nasopharynx and gastrointestinal tract [118]. In GBS-colonized neonates, 1-2% of term infants and 8% of preterm infants will develop GBS early-onset disease [119]. GBS disease of the newborn usually presented as neonatal sepsis is one of the most common and serious infections in the first week after birth [120]. In addition to maternal colonization at delivery, the most important correlate of neonatal infection [121], several other risk factors have been identified, including gestational age less than 37 weeks, prolonged rupture of membranes (>12-18 hours), intra-amniotic infection, young maternal age, black race, hispanic ethnicity, and low maternal levels of anticapsular antigen [ ] Since the beginning of the eighties, several clinical trials demonstrated that administering intrapartum antibiotic prophylaxis during labor to women at risk of transmitting GBS to their newborns could prevent early-onset group B streptococcal disease [125]. The use of intrapartum antibiotics promotes a significant reduction in the rate of colonization in the newborn and early neonatal infection [126]. Decreasing incidence of SGB neonatal sepsis have been recorded in countries which have implemented policies for prevention such as the US [127]. The first US public health guidelines for prevention of perinatal GBS disease issued in 1996 [128] recommended identification of pregnant women at risk according two different approaches: (1) universal culture-based screening at weeks gestation for all pregnant women, with intrapartum antibiotic prophylaxis given to those with positive results; (2) intrapartum antibiotic prophylaxis given to all pregnant women with risk factors for GBS transmission: less than 37 weeks gestation, an intrapartum temperature 38ºC, or rupture of membranes for 18 hours without prior screening. However, after demonstration that culture-based screening strategy was 50% more effective in prevention of neonatal infection than the risk-based approach [129], these guidelines were revised to recommended universal screening of all pregnant women for rectovaginal GBS colonization at weeks' gestation and administration of intrapartum antibiotic prophylaxis to carriers [130]. The risk-based approach was restricted to those cases in which maternal GBS status was unknown. The implementation of these policies, still being used nowadays, has contributed to a significant decline in the incidence of early-onset group B streptococcal disease in this country [127, 131]. Although implemented in other developed countries, measures for prevention of GBS disease vary mainly based on epidemiological data. As an example, the national policy introduced in 2003 by the Royal College of Obstetrics and Gynaecology (RCOG) do not advocate a universal swabbased screening approach on the grounds of the relatively low incidence of GBS infection in the United Kingdom and the perceived risks associated with widespread use of antibiotics. They recommend discussing intrapartum antibiotic prophylaxis with women with gestational age below 37 weeks, premature rupture of membranes (PROM) over 18 hours, a previous baby with GBS, maternal pyrexia and known carriage of GBS. Which Test to Use? The screening based on history and/or clinical signs cannot be dismissed even if the available evidence shows that no risk factors will be found in up to 65% of early-onset GBS neonatal disease [132]. A key element of screeningbased prevention strategies is the accurate identification of colonized parturients to select them as appropriate candidates for intrapartum antibiotic prophylaxis. GBS culture remains the reference standard for the detection of GBS colonization. This method consists of obtaining specimens for culture at 35 to 37 weeks of gestation, requiring hours and also depends on the presence of viable microorganisms. The combination of vaginal and anorectal swab collected from the lower one-third of the vagina by using a cotton swab without the use of a speculum is the method of choice for obtaining specimens. The use of selective culture media as Todd-Hewitt with gentamicin and nalidixic acid is advocated since it significantly increases detection rates of GBS when compared to cultures performed in a non-selective broth. The cost of selective culture media is greater but greater sensitivity justifies its use [133].

8 Screening for Infectious Diseases During Pregnancy Current Women s Health Reviews, 2012, Vol. 8, No Considering that maternal colonization can occur after weeks gestation and result in early onset neonatal GBS disease in previously negative women [134] and women who lack prenatal care, rapid intrapartum tests based on immunological or hybridization methods have been proposed and compared with culture. A systematic review performed in 2006 set out to determine the accuracy and rapidity of various intrapartum group B Streptococcus (GBS) colonization tests [135] have concluded that real-time polymerase chain reaction (PCR) and optical immunoassay (OIA) were candidates for rapid intrapartum GBS testing to determine the need for antibiotic prophylaxis to prevent neonatal GBS disease which large scale implementation in practice should be assessed. More recently studies have confirmed that (PCR) based assays have been shown to be sensitive and specific tests [ ] but their practical use is limited because they require specific laboratory equipment and are costly. 8. Chlamydia trachomatis Chlamydia trachomatis (CT) is a gram negative bacteria that is not part of the normal human microbiota. In women it can infect the urinary and lower genital tracts in particular the endocervix and can ascend to the upper genital tract infecting the uterus, fallopian tubes and pelvic cavity. It can be transmitted through tissue secretions during vaginal, anal, or oral contact. Infection with CT is the most common sexually transmitted infection around the world showing high prevalence among adolescents and young adults. Globally it is estimated that about 2.8 million new infections are diagnosed each year [139]. The prevalence of chlamydia in women of childbearing age is estimated to range from 5 to 15 percent [140] varying according to region and from 2.2% in England, 3.2% in Australia and 7.4% in Brazil [141]. Between 70-75% of infections in women are asymptomatic, complicating diagnosis and treatment, thus perpetuating the infection for months or years. Untreated Chlamydia infection in pregnancy increases a woman s risk of miscarriage, preterm labor, rupture of membranes and postpartum endometritis, while babies born to mothers with Chlamydia are more likely to be of low birth weight [142]. Mother to child transmission can occur when the newborn passes through the birth canal and can result in neonatal ophthalmia and/or neonatal pneumonia [143]. For the mother the unfavorable results are mainly related to postpartum endometritis [143, 144]. Screening young people for chlamydial infections as public health approach to preventing and controlling sexually transmitted infections focusing on preventing reproductive pathology and improving future fertility has been implemented in North-America, Europe and Australia [145]. Contrasting, while guidelines for screening CT during pregnancy are available in the US since 2001 [146], no European-wide or international guidelines are available [145, 147] even though CT screening during pregnancy based on predictors of infection [148] is performed in developed countries [147, ]. Based on evidence from observational studies that pregnant women who are treated for chlamydia have improved pregnancy and birth outcomes, the US Preventive Services Task Force recommends selective chlamydia screening of pregnant women based on risk factors. Clinicians should routinely screen for chlamydia and gonorrhea all asymptomatic pregnant women age 24 years or younger, and other pregnant women at increased risk such as those with a history of CT or other sexually transmitted infection (STI), new or multiple sexual partners, inconsistent condom use and exchanging sex for money or drugs, and those African-American and Hispanic women living in high prevalence communities and settings or in other individual circumstances of higher risk [152]. Screening should be done at the first prenatal visit and repeated in the third trimester for pregnant women who remain at increased risk and for those who acquire a new risk factor, such as a new sexual partner. In a universal approach, the Centers for Disease Control and Prevention [65] recommends that all pregnant women should be routinely tested for Chlamydia trachomatis at the first prenatal visit. Women aged <25 years and those at increased risk for chlamydia (i.e., women who have a new or more than one sex partner) also should be retested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant. Which Test(s) to Use? In 2005, Cook and colleagues presented a systematic review of noninvasive testing for chlamydial infection in which overall high sensitivities and specificities were found for polymerase chain reaction and other nucleic acid amplification test (NAATs) from both genital (vaginal/ cervical) and urine samples [153]. In recent years, culture testing for genital Chlamydia trachomatis has been largely supplanted by use of nonculture molecular tests [154]. It has been shown that the NAAT detected between 17 and 28% more infections than other diagnostic procedures [155]. There are several commercial technologies NAAT, the best known being the polymerase chain reaction (PCR), the ligase chain reaction (LCR) and strand displacement amplification (SDA) [156]. Considering culture is the most widely available test and has the advantage of providing antimicrobial susceptibility [15], screening can be performed with a culture on Thayer- Martin media, which is recommended in a population with a low prevalence of infection [154]. 9. Gonorrhea Following Chlamydia, Neisseria gonorrhoeae is the next most prevalent bacterial sexually transmitted infection and also present with a wide spectrum of clinical disease. Both organisms can infect the cervix, urethra, oropharynx, conjunctiva, and rectum. Most of these infections are asymptomatic with young age, not using barrier contraception, having multiple sexual partners, and being of a nonwhite race the strongest predictors of this infection [157]. N. gonorrhea can be transmitted to the newborn from the mother s genital tract at the time of birth and can cause ophthalmia neonatorum, systemic neonatal infection, maternal endometritis, or pelvic infection. The risk of

9 166 Current Women s Health Reviews, 2012, Vol. 8, No. 2 Mussi-Pinhata and Quintana transmission from an infected mother to her infant ranges from percent [158]. Similarly to Chlamydial infections, screening for gonorrhea is recommended in early pregnancy for those who are at risk or who live in a high-prevalence area, and again in the third trimester for patients who continue to be at risk [15, 65]. Which Test(s) to Use? Nucleic acid hybridization tests of cervical specimens and NAATs of cervical specimens or urine are also used, with NAATs being the most sensitive and specific [153, 156]. It can be performed with a culture on Thayer-Martin media, which is recommended in a population with a low prevalence of infection [154]. 10. Toxoplasma gondii Toxoplasma gondii is an obligate intracellular protozoan parasite that infects up to a third of the world s population. The prevalence of this infection is highly variable and depends on the geographic region, hygienic measures and dietary habits, climatic conditions, lifestyle and cultural differences of each population. The main routes of infection occurs by ingestion of oocysts excreted by cats and contaminating soil or water, or by eating tissue cysts that remain viable in raw or undercooked meat of infected animals [159]. Overall seroprevalence rates ranges from around 9% in the United States of America, 9-58% in European countries, 51-72% in South American and 54-77% in African countries [160]. Foci of high prevalence exist in Latin America, parts of Eastern/Central Europe, the Middle East, parts of South-East Asia and Africa [161]. With very few exceptions [162] congenital infections acquired from immunocompetent mothers are a result of primary maternal infection during pregnancy. Fetal infection is very rare when maternal infection is acquired before the tenth week of pregnancy and rises with gestational age at maternal infection. Vertical transmission rates are 14%, 29%, 59%, and 80% in the first, second, third trimester and last weeks of pregnancy, respectively [163]. Early gestational infection may cause severe damage to the fetus while late maternal infection results in subclinical toxoplasmosis. Even though, neurological damage and/or visual impairment can be detected in the first years of the child s life [163]. Although testing for antibodies against T. gondii in pregnancy is common and routinely offered in some countries, no consensus exists about the benefits, diagnostic tests or the most effective antenatal screening strategy to prevent congenital toxoplasmosis. The need, costs, practical and ethical dilemmas, and modality of screening pregnant women for antibodies against toxoplasmosis is being debated for years [ ]. The main reasons for this debate is the uncertainty about the benefits of prenatal treatment and the concerns on the magnitude of the negative impact of screening, such as induced abortion of healthy fetuses, anxiety in women with false positive screening tests, and side effects of treatment [171, 172]. No randomized controlled clinical trial evaluating the benefits of prenatal treatment of maternal toxoplasmosis exists. The most recent systematic review of observational studies with respect to the effect of prenatal treatment on mother-to-child transmission and on the clinical manifestations of congenital toxoplasmosis found weak evidence for an association between maternal treatment < 3 weeks after seroconversion and reduced risk of congenital toxoplasmosis. However, no reduction in the risk of clinical manifestations in affected infants was shown [173]. Conversely, promotion of simple measures targeting primary prevention of toxoplasmosis during pregnancy such as reinforcement of the physician orientations by means of antenatal classes and leaflets containing recommendations on the nature of the disease and its avoidance has been shown to significantly reduce [92%] seroconversion during pregnancy in Germany [174]. In different countries, implementation of screening for congenital toxoplasmosis have led to diverse policies including no routine screening [175], neonatal screening [176, 177], and prenatal screening starting in the first visit with monthly [178] or 3-monthly re-testing of seronegative women [179]. Which Test(s) to Use? As most of immunocompetent individuals with primary infection are asymptomatic, including pregnant women, the diagnosis of infection is mainly performed with the use of serological techniques. The objective is to identify pregnant women who acquire infection during gestation, i.e. those with the greatest risk of giving birth to an infant with congenital toxoplasmosis. When the first maternal test results negative, periodical testing can identify seroconversion or significant rise in IgG antibodies consistent with established recently acquired infection. Available assays include the Sabin-Feldman, Indirect Hemagglutination (IHA), Indirect Immunofluorescence (IIF) and enzyme techniques of ELISA (Enzyme Linked Immunosorbent Assay), ELFA (Enzyme- Linked Immunofiltration Assay), and ISAGA (Immunosorbent Agglutination Assay). ELISA, ISAGA, and ELFA are currently the most widely used techniques for screening of populations at large scale because they are automated and accurately identify IgM and IgG antibodies, with high sensitivity and reproducibility [180]. On the other hand, the presence of IgG and/or IgM toxoplasma antibodies in a single serum sample drawn during gestation cannot define whether the infection was recently acquired or chronic, since IgM toxoplasma antibodies cannot be true positives [181] or be long lasting [182]. More recently, the IgG avidity test, which is a test based in the measurement of the functional affinity of toxoplasma-specific antibodies, was developed to help discriminate between past and recently acquired infection [183]. High avidity indexes are helpful to rule out that a patient infection occurred within the prior 4 to 5 months. However, a low avidity result does not mean the patient had a recently acquired infection because low-avidity antibodies may persist for as long as 1 year. In addition, substantial