The Impact of Infection During Pregnancy on the Mother and Baby

16 The Impact of Infection During Pregnancy on the Mother and Baby

Heather E. Jeffery and Monica M. Lahra

Infection continues to account for a major pro- ascending infection from the lower genital tract, portion of maternal, fetal, and neonatal mortality and perinatal acquisition, which includes nos- and morbidity worldwide. ocomial infection and transmission of infection In the developing world, maternal systemic via breast milk (maternal or banked milk). infections, such as pneumonia, malaria, tubercu- The impact of infection (bacterial, viral, or losis, typhoid fever, and pyelonephritis, which are other) on the mother or the fetus is dependent often functions of poverty, crowding, and malnu- on maternal and fetal factors in addition to the trition, impose health costs to the mother and pathogenic properties of the infecting agent. risks to the fetus. These risks include spontaneous Maternal factors include immune function and abortion, stillbirth, preterm labor and preterm status, anatomical factors, and comorbidity. birth, low birth weight, intrauterine growth Infecting agent factors include dose, exposure, restriction (IUGR), and infection. This is in addi- and individual virulence factors. Fetal factors tion to the rapidly escalating rates of a number of include gestational age, developmental stage, and sexually transmitted diseases, in particular, fetal immune function. Table 16.1 summarizes human immunodefi ciency virus (HIV) infection the potential impact on the fetus and neonate with its associated comorbidities. with respect to the ante-, peri-, and postnatal In the developed world, preterm birth remains periods. a major, unresolved public health issue. Intrauter- The impact of infection in pregnancy on both ine infection has been shown to play a major role mother and baby is discussed in this chapter. in induction of preterm birth and neonatal infection (Goldenberg et al. 2000b). More recently the contribution of asymptomatic bacteruria (Rouse Infection and Preterm Birth et al. 1995; Smaill 2001), periodontal disease (Offenbacher et al. 1996; Newnham et al. 2005), Preterm birth is the leading cause of perinatal and abnormal vaginal fl ora (Kiss et al. 2004) to death and long-term handicap, accounting for preterm labor and delivery has been recognized. 70% of perinatal deaths in developed countries such as the United States, where approximately 10% of all births are preterm (Goldenberg et al. Congenital Infections 2000b). Preterm births can be categorized into three Vertical transmission of infection (from mother groups (Arias and Tomich 1982): (1) spontaneous to baby) occurs across mammalian species preterm labor and intact membranes; (2) preterm causing injury, malformation, sepsis, and death. labor with prelabor rupture of membranes; and The mode of transmission of infection from (3) preterm birth indicated for maternal or fetal mother to fetus includes the hematogenous route, reasons. Preterm deliveries that fall into the fi rst

379 380 H.E. Jeffery and M.M. Lahra

TABLE 16.1. Impact of congenital infection on pregnancy infection (e.g., listeriosis). Uncommonly, retro- outcome grade infection via the fallopian tubes or Antenatal Perinatal Postnatal iatrogenic infection introduced from invasive Preterm labor Sepsis Infection procedures such as amniocentesis occurs Fetal injury Perinatal death Malformation (Goldenberg et al. 2000b) (Fig. 16.1). Malformation Developmental Ascending infection resulting in chorioamnio- Intrauterine growth abnormalities nitis may account for up to 50% of preterm restriction Small for gestational age births at less than 30 weeks’ gestation (Lockwood Intrauterine death Neonatal death 2002). The organisms implicated are largely anaerobes and genital mycoplasmas, but can two categories are most commonly associated include organisms such as group B streptococcus with ascending intrauterine infection. (GBS). The source of intrauterine infection is most The inﬂ ammatory response in chorioamnion- commonly ascending organisms from the lower itis is predominantly maternal in origin. Chorio- genital tract and less commonly blood-borne amnionitis may be diagnosed by histological or

FIGURE 16.1. Cross section of a gravid uterus illustrating routes of intrauterine infection. (From Goldenberg et al. 2000b, with permission. Copyright © 2000, Massachusetts Medical Society. All rights reserved.) 16. The Impact of Infection During Pregnancy on the Mother and Baby 381

70 n = 261 n = 200 60 n = 139

n = 164 50

40 n = 236 n = 284 n = 375 n = 380 30 n = 539 n = 580

Histological chorioamnionitis % 20 n = 770

10 n = 6139

0 20–24 25 26 27 28 29 30 31 32 33 34 37–40

Gestational Age (completed weeks)

FIGURE 16.2. Incidence of histological chorioamnionitis by gestational age in a large preterm cohort compared with a term cohort. (From Lahra and Jeffery 2004, with permission from Elsevier.)

by clinical fi ndings. The hallmarks of clinical rupture (preterm prelabor rupture of membranes) chorioamnionitis are maternal fever, uterine and cervical maturation leading to preterm birth tenderness, and discharge. However, it is (Romero et al. 2003). im portant to note that in the vast majority of Entry of organisms or bacterial products into cases chorioamnionitis is clinically silent and is the amniotic fl uid and subsequently into the fetus most often diagnosed histologically. There is a similarly provokes elevated fetal proinfl amma- linear and inverse relationship between histo- tory cytokine levels in a response known as the logical chorioamnionitis and gestational age, fetal infl ammatory response syndrome (FIRS). and it is most common at gestations less Subclinical fetal infection is underrecognized and than 30 weeks (Lahra and Jeffery 2004) (Fig. is associated with preterm birth, fetal injury, and 16.2). The incidence of histological chorio- intrauterine death. It is also associated with infec- amnionitis at term gestation, using the same tion in the neonatal period. One study found that methodology and diagnostic criteria, was 3.8% fetal bacteremia was eight times more likely in (Russell 1979). women with positive amniotic fl uid cultures than The infl ammatory response includes the pro- those with negative cultures (33% versus 4%) duction of proinfl ammatory cytokines and infl am- (Carrol et al. 1996). matory mediators (prostaglandins, leukotrienes, The fetal infl ammatory response is manifested etc.). The associative evidence suggests that histologically as chorionic vasculitis, umbilical infl ammation triggers prostaglandin synthesis in vasculitis, or funisitis (Yoon et al. 2000; Pacora the amnion, chorion, decidua, and myometrium, et al. 2002). leading to myometrial contractions and cervical The fetal infl ammatory response and its impor- dilatation (preterm labor) with further augmenta- tance has been summarized by Leviton et al. tion of the whole process. Proinfl ammatory cyto- (1999): kines also stimulate production of matrix metalloproteases by the chorion and amnion, • The fetus contributes to the cellular infl amma- which lead to cervical ripening and membrane tory response in amniotic fl uid infection. 382 H.E. Jeffery and M.M. Lahra

• The more severe the histological infl ammatory These fi ndings highlight the importance of response, the higher the level of cytokines in the histological and microbiological examination of amniotic fl uid. the placenta, extraplacental membranes, and • Funisitis is better than membrane infl amma- umbilical cord in preterm birth, stillbirth, and tion in predicting preterm labor and perinatal term babies requiring admission to an intensive death. care facility. The role of cytokine measurement in • Elevated proinfl ammatory cytokine levels in the clinical practice and prediction of preterm labor amniotic fl uid, umbilical cord blood, and early is in evolution. neonatal blood are some of the best predictors of preterm parturition, cerebral white matter damage, and cerebral palsy. Specific Maternal Infections • Proinfl ammatory cytokines are elevated in the brains of infants who die with histological evi- Urinary Tract Infection dence of white matter damage. Background

Chronic Uterine Infection Urinary tract infections (UTIs) are the most common bacterial infection in pregnancy and While intrauterine infection has been considered occur when bacteria enter and infect the normally to be acute, there is evidence suggesting that sterile urinary tract. Urinary tract infection may it may be chronic. Genetic amniocentesis at 16 be classifi ed as symptomatic bacteruria and to 21 weeks identifi ed Mycoplasma hominis and asymptomatic bacteruria. Ureaplasma urealyticum on culture in a small Symptomatic infections may be localized to number of women (Cassell et al. 1983). This the bladder (cystitis) or involve kidney infection clinically silent infection was associated with (pyelonephritis) with systemic symptoms and adverse pregnancy outcome (pregnancy loss and signs. Urinary tract anomalies, HIV, and diabetes preterm birth) and histological chorioamnion- increase the risk of pyelonephritis as does preg- itis. Similarly, in summarizing cytokine fi ndings nancy (Foxman 2003). in midtrimester amniotic fl uid, Romero et al. By contrast, asymptomatic bacteruria (ASB) is (2003) reported higher median interleukin-6 (IL- more common and requires screening midstream 6) levels in amniotic fl uid of those who delivered urine at the fi rst antenatal visit for detection, pref- preterm compared to those who delivered at erably at 12 to 16 weeks’ gestation (Nicolle et al. term. Maternal IL-6 levels were not associated 2005). Identifi cation is important as UTI in preg- with adverse pregnancy outcome. In contrast, nancy can lead to maternal and perinatal compli- elevated levels of maternal granulocyte colony- cations (Pastore et al. 1999). stimulating factor at 24 and 28 weeks’ gestation was associated with preterm birth at <32 weeks’ Microbiology gestation but not with late spontaneous preterm Causative organisms are predominantly gram birth, in a case-control study of asymptomatic negative (>90%), most commonly E. coli and less women (Goldenberg et al. 2000a). often Enterobacter species, Proteus mirabilis, Animal models support the human evidence Klebsiella species, Citrobacter species, and Pseu- that bacteria or bacterial products (lipopoly- domonas species. Gram-positive organisms such saccharides) can precipitate preterm birth. In as GBS account for about 5% of UTIs in pregnant rabbits and monkeys, intraamniotic injection of women (Le et al. 2004). a range of bacteria including GBS, fusobacterium species, gram-negative anaerobes, Prevotella Epidemiology bivia and Escherichia coli lead to rapid onset of labor accompanied by increased cytokine levels Acute pyelonephritis occurs in 1% to 2% of preg- and histological chorioamnionitis (Romero et al. nant women, predominantly at around 28 to 30 2001; Newnham et al. 2005). weeks’ gestation, acute cystitis in 1% to 4%, 16. The Impact of Infection During Pregnancy on the Mother and Baby 383 and asymptomatic bacteruria in 2% to 10% (Le Initial antibiotic therapy for asymptomatic bac- et al. 2004). teruria and for cystitis, while awaiting results of culture and sensitivity, should cover E. coli and Pathogenesis depends on local resistance patterns. β-lactams including cephalosporins and other derivatives Factors increasing the risk of UTI include (1) the are well tolerated, safe, and have minimal mater- normally short female urethra, which is exposed nal side effects. Intravenous penicillin G or ampi- to enteric bacteria from the nearby vagina cillin is recommended for GBS infections (Le et al. and rectum; (2) ureteral dilatation occurring 2004). Currently as it is unknown if a 1-day course throughout pregnancy beginning from the sixth is as effective as a 4- to 7-day course for asymp- week and decreased ureteral and bladder tone, tomatic bacteruria (Villar et al. 2000), 3 to 7 days contributing to urinary stasis and ureterovesical of treatment is recommended (Nicolle et al. 2005). refl ux; and (3) mechanical compression of the A 10-day follow-up culture after completion of the ureters and bladder from the enlarging uterus, course is recommended. leading to urinary stasis (Le et al. 2004). Untreated Both symptomatic and asymptomatic GBS bac- asymptomatic bacteruria will lead to pyelone- teruria require immediate treatment as well as phritis in up to 35% of women (Nicolle et al. intrapartum antibiotic prophylaxis (Centers for 2005). Disease Control and Prevention 2002a). Treat- Clinical Features ment of UTIs due to GBS signifi cantly reduced preterm rupture of membranes and preterm Typically, cystitis is associated with burning on delivery in the only reported randomized control urination, urgency, frequency, and suprapubic dis- trial (Thomsen et al. 1987). comfort, although the last two symptoms may also Acute pyelonephritis requires hospitalization occur as part of advancing pregnancy. Pyelone- and urgent treatment to reduce perinatal and phritis is often characterized by high temperature maternal complications. Injectable cephalospo- and costovertebral tenderness; other symptoms rins and the combination of ampicillin and genta- may include chills, nausea, and vomiting. mycin are usually effective. Other antimicrobial regimens are available (Le et al. 2004). Insuffi cient Diagnosis data limit recommendation of any specifi c regimen for symptomatic UTIs in pregnancy (Vazquez and On culture of a midstream clean-catch specimen Villar 2003). Close follow-up of UTIs in pregnancy of urine, ASB is defi ned as у105 colony-forming is necessary to prevent complications and to eval- units per milliliter (CFU/mL), cystitis у103 CFU/ uate the need for suppression therapy to prevent mL, and pyelonephritis у104 CFU/mL (Le et al. recurrences. 2004). Rapid diagnostic tests such as nitrites, urine dipstick, or Gram staining of urine have poor sensitivity and positive predictive values Public Health Issues (Bachman et al. 1993). 1. The cost-effectiveness of screening and Treatment treatment for asymptomatic bacteruria in pregnancy is justifi ed (Rouse et al. 1995). A systematic review has confi rmed that treatment 2. Group B streptococcus bacteruria in preg- of asymptomatic bacteruria signifi cantly improves nancy, whether symptomatic or asymptomatic, outcomes for the mother and baby and is cost- requires intrapartum prophylaxis to prevent effective (Rouse et al. 1995). The odds ratio (OR) early-onset GBS neonatal disease (Centers for and confi dence interval (CI) indicate a signifi cant Disease Control and Prevention 2002a). reduction in subsequent pyelonephritis (OR 0.24, 3. A reported possible association between UTI 95% CI 0.19–0.32) and preterm or low birth weight in pregnancy and cognitive delay of the infant delivery (OR 0.60, 95% CI 0.45–0.80) (Smaill emphasizes the importance of health education, 2001). screening for bacteruria in early pregnancy, rapid 384 H.E. Jeffery and M.M. Lahra diagnosis of UTIs, and immediate treatment However, microorganisms can enter the lower (Mittal and Wing 2005). respiratory tract by aspiration, inhalation, or occasionally spread from the blood to lung. Pneumonia Pneumonia then occurs if there is a defect in host defenses (e.g., HIV) or the microorganisms Background are especially pathogenic or profuse. In Western countries, pneumonia in pregnancy is uncommon despite a potential maternal vulnera- Clinical Features bility to respiratory infection from the reported Typically the features include dyspnea at rest, decrease in cell-mediated immunity, changes in cough, and fever, and may include pleuritic chest respiratory physiology, and anesthetic interven- pain and fi ne rales on auscultation, but none are tions (Lim et al. 2001). defi nitive. Misdiagnosis (pyelonephritis, appendi- citis, preterm labor) or delay in diagnosis in preg- Microbiology nancy has been documented (Yost et al. 2000; Lim More often than not, the causative organism et al. 2001). is unknown, which is in part due to underinvesti- gation. Streptococcus pneumoniae is the Diagnosis most common pathogen isolated followed by Chest x-ray (CXR) is important for diagnosis, Haemophilus infl uenzae. Very occasionally although the presence of an infi ltrate is not diag- Mycoplasma pneumoniae, Legionella species, nostic of the causative agent. Gram stain of Staphylococcus aureus, infl uenza virus, and vari- sputum, cultures of sputum and blood, serology, cella-zoster virus are causative (Lim et al. 2001). and nucleic acid amplifi cation testing (NAAT) Infl uenza A (types A, B, and C) is usually associ- improve the likelihood of identifying the caus- ated with epidemics and can be particularly severe ative pathogen. in pregnancy (Lim et al. 2001).

Epidemiology and Transmission: Incidence, Treatment Carriage, and Seroprevalence Antibiotics with a clear safety record in pregnancy The incidence of hospitalization for pneumonia in for treatment of bacterial pneumonia include pregnancy does not seem to differ from that in penicillins, cephalosporins, and macrolides. The young, nonpregnant adults (Lim et al. 2001) and safety in pregnancy of other antimicrobials are has been reported as 1.5 per 1000 deliveries (Laibl listed elsewhere (Lim et al. 2001). and Sheffi eld 2005b). However, the incidence is much higher in patients with HIV, especially if Prevention the CD4+ lymphocyte count is <500/mm, when Primary prevention of the most common bacte- Pneumocystis jiroveci (previously Pneumocystis rial and viral pneumonias is by vaccination. Pre- carinii) pneumonia and bacterial pneumonia are pregnancy counseling should include disease or more likely (Laibl and Sheffi eld 2005b). vaccination history of S. pneumoniae, H. infl uen- Risk factors include anemia, smoking, and zae type b, infl uenza (inactivated vaccine), and immunosuppression, whether by prescribed varicella. In adults, while systematic review indi- drugs, HIV, illicit drug use, asthma, or chronic cates that the pneumococcal vaccine does not respiratory diseases (Berkowitz and LaSala 1990; appear to reduce the incidence of pneumonia or Lim et al. 2001). death, the reports of case-control studies indicate Pathogenesis a signifi cant 53% reduction in invasive pneumococcal disease (Dear et al. 2003). The normal host defenses (anatomical barriers, Secondary prevention methods include hand ciliary function, immune function, phagocytic washing, respiratory and contact isolation, and activity) ensure sterility of the lower airways. contact prophylaxis. 16. The Impact of Infection During Pregnancy on the Mother and Baby 385

Public Health Issues Epidemiology Viral pneumonias, especially infl uenza and vari- The reported carriage rate in women varies widely cella, are readily spread by aerosol in both the from 5% to 51%. In the pregnant population, community and hospital settings. Identifi cation of prevalence ranges from 6% to 32%. Risk factors these agents as being causative requires special include smoking, sexual activity, douching, and infectious disease precautions, particularly in black race (Yudin 2005). The etiology is unknown; hospitals. Varicella-zoster immunoglobulin, given however, the epidemiology of BV does have some within 96 hours of exposure to varicella, can features of a sexually transmitted infection (STI). prevent or attenuate the disease and is safe in Furthermore, fi ndings from a recent cohort study pregnancy, as is the inactivated vaccine, but the suggest BV is sexually transmitted (Bradshaw live attenuated vaccine is not safe in pregnancy et al. 2005). (Laibl and Sheffi eld 2005b). Pathogenesis The replacement of the predominant commensal Abnormal Vaginal Tract Flora vaginal lactobacilli (normally >95%) with a high concentration of polymicrobes may be due to Bacterial Vaginosis transmissible lactobacillus phages (Blackwell Background 1999), which destroy the normal fl ora with secondary overgrowth of anaerobes. Bacterial vaginosis (BV) is an overgrowth of vaginal anaerobes with depletion of the normal lactobacillus leading to an increase in vaginal Clinical Features pH from normal (<4.5) up to 7. The etiology The clinical feature is vaginal discharge with a is unclear and BV may be symptomatic or distinctive fi shy odor, which is due to polyamines asymptomatic. and trimethylamine. Approximately 50% of Bacterial vaginosis is the commonest cause women are asymptomatic. of abnormal vaginal discharge in women of reproductive age. During pregnancy it is Diagnosis important because of the associated adverse perinatal outcomes including chorioamnionitis, Gram-stained, vaginal smears are examined using intraamniotic infection, late miscarriage, pre- either Nugent’s criteria or Spiegel’s criteria, and mature rupture of membranes, preterm birth, estimating relative proportions of bacterial types and postpartum endometritis. In addition, is most commonly used and is reliable (Yudin there is an increased susceptibility to HIV 2005). Alternatively, a clinical but more problem- in fection if exposure to the virus occurs (Yudin atic method is used (Amsel’s criteria), which 2005). requires the presence of at least three of the following: thin, white-gray, homogeneous discharge; > Microbiology pH of vaginal fl uid 4.5; fi shy odor released on adding alkali (1% or 10% potassium hydroxide), The most common organisms implicated in BV and examination for clue cells on direct micros- are Gardnerella vaginalis, Mobiluncus spp., copy (Yudin 2005). Bacteroides spp. and Mycoplasma hominis in conjunction with a decrease in the normal popu- Treatment lation of lactobacilli. The spectrum of organisms is dynamic over the course of BV. Studies using Oral or topical antimicrobials include metronida- polymerase chain reaction (PCR) methodology zole and clindamycin. Screening of partners does suggest a greater complexity than is currently rec- not affect the recurrence rate, which can be as ognized and is one reason for treatment failure high as two thirds of treated women, due to relapse (DeVillard et al. 2005). or reinfection (Yudin 2005). 386 H.E. Jeffery and M.M. Lahra

Prevention TABLE 16.2. Classification of vulvovaginal candidiasis (VVC) Uncomplicated VVC Complicated VVC Primary prevention by vaccination is not available, but risk can be reduced by limiting factors Sporadic or infrequent Recurrent such as smoking, douching, and number of sex OR OR Mild to moderate vulvovaginal Severe vulvovaginal candidiasis partners. candidiasis Screening for BV in high-risk pregnant women OR OR (previous preterm birth) and treatment may Likely to be C. albicans Nonalbicans candidiasis prevent preterm rupture of membranes and low OR OR birth weight. No evidence is provided from the Nonimmunocompromised host Women with uncontrolled diabetes, debilitation or same systematic review that screening and treat- those who are pregnant ing low risk women prevents preterm birth (McDonald et al. 2005). This advice is challenged Source: Centers for Disease Control and Prevention (2002b). by Lamont et al. (2003) and Lamont (2005), who conclude that, if screening and treatment is performed early in the second trimester in low risk Epidemiology pregnant women, intervention is protective. Most candidal infections are endogenous, but Public Health Issues human-to-human transmission exists (vertical from mother to baby) (Fig. 16.3). Sexual transmis- Further controlled trials are needed to evaluate sion, however, is not a signifi cant factor (Carr the role of early treatment of BV in the fi rst or et al. 1998). Recurrent vulvovaginal candidiasis, early second trimester in the prevention of defi ned as four or more attacks of symptomatic preterm birth. candidal vaginitis in a 12-month period, is estimated at 5% of women during reproductive years Candidiasis (Centers for Disease Control and Prevention 2002b). Background Pathogenesis Candidal vulvovaginitis is a common clinical problem, affecting most adult women at least once Pregnancy is one factor that increases susceptibil- during their lifetime. An estimated 75% of women ity to vaginal yeast infection, by enhancing the will have at least one episode and 40% will have adherence of Candida to vaginal epithelial cells, two or more episodes. Vulvovaginal candidiasis through the effect of estrogen. Other factors can be classifi ed as uncomplicated or complicated, include oral contraceptives, broad-spectrum anti- based on clinical presentation, microbiology, host factors, and response to therapy (Centers for Disease Control and Prevention 2002b) (Table 16.2). Candida is a normal commensal fl ora in humans and is commonly found on the skin and in the gastrointestinal and genital tracts.

Microbiology Yeasts are unicellular organisms that form part of the commensal fl ora in humans and are recognized as opportunistic pathogens. Candida albicans causes approximately 80% of yeast infections and Candida glabrata and Candida tropicalis most of the remainder. Laboratory identifi cation FIGURE 16.3. Candida albicans congenital infection showing pus- to species level is based on growth and morpho- tules, vesicles, and diffuse erythema on day 3. Monochorionic twin logical and biochemical characteristics. died day 1 from septicemia with Candida albicans. 16. The Impact of Infection During Pregnancy on the Mother and Baby 387 biotics, diabetes, systemic steroids, obesity, and Diagnosis immunocompromised states including HIV infec- Vaginal swab is used for microscopy, culture, tion. Stress-induced and premenstrual yeast vagi- and sensitivity. In determining the cause of nitis is frequently described by women, but the vaginitis (Table 16.3), the following points are cause is unknown (Carr et al. 1998). noteworthy: Recurrent candidal vaginitis can be partly attributed to reduced T-lymphocyte reactivity to • Failure to identify the cause of vaginitis by Candida antigen, thus permitting proliferation laboratory testing occurs in only a minority and germination that is limited to the genital of women. tract. Relapse rather than reinfection is suggested • Culture for Trichomonas vaginalis is more sen- by negative cultures after treatment and by same- sitive than microscopic examination. strain Candida-positive cultures at 30 days in 25% • Chlamydia trachomatis and Neisseria gonor- to 30% of women (Carr et al. 1998). rhoeae can sometimes cause vaginal discharge in addition to candidal, trichomonal, and chla- Clinical Features mydial infections. Most women with candidal vulvovaginitis have symptoms. Prominent but nonspecifi c symptoms Treatment are vaginal discharge, pruritus, vaginal soreness, external dysuria, and dyspareunia. The vulva is Topical azole therapy, applied for 7 days, is red, often with scaling and fi ssures, and the vaginal recommended for candidiasis in pregnancy rugations are red and infl amed with adherent (Young and Jewell 2001). Treatment of sex vaginal discharge that is thick, white to yellow in partners is not recommended, other than for color, and odorless (Carr et al. 1998; Centers for recurrent infection (Centers for Disease Control Disease Control and Prevention 2002b). and Prevention 2002b). Candida, although common in the vagina, is a rare cause of amnionitis (Chaim et al. 1992) and Prevention an even rarer cause of neonatal skin infection at Prevention entails avoidance of factors that birth (pustules, vesicles, or diffuse erythema), increase susceptibility, such as broad-spectrum which is responsive to topical therapy (Fig. 16.3). antibiotics. In the 1980s a trial of C. albicans oral Disseminated candidiasis in the neonate is vaccine was discontinued, although phase I efforts usually limited to the extremely low birth weight/ continue (Fletcher 2001). early gestational age infant, typically as a nosocomial, catheter-acquired complication. The menin- Public Health Issues ges, kidneys, and eyes may be involved. There is insuffi cient evidence from systematic review to A large randomized trial found a signifi cant recommend prophylactic oral antifungal agents to reduction in preterm delivery following screening prevent systemic Candida infection in preterm and standardized treatment for vaginal infections infants (Austin and Darlow 2003). at 15 to 19 weeks’ gestation. The most prevalent

TABLE 16.3. Diagnosis of vaginal infection Infection Symptoms Physical examination Discharge Odor pH Diagnosis Yeast infection Pruritus Fissures, labial rash Thick, white to yellow Absent <4.5 KOH wet prep + hyphae C&S “cottage cheese” Bacterial vaginosis Variable, 50% Thin, white to gray, Present >4.5 Clinical criteria, 3 of 4 Gram asymptomatic homogeneous (fishy) stain Trichomonas infection Pruritus, often Strawbery cervix Profuse, green Present >4.5 NS wet prep + trichomonads asymptomatic watery or absent C&S

C&S, culture and sensitivity. Source: Modified from Carr et al. 1998, with permission from Blackwell Publishing. 388 H.E. Jeffery and M.M. Lahra infection was candidiasis (Kiss et al. 2004). This example, condoms (Stevens-Simon and Sheeder needs conﬁ rmation from further trials as the 2005). Current vaccine development is discussed potential impact in the prevention of preterm by Fletcher (2001). birth is great. Polizzotto (2005), in critically reviewing the literature, concluded that successful behavioral interventions for STI prevention necessitate tai- Sexually Transmitted Infections in loring it to culture, ethnicity, and gender, employ- Women and Adverse Pregnancy and ing interpersonal skills training and delivering the Neonatal Outcomes intervention to small groups.

Sexually transmitted infections (STIs), a leading Trichomonas vaginalis public health problem worldwide, produce a large Background burden of disease in women of reproductive age. Vertical transmission to the fetus occurs either by Trichomonal infection is one of the most common ascending infection from the vagina or cervix STIs and has signifi cant health consequences for or by transplacental transmission from infected men and women. maternal blood. The estimated number of preg- Microbiology nant women in the U.S. with STIs each year is listed in Table 16.4. Early detection and treatment Trichomonas vaginalis is a fl agellated protozoan. are important because of the often severe conse- The parasite is not normally present in the quences to mother, fetus, or neonate. The bacte- vagina. rial infections are discussed fi rst and viral infections in a later section. Epidemiology Public health control measures that are common Compared with other STIs, rates are not higher in to all STIs with their potentially adverse repro- the young but are evenly distributed across sexu- ductive health consequences include primary pre- ally active women of all age groups. Transmission vention by community education concerning safe is almost always sexual, and prevalence is highest sexual practices and high-risk behavior; screening among women with multiple sex partners and a of at-risk women at STI clinics and elsewhere, and history of gonorrhoea (Cotch et al. 1991). Trans- routine screening and treatment of patients’ sex mission rate from infected women to men and partners; testing for other common STIs; report- vice versa is high, 70% and 80% to 100%, respec- ing of cases by health providers to determine epi- tively (Soper 2004). The World Health Organiza- demiological trends and facilitate targeted control; tion (WHO) estimates T. vaginalis infection personal counseling to induce safe sexual behav- accounts for almost half of all curable STIs. Preva- ior including the use of barrier methods, for lence rates are approximately 10%, depending on the population sampled. T. vaginalis infection is commonly associated with other STIs especially TABLE 16.4. Sexually transmitted infections in pregnant women in the United States gonorrhea and may be a marker of high-risk behaviour, and most infected women also have Estimated number of pregnant women Infection infected per annum bacterial vaginosis (Risser et al. 2005). In pregnant women, there is an association Bacterial vaginosis 800,000 (some evidence of STI) with preterm birth, an increased risk of postce- Herpes simplex 800,000 Chlamydia 200,000 sarean endometritis, and an increased risk of Trichomoniasis 80,000 HIV transmission and infectivity (Heine and Gonorrhea 40,000 McGregor 1993; Cotch et al. 1997; Soper 2004). Hepatitis B 40,000 Generally, there is a greater risk of tubal infertil- HIV 8,000 ity and pelvic infl ammatory disease (PID), ectopic Syphilis 8,000 pregnancy, and increased risk of cervical cancer Source: Centers for Disease Control and Prevention (2005i). (Soper 2004). 16. The Impact of Infection During Pregnancy on the Mother and Baby 389

Pathogenesis Prevention Symptoms develop after an incubation period Prevention is dependent on reduction in exposure of up to 28 days following sexual contact. T. by abstinence or by having single rather than mul- vaginalis produces epithelial damage and micro- tiple partners, and consistent and correct use of ulcerations. condoms, which possibly reduces acquisition of T. vaginalis infection by women (Holmes et al. 2004). Clinical Features There is no vaccine. Only about half of all women with infection are Public Health Issues symptomatic. The most frequent symptoms and signs include excessive yellow/green vaginal dis- Trichomoniasis is underdiagnosed and underre- charge, vulvar itching, vaginal/vulvar erythema, ported, despite high prevalence rates and the vaginal odor, and occasionally a red, erythema- serious consequences of infection for both men tous cervix—”strawberry cervix” (Soper 2004). and women. In general, problems relate to routine Symptomatic neonatal infection is unusual. screening that is limited to STI clinics, vaginal wet Vaginal discharge in neonates is described, and mount preparations that are used as diagnostic transmission is probably due to exposure to standards despite limited sensitivity, and non- maternal trichomoniasis (Danesh et al. 1995). mandatory public health reporting. Public health control measures similar to those for chlamydia Diagnosis and gonorrhea are needed (see below). Several diagnostic methods are available. Those with the highest sensitivity (Sn) and specifi city Chlamydia trachomatis (Sp) include culture in Diamond’s media (Sn 85– Background 95%; Sp >95%), antigen based point of care testing (Sn 95%; Sp >95%), and NAATs (Sn >90%; Sp Chlamydia is an STI caused by C. trachomatis and >95%) (Soper 2004). is one of the most common infections occurring The most commonly used test is a wet mount worldwide. It is the most common STI in the U.S., preparation and detection of motile trichomo- with an estimated 3 million new cases annually nads. This method is highly specifi c (>90%), but (Workowski et al. 2002). C. trachomatis causes sensitivity is only 50% to 60%. Thus a negative ocular trachoma, the commonest cause of pre- result does not rule out trichomoniasis (Soper ventable blindness, and genital tract infection 2004). Screening for other STIs is indicated. (cervicitis), which can have both maternal and neonatal complications. Adverse outcomes for Treatment women include PID, ectopic pregnancy, and infertility, and for neonates, conjunctivitis and pneu- Treatment of symptomatic pregnant women is monia (Centers for Disease Control and Prevention indicated, but it remains unknown whether this 2004). The natural history is unknown, but data will have any effect on pregnancy outcomes suggest chronic asymptomatic or persistent infec- (Gülmezoglu 2002). In asymptomatic pregnant tion is frequent, as is reinfection. women, uncertainty remains as to whether to treat. One trial reported a higher rate of preterm Microbiology delivery in the treated group (Klebanoff et al. 2001). Chlamydia trachomatis is an obligate intracellular Sex partners require concomitant treatment. bacterium with a biphasic life cycle. It belongs to Current therapy uses nitroimidazoles as either a the family Chlamydiaceae consisting of one genus, stat dose or longer course. It is advisable not to Chlamydia, with three species, C. trachomatis, C. use metronidazole during the fi rst trimester in pneumoniae, and C. psittaci that cause human pregnancy. Resistance is an emerging problem, disease. C. trachomatis is the causative bacterium estimated at 2.5% to 5% in the U.S. (Brocklehurst of trachoma, oculogenital disease, infant pneu- 1999). monia, and lymphogranuloma venereum (LGV). 390 H.E. Jeffery and M.M. Lahra

Epidemiology and Transmission Diagnosis The disease is most prevalent in adolescents, with As Chlamydiae are intracellular parasites, swabs a median prevalence of 15% in young, sexually rather than exudate is necessary for analysis. active women. In particular, young age, female Laboratory diagnosis includes the following sex, and minority race/ethnicity are the most reli- (Spigarelli and Biro 2004): able predictors of infection (Risser et al. 2005). 1. Nucleic acid probes: Screening has been sig- The reported rate in women in the U.S. in 2004 nifi cantly improved by use of NAATs on urine was 485 cases per 100,000. Between 4% and 10% and self-collected vaginal swab or on an endocer- of all pregnant women in the U.S. are diagnosed vical swab if a pelvic examination is acceptable. with chlamydia (Centers for Disease Control and Alternative tests include the following: Prevention 2004). Transmission is by vaginal, 2. Cytologic examination for intracytoplasmic anal, or oral sex with an infected partner, and inclusions (specifi c for C. trachomatis as iodine vertical transmission can occur from mother to stains glycogen in the inclusion bodies). baby during vaginal delivery. 3. Cell culture (e.g., McCoy or HeLa) with isolation of C. trachomatis determined by presence Pathogenesis of inclusion bodies. Organisms initially infect the cervix and urethra 4. Antigen detection by enzyme-linked immu- and can then spread to fallopian tubes. Primary nosorbent assay (ELISA) kits or direct immuno- infection can also occur in the rectum after anal fl uorescence but not as sensitive as culture, intercourse. The target cells are the squamous/ especially if few organisms present. columnar epithelial cells of the endocervix and 5. Serology is of limited value, as no distinction upper genital tract. The naturally alkaline pH is shown between current and past infection. and exposed cervical columnar cells in the Immunoglobulin M (IgM) antibody detection is adolescent woman increase vulnerability to infec- useful in neonatal infection. tion. The histopathology is that of granulomas Co-infection with gonorrhea should be and microabscess formation. Natural infection considered. confers limited protection (Risser et al. 2005; Stevens-Simon and Sheeder 2005). Treatment Clinical Features Antibiotic treatment is recommended in pregnancy for the infected mother and partner(s) Chlamydia infection is asymptomatic in about (Workowski et al. 2002; Holmes et al. 2004). 75% of women. If symptoms occur, 1 to 3 weeks Currently azithromycin or doxycycline is after exposure, they include vaginal discharge and re commended for nonpregnant women and oral dysuria. Signs most commonly include mucopu- erythromycin or amoxicillin for pregnant women rulent cervical discharge and hypertrophic cervi- (Brocklehurst 1999; Peipert 2003). cal ectopy (Peipert 2003). Complications include pelvic (upper genital) infl ammation causing PID Prevention (in at least 10% to 20% cases), infertility, ectopic pregnancy, and chronic pelvic pain (Risser et al. Primary prevention includes personal and com- 2005). Chlamydia and other infl ammatory STIs munity sexual health education to promote future increase the risk of acquiring HIV, if exposed to sexual risk reduction. This includes education to the virus. ensure consistent and correct condom use, which The neonate can become infected during effectively reduces acquisition of chlamydial birth from an untreated mother, with resulting infection by women and men (Holmes et al. risk of conjunctivitis (30–50%), nasopharyngitis 2004). (15–20%), and pneumonia (5–10%) (Peipert Secondary prevention, through screening pro- 2003). grams and treatment of those infected and their 16. The Impact of Infection During Pregnancy on the Mother and Baby 391 partners, has led to reductions in disease and inci- Epidemiology dent PID by around 50%, with demonstrated cost- The reported rate of gonorrhea in the U.S. benefi t and cost-effectiveness (Centers for Disease in 2004 was 113 cases per 100,000 population Control and Prevention 2004). Screening is rec- (Centers for Disease Control and Prevention ommended for all sexually active women of age 25 2004). N. gonorrhoeae is transmitted by sexual years or younger and other asymptomatic women intercourse with an infected partner, with risks at increased risk for infection including pregnant of about 20% female to male per unprotected women (Peipert 2003; Centers for Disease Control vaginal intercourse and 50% to 70% male to and Prevention 2004). female per contact. The risk of transmission Chlamydia DNA vaccines are in the early stages from an infected mother to her neonate is 30% of development, with an attenuated live vaccine to 47% (Brocklehurst 1999). increasingly possible (Rupp et al. 2004).

Public Health Issues Pathogenesis Chlamydial infection is largely asymptomatic and Primary infection of cuboidal or columnar epi- of epidemic proportions. It is the most common thelial cells is mediated by pili attaching to the notiﬁ able disease in the U.S. and can cause severe mucosal epithelium followed by penetration of reproductive sequelae and costly complications— organisms through and between epithelial cells infertility, ectopic pregnancy, and neonatal within 24 to 48 hours. A marked neutrophilic disease. Clinicians play a crucial role in recogniz- response ensues with sloughing of the epithelium ing, screening (and notifying the proper authori- and development of microabscesses and dis- ties), and treating Chlamydia infections especially charge of pus. Thus incubation is brief and in adolescents, young adults age 25 years or symptoms develop rapidly (Edwards and younger, and other asymptomatic women at Apicella 2004). increased risk of infection. Clinical Features Gonorrhea In women gonorrhea is often asymptomatic or with only minor symptoms, so medical care is Background not sought. Symptoms and signs usually occur Gonorrhea is the second most commonly reported within 10 days and include vaginal discharge, infectious disease in the U.S. (after chlamydia). dysuria, intermenstrual bleeding, and abdominal Among women gonorrhea is a major cause of PID, pain if ascending infection occurs with PID, which can lead to infertility, ectopic pregnancy, with or without mucopurulent cervicitis (Bignell and chronic pelvic pain, and increase the risk of 2001). acquiring HIV. Infected neonates develop con- Gonorrhea during pregnancy has been associ- junctivitis and occasionally sepsis. ated with prelabor rupture of membranes and with preterm delivery (Brocklehurst 1999). Clini- Microbiology cal symptoms and signs are unchanged in pregnant women. However, PID is uncommon after N. gonorrhoeae is a gram-negative diplococcus. It the ﬁ rst trimester. Postpartum endometritis and is a fastidious organism and an obligate human pelvic sepsis can occur. pathogen. The surface structure is similar to other Neonates are infected during delivery and gram-negative bacteria containing an outer mem- occasionally by ascending infection before brane, a middle peptoglycan cell wall, and an birth, after prolonged rupture of membranes. inner cytoplasmic membrane. Numerous pili Neonatal infection causes purulent bilateral con- extend from the cell surface. N. gonorrhoeae can junctivitis (Fig. 16.4). Occasionally, infection dis- be cultured, and typing methods can be used to seminates, causing sepsis, arthritis, or meningitis track the epidemiology. (Brocklehurst 1999). 392 H.E. Jeffery and M.M. Lahra

spectrum of action, and offer female control. These products are at various stages of development (Rupp et al. 2004). Health promotion and prevention includes personal and community sexual health education to promote sexual risk reduction, including consistent and correct condom use, which effectively reduces acquisition of gonorrhea by women (Holmes et al. 2004). In the U.S., eye antibiotics soon after delivery or silver nitrate (1%) aqueous eye drops are recommended for all newborns and are highly effective in preventing gonococcal conjunctivitis FIGURE 16.4. Gonococcal conjunctivitis with bilateral, profuse discharge on day 3. in neonates (Centers for Disease Control and Prevention 2002b).

Public Health Issues Diagnosis Public health control measures include screening Endocervical swab and culture on antibiotic- of at risk women at STI clinics and elsewhere, and containing selective medium has a sensitivity of routine screening and treatment of patients’ sex 80% to 90%. A NAAT test on the swab is an alter- partners; testing for other common STIs; and native if viability is in doubt due to delay or alter- reporting of cases by health providers to facilitate natively a NAAT test on urine. There is no epidemiological trends and targeted control. clinically useful serological test. Co-infection with Chlamydia should be considered (Donovan 2004). Eye swabs should be collected in neonates Syphilis with purulent conjunctivitis for light microscopy, Background culture, and sensitivity testing. In gonococcal conjunctivitis, after Gram staining, intracellular, Syphilis remains a major cause of adverse preg- gram-negative diplococci can be seen on light nancy outcomes in developing countries. Con- microscopy. genital syphilis continues to be a global public health problem, with more than 1 million infected Treatment infants born each year, exceeding other neonatal infections such as HIV and tetanus (Saloojee All tested antibiotic regimens are highly effective et al. 2004). in producing microbiological cure with eradica- Untreated syphilis can lead to serious long- tion rates of 89% to 97% (Brocklehurst 2002). term complications and death. Common to certain Penicillin is used for uncomplicated gonorrhea, other STIs, syphilis facilitates transmission of but alternative antibiotics are recommended for HIV. Congenital syphilis can cause stillbirth, penicillinase-producing N. gonorrhoeae (PPNG). preterm birth, neonatal death, and neurodisabil- Partners should be assessed for treatment. ity in survivors. Prevention In the U.S. the rate of primary and secondary syphilis in 2004 was 2.7 cases per 100,000 popula- There seems to be little if any natural immunity tion. Congenital syphilis declined to 8.8 cases per to gonococcal infection (Hedges et al. 1999). 100,000 live births, reﬂ ecting the reduction in Vaccine development is at an early stage syphilis in women (Centers for Disease Control (Fletcher 2001). and Prevention 2004). In contrast, the incidence Topical or vaginal microbiocides offer intra- of congenital syphilis has increased in rural areas vaginal chemoprophylaxis, before or after inter- of Eastern Europe and central Asia, and high rates course to prevent infection, have a broad of seropositivity are reported in sub-Saharan 16. The Impact of Infection During Pregnancy on the Mother and Baby 393

Africa at antenatal clinics (3–18%) (Saloojee et al. stages are contagious. Tertiary disease is symp- 2004). tomatic or unapparent and involves small blood vessels of the aorta, CNS, or both in an oblitera- Microbiology tive endarteritis as well as a widespread granulo- matous lesion called gummas (Zeltser and Kurban Treponema pallidum are tightly coiled, unicellu- 2004). lar, helical organisms. The spirochete cannot be grown on artifi cial medium and historically has Clinical Features been distinguished under dark fi eld microscopy from nonpathogenic treponemas by the undulat- The clinical manifestations of syphilis, particu- ing movement about its center. The complete larly secondary and tertiary syphilis, are protean sequencing of the genome of T. pallidum is recent, (Zeltser and Kurban 2004). Transplacental infec- and many of the gene functions in the sequence tion can occur at any stage of pregnancy. More are as yet unknown (Fraser et al. 1998). than half of all infected infants are either asymptomatic at birth or have nonspecifi c signs. Thus Epidemiology suspicion is necessary when positive maternal serology occurs, especially with inadequate or no Transmission is largely due to sexual intercourse. treatment in pregnancy. Infants of such mothers Transmission of infection to the fetus is vertical require treatment. from an infected mother by either hematogenous Early congenital syphilis is characterized by spread or direct contact with infectious genital prematurity and low birth weight (10–40%), hepa- lesions. The likelihood of fetal infection is nearly tomegaly with or without splenomegaly (33– 100% if the mother has early syphilis character- 100%), generalized vesicular, bullous skin rash ized by spirochetemia [identifi ed by rapid plasma initially with mucus patches that then slough reagent (RPR) у1 : 8] and up to 70% four years (40%), and bone changes of osteochondritis on after the acquisition of maternal disease (Berman x-ray (75–100%). None of these are pathogno- 2004; Zeltser and Kurban 2004). Seroprevalence is monic (Saloojee et al. 2004) (Fig. 16.5). generally low in high-income countries. Diagnosis Pathogenesis Key points in testing are summarized below from T. pallidum either penetrates intact mucosa or the more detailed overview by Peeling and Ye enters via abraded skin with rapid spirochetemia (2004). and invasion of organs, especially the central Serological testing is the mainstay of laboratory nervous system (CNS). The incubation period is diagnosis for primary, secondary, and tertiary dependent on the size of the inoculum, with a median period of 21 days and a range of 3 to 90 days. The host immune response is intense, and the resulting infl ammation is responsible for clinical expression. The underlying histological response is an obliterative endarteritis (Zeltser and Kurban 2004). Untreated syphilis passes through three disease stages: primary, secondary, and tertiary. The primary lesion, the chancre, is a painless ulcer at the site of inoculation, healing after 2 to 8 weeks. The secondary stage occurs at a mean of 6 weeks after contact and consists of parenchymal involvement, constitutional symptoms, and mucocutaneous manifestations with a character- FIGURE 16.5. Congenital syphilis infection illustrating mucocuta- istic maculopapular rash. Primary and secondary neous rash. Death occurred on day 1 despite treatment. 394 H.E. Jeffery and M.M. Lahra syphilis. Serological tests are divided into trepo- (Centers for Disease Control and Prevention nemal and nontreponemal tests and neither alone 2002b). Treatment decisions are based on the fol- is suffi cient for diagnosis. lowing steps: Nontreponemal tests are used for screening, and they detect antibodies to phospholipid anti- • Identifying syphilis in the mother gens on the treponemal surface. These tests are • Confi rming the adequacy of maternal nonspecifi c and include the RPR test and the treatment Venereal Diseases Research Laboratory (VDRL) • Identifying clinical, laboratory, or radiographic evidence of syphilis in the infant test. They are useful in identifying active infection • Comparing maternal RPR or VDRL titers at and monitoring effi cacy of treatment. As the non- delivery with those of the infant treponemal tests give false-positive results, confi rmation with a treponemal test is needed, such The WHO recommendations are as follows: as enzyme immunoassay (EIA), T. pallidum hem- agglutination assay (TPHA), or fl uorescent trepo- 1. Asymptomatic infants born to RPR-positive nemal antibody absorption test (FTA-ABS). All mothers should receive a single intramuscular pregnant women should be screened serologically injection (IMI) dose of 50,000 units/kg benzathine at least once in pregnancy and at the fi rst antena- penicillin G. tal visit (Centers for Disease Control and Preven- 2. Symptomatic infants receive IMI or intrave- tion 2002b). nous injection (IVI) aqueous crystalline penicillin Rapid, simple, immunochromatographic trepo- G, 50,000 units/kg every 12 hours for the fi rst 7 nemal tests that use strips coated with T. pallidum days, then every 8 hours for 3 days (Saloojee et al. antigens on whole blood, serum, or plasma can be 2004). used in primary care settings, are simple to use, require no equipment and minimal training, and Prevention give a color readout in 10 to 20 minutes. Primary prevention includes programs promot- In the neonate, diagnostic confi rmation of con- ing safe sex including consistent, correct condom genital syphilis is complicated fi rst by passive use, which will reduce acquisition of syphilis by transfer of maternal immunoglobulin (IgG), and men and women (Holmes et al. 2004). No vaccine second by the time taken for detection of IgM is available. antibodies (which do not cross the placenta). Secondary prevention depends on screening Congenital syphilis cannot be excluded by nega- programs for syphilis in pregnancy with emphasis tive tests. Any increased RPR titer compared to on providing access to antenatal care early in the mother is suspicious. Lumbar puncture, cere- pregnancy, decentralized services that provide brospinal fl uid (CSF), and radiography form part rapid simple test results with appropriate treat- of the clinical assessment. However, such investi- ment, partner notifi cation and repeat testing in gations in asymptomatic infants in resource poor pregnancy, opportunistic testing at sites other settings are problematic. than antenatal clinics, and combining programs Identifi cation of T. pallidum is only possible for prevention of vertical transmission of HIV when patients present with an ulcer, lesion, or with that of syphilis (Schmid 2004). rash, and a specimen is collected for dark fi eld Congenital syphilis can be prevented by microscopy or antigen detection by direct fl uores- detection of maternal infection by the second cent antibody to T. pallidum (DFA-TP), or T. trimester and appropriate maternal treatment pallidum DNA may be detected by NAATs. with penicillin.

Treatment Public Health Issues T. pallidum has remained sensitive to penicillin Syphilis, both maternal and congenital, is still a for more than half a century and is effective for major public health problem worldwide. Screen- maternal infection, preventing maternal trans- ing programs in pregnancy are justiﬁ ed and mission to the fetus, and treating fetal infection cost-effective even in low-prevalence areas. The 16. The Impact of Infection During Pregnancy on the Mother and Baby 395 barriers to achieving this, especially in low-income trate as far as the alveoli (Frieden et al. 2003). countries, have been outlined by Schmid (2004) Patients who have smear-positive disease are and include recommended interventions at the most infective, those with smear-negative/culture- international, national, and local levels. positive pulmonary disease are less infectious, and culture-negative/pulmonary-disease and extra-pulmonary TB are noninfectious (Laibl Specific Bacterial Infections and Shefﬁ eld 2005a).

Tuberculosis Pathogenesis Background If droplets containing M. tuberculosis access the terminal airspaces, activated macrophages ingest Tuberculosis (TB) has been documented since the bacilli, which multiply and lyse the cell. The antiquity but became epidemic with high mortal- infection is then either contained at the site of the ity in the industrialized world of the 17th and 18th primary lesion (the Ghon focus) and draining centuries. Tuberculosis became treatable and regional lymph nodes, or active disease occurs in curable post–World War II with the discovery of the lung or by hematogenous spread to the CNS streptomycin and then isoniazid. The decline in (meningitis with or without tuberculomas), bones TB was halted by the HIV epidemic, when co- or joints (most commonly the spine, referred to infection occurred and transmission to others led as Pott’s disease), genitourinary system (an to a rise in the incidence in the mid-1980s. While important cause of infertility in high TB-incidence pregnancy is not considered to change the course areas), lymph nodes, pleura, and peritoneum. of TB, it does present a risk to the pregnant woman Cell-mediated immunity appears 3 to 8 weeks and her fetus (Laibl and Sheffi eld 2005a). after infection. Active disease, uncontained by cell-mediated immunity, is most common in chil- Microbiology dren younger than 5 years of age and in immuno- Tuberculosis is most commonly caused by infec- suppressed HIV patients (Frieden et al. 2003). In tion with Mycobacterium tuberculosis and rarely infected women the incidence of TB peaks at 25 to M. bovis, M. microti, M. africanum, and M. to 34 years (Laibl and Sheffi eld 2005a). canetti. Mycobacteria are aerobic, nonmotile, non–spore-forming bacillus with slow growth in Clinical Features solid media (3 to 8 weeks) compared with liquid In healthy adults infected with TB, 90% to 95% broth media (1 to 3 weeks). Typically mycobacte- have persistent, asymptomatic, latent TB, and ria are acid-fast bacilli (Laibl and Sheffi eld only 5% to 10% develop active TB (Smith 2002). 2005a). The most common type of TB is pulmonary Epidemiology and Transmission disease, although 5% to 10% of pregnant women have extrapulmonary TB (Laibl and Sheffi eld Humans are the only reservoir for M. tuberculosis. 2005a). Risk factors include HIV, malnutrition, In 2000, there were an estimated 8 to 9 million new poorly controlled diabetes, and malignant disease. cases worldwide, most in developing countries Common symptoms and signs include persistent with approximately 2 million deaths. The Centers cough of longer than 2 weeks, fever, night sweats, for Disease Control and Prevention (CDC) weight loss, dyspnea, hemoptysis, chest pain, and reported an incidence of TB of 4.9 per 100,000 in malaise (Ormerod 2001; Frieden et al. 2003). the U.S. in 2004 (Centers for Disease Control and Congenital infection is rare (hematogenous or Prevention 2005h). ingested from infected amniotic fl uid), and infec- Transmission risk is not altered by pregnancy. tion is more common after birth from family Almost all infection is spread by respiratory members with open TB. Neonatal manifestations droplets from coughing, sneezing, talking, and mimic bacterial or viral infections, unresponsive singing. Droplets can remain airborne for hours to usual treatment, in a mother with risk factors and, because of the small particle size, can pene- for TB. The most common presentation is with 396 H.E. Jeffery and M.M. Lahra hepatosplenomegaly (76%), respiratory distress • Use of directly observed therapy strategy (72%), fever (48%), and lymphadenopathy (38%) (DOTS) wherever possible, although a recent (Frieden et al. 2003). systematic review indicates that the effects of direct observation of therapy on treatment Diagnosis completion or cure was similar to self-adminis- tered treatment (Volmink and Garner 2003) The intradermal administration of tuberculin, • Use of in vitro drug susceptibility and local standardized, purifi ed protein derivative (PPD-S) resistance patterns to guide initial drug assesses cell-mediated immunity to tuberculin, + choices for example, the Mantoux or Heaf test. CD4 lym- • Add multiple not single drugs to a failing phocytes travel to the site, proliferate, and produce regimen cytokines that cause a raised erythematous area, • Emphasize completion of courses the size of which determines a positive test. This skin test is the only method of reliably detecting The usual drugs used initially, isoniazid, M. tuberculosis in asymptomatic individuals and rifampin, ethambutol, and pyrazinamide, do cross is safe in pregnancy (Ormerod 2001). If positive, the placenta but are not teratogenic, and women evidence of disease is assessed by CXR. Tubercu- can breast-feed. In addition, pregnant and lin testing may be negative for months in congeni- postpartum women should receive pyridoxine tal TB (Laibl and Sheffi eld 2005a). (Laibl and Sheffi eld 2005a). Investigations include direct sputum smears, culture, and NAATs. Culture is required for Prevention defi nitive diagnosis and is essential for drug- Prevention and treatment of disease in pregnant susceptibility testing (15% to 20% adults with TB women will prevent congenital TB. The Bacille are culture-negative) (Frieden et al. 2003). The Calmette-Guérin (BCG) vaccine has an overall NAAT testing using PCR is especially valuable effi cacy of 50% (Colditz et al. 1994) but high pro- and highly predictive for suspicious pulmonary tective effi cacy against disseminated disease TB that is smear-negative (Frieden et al. 2003). (meningitis and miliary TB) in infants. Advances Positive direct sputum smears using the Ziehl- in vaccine development should lead to more effec- Neelsen method of acid-fast staining are recom- tive vaccines (Haile and Kallenius 2005; Martin mended by the WHO, and in high-prevalence, 2005). resource-poor areas the smears are considered diagnostic of TB (Schmid 2004). Public Health Issues Treatment The WHO recommends the fi ve-point DOTS strategy, which achieves average cure rates of Treatment in pregnancy depends on whether the 82%, and in HIV areas combine this strategy with diagnosis is PPD positive alone, that is, infection effective HIV prevention and cure (Frieden et al. but no evidence of active disease (treatment is 2003). Effective control is inexpensive and cost- debatable in pregnancy due to possible isoniazid effective. In areas of high incidence and no HIV, toxicity), active disease is present (treat), and HIV case-detection of 70% and cure rates of 85% will infected or other risk factors are present (treat). lead to a decline in TB of 5% to 10% per year Treatment principles aim to eradicate TB, ensure (Frieden et al. 2003). fewer relapses/failures, achieve higher cure rates, and reduce resistance and include the following (Neralla and Glassroth 2003; Centers for Disease Group B Streptococcus Control and Prevention 2005h): Background • Use of multiple drugs to which M. tuberculosis Group B Streptococcus (GBS) was recognized as a is sensitive major cause of bovine mastitis in the 1930s, and • Appropriate drug combinations for a suffi cient emerged as a neonatal human pathogen in the period of time late 1960s. Preventative strategies, based on intra- 16. The Impact of Infection During Pregnancy on the Mother and Baby 397 partum chemoprophylaxis for maternal carriers preterm labor. Less commonly, colonization (Smaill 1996), in Australia, North America, and occurs during delivery, with subsequent infection some countries in Western Europe have led to up transmitted via either maternal or nosocomial to 80% to 90% reduction in early onset (<48 hours routes. Neonatal infection is related to absence of of life) GBS disease (EOGBSD). Most recently, maternal type-specifi c IgG antibodies. The patho- phylogenetic analysis of multilocus sequencing genesis of late-onset GBS disease (LOGBSD) is less type data has uncovered common ancestry of well understood and is thought to be due to per- bovine and human GBS (Bisharat et al. 2004). sistence of oropharyngeal colonization with development of invasive infection or nosocomial Microbiology transmission of infection. Breast milk transmission of GBS does occur in LOGBSD (Kotiw et al. Streptococcus agalactiae is a gram-positive coccus 2003). Maternal febrile morbidity occurs in 21% that form chains when grown in broth media and of untreated carriers (Boyer and Gotoff 1986). exhibit β-hemolysis on blood agar. Defi ned as Lancefi eld group B by carbohydrate cell surface Clinical Features antigens, the organism is known as group B β- hemolytic streptococcus. Maternal carriers are usually asymptomatic but may develop clinical chorioamnionitis with or Epidemiology without ruptured membranes or a UTI. EOGBSD most commonly presents with respiratory distress The reservoir in humans is the gut. The organism or apnea in the term infant, and presentation may colonizes the lower genital tract of 5% to 40% be protean in the preterm infant (Jeffery 1996). women and 50% to 75% of their newborns become ∼ colonized, but only 2% acquire EOGBSD. Vari- Diagnosis ance in maternal carriage is due to demographic, endocrine, and behavioral factors, in addition to Maternal carriage is diagnosed by culture on site swabbed and microbiologic methodology selective media of a low vaginal swab. Presump- (Jeffery 1996; Bisharat et al. 2004; Gibbs et al. tive identifi cation of GBS is by colony morphology 2004). and Gram staining, and defi nitive identifi cation is Risk factors that have high attack rates (>50/1000 by serologic detection. Alternatively, selective live births) but are relatively uncommon include media is used for culture of rectovaginal swabs. GBS bacteruria and a sibling with EOGBSD. Risk The most rapid method of GBS detection is cur- factors with lower attack rates (>10–25/1000 live rently by PCR at labor onset; this requires 24-hour births) but more prevalent include heavy vaginal laboratory staffi ng. Initial analysis suggests it culture at delivery, preterm birth, prolonged would be cost-effective and the most accurate and rupture of membranes, and intrapartum fever effective method to determine intrapartum che- (Benitz et al. 1999). moprophylaxis (Haberland et al. 2002). Neonatal infection can be early onset or late Neonatal EOGBSD is diagnosed by positive onset (>48 hours and up to 3 months of age); blood culture, CSF, or CXR consistent with infec- EOGBSD is the commonest cause of early-onset tion, supported by a positive urine streptococcal infection in neonates in the developed world. antigen, abnormal white cell count, elevated C Neonatal infection manifests as pneumonia, bac- reactive protein, or proinfl ammatory cytokine, teremia, and less commonly meningitis (Jeffery for example, IL-6 (Jeffery 1996). 1996). Treatment Pathogenesis Maternal chorioamnionitis and EOGBSD are Neonatal GBS infection is most commonly caused usually treated with parenteral penicillin and gen- by ascending infection via the amniotic fl uid. tamicin (for non–penicillin-allergic mothers) or Infected amniotic fl uid interfaces with the fetal if allergic an alternative antibiotic (Centers for lungs causing fetal infection and may initiate Disease Control and Prevention 2002b). 398 H.E. Jeffery and M.M. Lahra

Prevention Microbiology A screening-based approach to intrapartum che- Listeria monocytogenes is a gram-positive motile moprophylaxis is the recommended method of rod that can be cultivated in the laboratory and prevention (Centers for Disease Control and has characteristic tumbling motility at room tem- Prevention 2002b). perature. Specimens from nonsterile sites, such Evaluation of a universal screening approach as the vagina, require selective media. Of six signiﬁ cantly reduced EOGBSD by >85%, whether species only L. monocytogenes is pathogenic for performed at 28 weeks’ (Jeffery and Lahra 1998) humans. or 35 to 37 weeks’ gestation (Puopolo et al. 2005). The decline reported was to 0.22 and 0.37 per 1000 Epidemiology live births, respectively. Recommended prophy- The organism is commonly found in soil, dust, lactic antibiotic regimens rely on penicillin G or, processed food, produce, the gut, and feces of if not available, ampicillin for nonallergic mothers. domestic and wild animals as well as the human For alternative regimens, see Centers for Disease gastrointestinal tract (70% healthy people and Control and Prevention (2002b) recommenda- up to 44% pregnant women), although positive tions. Surveillance data for 2004 for the U.S. dem- vaginal swabs are rare, except with perinatal liste- onstrates a sustained decline in EOGBSD to 0.34 riosis. The incidence of listeriosis in pregnant per 1000 live births (Centers for Disease Control women is 12 per 100,000 compared with 0.7 per and Prevention 2005d). 100,000 in the general population (Silver 1998). Capsular, polysaccharide-protein conjugate, Transmission is either transplacental or ascend- GBS vaccines exist. Signiﬁ cant protective IgG ing from maternal colonization of the vagina. titers in the mother provide passive protection by transplacental transfer. Phase three trials have not Pathogenesis yet commenced (Baker and Edwards 2003). L. monocytogenes is an unusual bacterium, spread- Public Health Issues ing from cell to cell, avoiding extracellular exposure, and thus bypassing the usual host defenses. Intrapartum chemoprophylaxis for maternal GBS Cell-mediated immunity is the primary defense, carriers has been very successful in reducing and as this is depressed in both pregnant women EOGBSD. The most effective prevention is likely and their neonates, vulnerability to infection is to be an adolescent or maternal vaccine (Baker increased. Incubation periods range from 11 to 70 and Edwards 2003; Moore et al. 2003). days with a mean of 31 days. Once L. monocytogenes crosses the intestinal mucosal barrier, Listeria monocytogenes hematogenous spread occurs, especially to the CNS and placenta (Southwick and Purich 1996; Background Silver 1998).

Listeriosis is the disease caused by Listeria mono- Clinical Features cytogenes. Although an uncommon disease in pregnancy, the incidence of listeriosis is increased Common maternal manifestations, identifi ed in in the otherwise healthy, pregnant woman. Most 222 patients with perinatal listeriosis included cases in pregnancy are sporadic with occasional fever of >38°C (65%), fl u-like illness (34%) or outbreaks traced to a common source. Both spo- asymptomatic (31%), leukocytosis and positive radic and epidemic cases are due usually to con- blood (43%) or amniotic fl uid culture (8%), and taminated food. Adverse pregnancy outcomes cervical/vaginal culture (34%) or placental culture include spontaneous miscarriage, stillbirth, cho- (11%). Serious maternal illness rarely occurs rioamnionitis, preterm delivery, and neonatal (Mylonakis et al. 2002). Spontaneous miscarriage infection. The latter can be early-onset sepsis or stillbirth occurred in 20%, and 68% of neonates (vertical ascending or hematogenous transmis- were infected. The most common neonatal mani- sion) or late-onset meningitis (nosocomial infec- festations of early listeriosis were respiratory dis- tion) (Silver 1998). tress (60%), fever у38°C (48%), and neurological 16. The Impact of Infection During Pregnancy on the Mother and Baby 399 signs with meningitis (25%) (Mylonakis et al. burden of disease from toxoplasmosis acquired in 2002). pregnancy is related not to maternal disease, which is largely asymptomatic, but to vertical Diagnosis transmission to the fetus, with development of The diagnosis is reliant on suspecting listeriosis congenital toxoplasmosis or sequelae at various in pregnant women with fever or fl u-like illness times after birth. Prevention is possible but effec- and confi rmation of infection with microbiologi- tive treatment of congenital toxoplasmosis is cal fi ndings and culture of blood or other sites contentious. including placental macroscopic and microscopic fi ndings. In early-onset neonatal infection, L. Microbiology monocytogenes can be isolated from blood, CSF, superfi cial swabs, placenta, or skin biopsy T. gondii is an obligate intracellular protozoan of a rash. with three forms: (1) oocysts (which release sporozoites), formed in the small bowel of cats Treatment usually following ingestion of uncooked meat, are excreted in their feces and become infectious Ampicillin is generally considered the treatment in 1 to 5 days; (2) tissue cysts (which contain and of choice. In those with immune impairment and may release bradyzoites); (3) tachyzoites, which for all cases of meningitis, dual therapy is recom- rapidly divide in macrophages following invasion mended. Expert advice should be sought. Success- of the host intestinal wall by either sporozoites ful in utero therapy has been reported. from oocysts or bradyzoites from tissue cysts Prevention (Kravetz and Federman 2005; Montoya and Rosso 2005). Pregnant women should avoid soft cheeses, unpasteurized milk, and refrigerated ready-to-eat Epidemiology food that is not freshly prepared, for example, delicatessen meats, pates, and salads, and should Toxoplasmosis is a worldwide zoonosis. Reported peel or wash raw fruit and vegetables to remove rates vary within and between countries. In the soil. Hand washing is important. There is no U.S. seroprevalence among girls and women who vaccine. are 15 to 44 years of age is reported to be 15% (Jones et al. 2001). Congenital toxoplasmosis, Public Health Issues however, is less common, and the estimated rates U.S. surveys indicate that most pregnant women from two U.S. surveys varied from 1 to 10 per have limited knowledge of prevention, and hence 10,000 live births, or 400 to 4000 infants per year educational advice both prepregnancy and early (Lopez et al. 2000). The incidence depends on in pregnancy is advisable (Ogunmodede et al. primary infection in pregnancy, gestational age 2005). at acquisition, and prevention/detection pro- Surveillance of cases by the CDC in the U.S. and grams. Transmission increases throughout preg- a zero tolerance policy for contaminated foods nancy, from 6% at 13 weeks’ to 40% at 26 weeks’ has seen a 44% decline in perinatal listeriosis and 72% at 36 weeks’ gestation, with less severe (Silver 1998). consequences to the fetus the later the occur- rence of congenital infection in pregnancy. The highest risk of developing early signs such as Specific Protozoan Infections chorioretinitis and hydrocephaly was approximately 10% when seroconversion occurred at Toxoplasmosis between 24 and 30 weeks’ gestation (Dunn et al. Background 1999). Risk factors include contact with raw or under- Humans are infected with the protozoan organ- cooked meat, and contact with soil as with gar- ism Toxoplasma gondii by either oral ingestion of dening or eating unwashed vegetables, and contact the parasite or transplacental transmission. The with infected cat feces. 400 H.E. Jeffery and M.M. Lahra

Pathogenesis Prenatal diagnosis is based on PCR testing of amniotic fl uid at ≥18 weeks and ultrasound for Human and thus maternal infection can occur in evidence of calcifi cation or hydrocephalus (Foulon three ways: ingestion of tissue cysts in infected et al. 1999). Neonatal diagnosis is based on serol- undercooked meat; ingestion of infected oocysts ogy (IgA and IgM), placental tissue or body fl uid through fecal-oral contact; and uncommonly culture, PCR of body fl uids, and ophthalmological from infected blood to a nonimmune mother. and radiological examination. Congenital toxoplasmosis then develops from the transplacental passage of tachyzoites to the fetus Treatment (Kravetz and Federman 2005). The widespread dissemination of T. gondii in There are no randomized trials to guide the effec- virtually all cells and tissues is a result of release tiveness of antenatal treatment with either spira- of tachyzoites from cells with parasitemia via mycin or pyrimethamine-sulfadiazine on risk of blood and lymphatic routes. Primary maternal congenital infection. Two systematic reviews of infection with parasitemia and before adequate observational studies found insuffi cient evidence maternal humoral or cellular immunity, combined on the effects of current antiparasitic treatment with high placental blood fl ow, is conducive to compared with no treatment in pregnancy (Peyron placental transmission being greater with advanc- and Wallon 2001; Olliaro 2004). ing pregnancy (Montoya and Rosso 2005). Prevention Clinical Features Primary prevention by health education at the Over 90% of primary infection in pregnancy is fi rst antenatal visit for women of child bearing age asymptomatic if the mother is immunocompe- must include the risks associated with eating tent. Symptomatic infection causes headache, undercooked meat, soil-borne transmission, and malaise, and cervical lymphadenopathy. Congeni- exposure to cat feces. Hand washing after han- tal toxoplasmosis is not initially apparent in about dling raw meat, cat feces, and soil is important. 85% of neonates, but chorioretinal and neurologi- Screening for primary T. gondii infection in cal abnormalities develop later. Signs at birth pregnancy is controversial, as the false-positive range from mild chorioretinitis to severe early IgM rate approaches the true positive rate in some presentation with microcephaly, hydrocephalus, countries, and the effectiveness of antenatal treat- and seizures (Kravetz and Federman 2005). ment for diagnosed maternal infection is uncer- Diagnosis tain (Peyron et al. 1999; Olliaro 2004). Routine screening is recommended in some countries As the majority of pregnant women are asymp- where prevalence is higher, for example, France tomatic, diagnosis is diffi cult and dependent on and Austria. detecting seroconversion via elevated IgG levels (1 to 2 weeks after infection and elevated indefi - Public Health Issues nitely) or IgM levels (elevated within days, usually Health care providers are central to implementing for 2 to 3 months, but can remain positive for primary prevention. Governments and the meat greater than 2 years) (Kravetz and Federman industry need to continue efforts to reduce T. 2005). gondii in meat (Lopez et al. 2000). Interpretation of serological tests leads to three possibilities: recently acquired infection with a fetus at risk of congenital disease; infection Malaria acquired before pregnancy with an almost zero Background risk to the fetus of congenital disease unless the mother is immunocompromised; and equivocal Malaria in pregnancy is a major cause of maternal results requiring repeat serum samples 3 weeks and neonatal death. An estimated 50 million preg- before or after the initial sample (Montoya 2002; nancies and more than 40% of all births world- Montoya and Russo 2005). wide occur in endemic malarial areas of the tropics 16. The Impact of Infection During Pregnancy on the Mother and Baby 401 and subtropics (Steketee et al. 2001). Malaria is Secondary effects of maternal malaria include more common in pregnant than in nonpregnant suppression of immune responses to vaccination, women, and the risk of adverse maternal and peri- for example, tetanus toxoid, and reduction in pla- natal outcome is greater during fi rst pregnancies cental transfer of specifi c antibodies to the fetus, and for all gravida women who are HIV positive for example, respiratory syncytial virus, measles, (ter Kuile et al. 2004). Adverse effects on preg- and pneumococcus (Duffy 2003). nancy (anemia) and pregnancy outcome [still- Placental malaria, characterized by parasitized birth, abortion, low birth weight (LBW), red cells in placental blood in the intervillous prematurity, perinatal mortality] are directly space, is a more common fi nding than parasites related to the extent of placental malaria and in the peripheral circulation of the mother. Con- partly to the degree of maternal anemia (Steketee sequences include increased risks of LBW and 2003; van Geertruyden et al. 2004). In addition, IUGR, anemia during infancy, and malaria during malaria worldwide is estimated to account for 8% the early months of life (Fischer 2003). of the 10.6 million deaths in children younger than 5 years of age (Bryce et al. 2005). Clinical Features Pregnant women in endemic (stable or high Microbiology transmission) areas are usually asymptomatic but Malaria is caused by an intracellular protozoan develop anemia, which may be symptomatic parasite of the genus Plasmodium. Four species depending on the degree. If severe, both maternal infect humans: P. falciparum, P. vivax, P. ovale, morbidity and mortality may be increased. In and P. malariae. epidemic (unstable or low transmission) areas, nonimmune pregnant women are at high risk Epidemiology and Transmission of cerebral malaria, hypoglycemia, pulmonary edema, severe hemolytic anemia, and perinatal Malaria occurs in most tropical regions of sub- death (van Geertruyden et al. 2004). Risk of still- Saharan Africa, Southeast Asia, and Latin America. birth may be increased sevenfold in unstable Infected, female, Anopheles mosquitoes transmit areas (Newman et al. 2003). Symptoms and signs malaria parasites person to person and are more (fever, chills, headache, sweats, vomiting) are attracted to pregnant than nonpregnant women nonspecifi c. The periodicity of malarial fever is (Lindsay et al. 2000). Spread can also occur from related to the periodic rupture of parasitized transfusion of infected blood or via infected red cells. Disease and death occur only during needles. the erythrocytic stages of the parasite and not the liver stage. Pathogenesis Maternal P. falciparum infection is one of the most important contributing factors to LBW in The mosquito releases sporozoite forms of the fi rst pregnancies and, to a lesser extent, in second parasite into the bloodstream, which travel to the pregnancies in Africa, and results in IUGR, pre- liver and invade hepatocytes. Rapid multiplica- maturity, increased neonatal and perinatal mor- tion occurs within the hepatocytes, typically over tality, and infant anemia (Guyatt and Snow 2001, 1 to 2 weeks, and leads to cell rupture and release 2004; Fischer 2003; Brabin et al. 2004). Congenital of merozoites, which then invade red blood cells. malaria may occur in 7% to 10% of neonates as Maturation and division in the erythrocytes occurs assessed by malarial parasites in cord blood. over 48 to 72 hours (species dependent), then cell Fever, anemia, jaundice, hepatosplenomegaly, rupture occurs, and new merozoites invade fresh and early death may occasionally occur (Fischer red cells. P falciparum is the most lethal malarial 2003). parasite, with mortality and morbidity concentrated on pregnant mothers and young children, Diagnosis due to the severity of syndromes such as cerebral malaria, pulmonary edema, and profound anemia Light microscopy of thick and thin Giemsa-stained (Duffy 2003; Planche and Krishna 2005). blood smears is the gold standard for diagnosis. 402 H.E. Jeffery and M.M. Lahra

Rapid diagnostic tests for malaria detect anti- effective in reducing childhood morbidity gens derived from malarial parasites and provide and mortality from malaria (Lengeler 2004). rapid results in 2 to 10 minutes with variable accu- Their impact is currently being evaluated for racy. Several laboratory tests exist; most accurate pregnant women (Cochrane Infectious Disease and most expensive are tests using PCR to detect group protocol). parasite nucleic acids. Serology detects antibodies • Febrile malaria case management and appropri- indicating past infection, either by indirect immu- ate treatment. nofl uorescence (IFA) or ELISA. Public Health Issues Treatment The diffi culties associated with mosquito control Prompt appropriate treatment of pregnant women and drug resistance to the parasite, together with with malaria requires early and effective case the large burden of disease due to malaria, have management in malarial areas together with provoked intense research for a suitable vaccine. screening and appropriate treatment of anemia. Currently there is no effective, licensed vaccine, However, although there is insuffi cient reliable although phase III trials are underway (Guerin et research on treatment options for malaria in preg- al. 2002; Duffy 2003). The global public health nancy (Guerin et al. 2002; Orton and Garner 2005), need, attributable to the economic and social the WHO (2004b) has outlined recommendations burden of malaria (Sachs and Malaney 2002), the for drug treatment in pregnancy. Morel et al. current situation, and the research and develop- (2005) concluded that artemisinin-based combi- ment needs are outlined by Guerin et al. (2002). nation treatment was the most cost-effective strat- Research to address the disease burden, in chil- egy for control of malaria in sub-Saharan Africa. dren and pregnant women in particular, and The CDC updates treatment options, depending vector control, vaccine development, deployment on location, for nonimmune travelers (www.cdc. of rapid tests adapted to fi eld situations, and gov/travel). effective combination drugs are essential priorities to reduce malaria and prevent escalation of Prevention the disease (Guerin et al. 2002). Nonimmune pregnant women are advised to avoid malaria-endemic areas. In general, chemo- Specific Viral Infections prophylaxis is not recommended in areas with fewer than 10 reported cases of P. falciparum Parvovirus B19 malaria per 1000 inhabitants per year (Petersen 2004). In endemic areas in Africa, the WHO rec- Background ommends a triple approach for prevention and Discovered by Australian virologist Yvonne control in pregnant women (WHO 2004b): Cossart in 1974 (Cossart et al. 1975), parvovirus B19 was not linked with human disease until 1981, • Intermittent preventive treatment (IPT) of at when it was associated with acute aplastic crisis in least two doses of antimalarial drugs should be a patient with sickle-cell disease. Parvovirus B19 given to all pregnant women in areas of stable is now known to cause a range of clinical syn- transmission. The relative risk (RR) of routine dromes in humans dependent on age and immune chemoprophylaxis (such as sulfadoxine- and hematological status. These range from a very pyrimethamine) for pregnant women (low common, mild, or asymptomatic childhood illness parity) in endemic malarial areas indicates sig- to acute aplastic crisis, chronic anemia, hydrops nifi cant reduction in severe anemia (RR 0.62, fetalis, and intrauterine death. 95% CI 0.50–0.78), LBW (RR 0.55, 95% CI 0.43– 0.70), and perinatal death (RR 0.73, 95% CI Virology 0.53–0.99) (Garner and Gülmezoglu 2002). • Insecticide-treated bed nets (ITNs) are recom- The family is Parvoviride, and the genus is Eryth- mended as early in pregnancy as possible and rovirus. The genome of parvovirus B19 is very postpartum (WHO 2004b). The ITNs are highly small (parvum is a Latin word meaning “small”), 16. The Impact of Infection During Pregnancy on the Mother and Baby 403 and is composed of single-stranded, linear DNA. prodromal illness corresponding with viremia Structural features of an icosohedral protein (Anderson et al. 1985), which may be absent, very capsid without an envelope make parvovirus B19 mild, or manifest as fever, malaise, and myalgia. resistant to heat and detergent inactivation, and During this time there is destruction of erythro- contribute to its transmissibility (Koch 2001). blasts in the bone marrow (White and Fenner 1994d) and a reticulocytopenia without anemia Epidemiology and Transmission (Anderson et al. 1985). The second stage of rash and arthralgia corresponds with the peak produc- Parvovirus B19 is ubiquitous and highly conta- tion of specifi c antibody and are thought to be the gious (White and Fenner 1994d). Infection with result of immune complex deposition. parvovirus B19 is very common in childhood and Importantly, the clinical manifestations of may be sporadic or epidemic, and occurs most parvovirus B19 vary widely, and infection is often in late winter and early spring in temperate frequently subclinical. The commonest clinical climates. Children aged 5 to 15 years are most presentation, erythema infectiosum or fi fth disease commonly infected, and by adulthood about 60% or “slapped cheek” because of the bright red of people have antibodies. Parvovirus B19 infec- cheeks the infection causes, occurs in normal, tion is transmitted by respiratory droplets, may healthy children. Parvovirus B19 can also cause an also occur via infected blood and blood products, acute polyarthropathy, usually in adult females. and has been reported in bone marrow transplan- The arthropathy is symmetrical and non-destruc- tation (Heegaard and Laub Peterson 2000). The tive, and may last for weeks. In those with incubation period is 4 to 21 days. increased erythropoiesis, infection may cause a transient aplastic crisis. In those unable to mount Pathogenesis an antibody response, infection may cause chronic Parvovirus B19 has a limited genome and is there- anemia (Young and Brown 2004). fore only able to replicate in dividing host cells, specifi cally in human erythroid progenitor cells in Infection in Pregnancy the blood, bone marrow, and fetal liver inhibiting A seroprevalence of about 60% means that erythropoiesis. The cellular receptor for parvovi- approximately 40% of pregnant women have no rus B19 is globoside, the P blood group antigen immunity. In pregnancy, primary maternal infec- (Brown et al. 1993) in conjunction with a range of tion can lead to transplacental transmission to the β-integrins (Corcoran and Doyle 2004). The P fetus. The transmission rate to the fetus is esti- blood group antigen is present on cells of the ery- mated to be 30% to 50% (Rodis et al. 1990; Koch throid lineage. It is also present on cells that are et al. 1998; Miller et al. 1998). The risk of adverse not permissive for replication of parvovirus B19 outcome after parvovirus B19 infection in preg- including endothelial cells, fetal myocardial cells, nancy is reported to be up to 9% (Koch 2001). placenta, and megakaryocytes. The mechanism of Fetal infection can cause anemia, nonimmune damage in these cells is yet to be clarifi ed; however, hydrops fetalis, and death. there is evidence, in myocardial cells at least, that it may be cytokine mediated (Nigro et al. 2004). Hydrops Fetalis The tissue distribution of globoside may account for a number of the clinical manifestations of par- In a study of parvovirus B19 infection in pregnant vovirus B19 infection (Koch 2001). Individuals women, the risk of developing nonimmune who lack P antigen are rare and apparently cannot hydrops fetalis was found to be about 10% be infected with parvovirus B19 (Corcoran and (Yaegashi et al. 1999). Parvovirus B19 infection Doyle 2004). has been estimated to cause between 10% and 20% of cases of all nonimmune hydrops fetalis Clinical Features (Yaegashi et al. 1994; Jordon 1996). The development of nonimmune hydrops fetalis usually The symptomatology of parvovirus B19 infection occurs about 2 to 4 weeks after maternal infection in the otherwise well host has the following patho- as a result of profound fetal anemia and cardiac physiological correlates: the initial nonspecifi c failure. The pathogenesis of cardiac failure was 404 H.E. Jeffery and M.M. Lahra once solely attributed to the associated hemody- blood sampling under ultrasound guidance may namic impact of severe anemia; however, infec- be indicated in the presence of hydrops, and intra- tion with parvovirus B19 is now thought also to uterine transfusion may be offered. affect the fetal myocardium (Koch 2001). Prevention Fetal Death Currently there is no vaccine available. Frequent Parvovirus B19 infection is reported to have an hand washing is recommended to reduce the estimated risk of fetal death of 5% to 9% (Young spread of infection. and Brown 2004). This has been described in all Public Health Issues trimesters, but the period of greatest risk is in the fi rst 20 weeks. Death usually occurs 4 to 6 weeks The CDC does not recommend that pregnant after infection, not always associated with hydrops women be excluded from the workplace in a par- (Corcoran and Doyle 2004). vovirus B19 outbreak, as this is unlikely to prevent Death in the third trimester has been associated the spread of infection, as those infected are con- with parvovirus B19. In a prospective, hospital- tagious prior to developing the characteristic rash based, cohort study, 7.5% of all third-trimester (Centers for Disease Control and Prevention intrauterine deaths had detectable parvovirus 2005g). B19 DNA and were otherwise unexplained (Skjoldebrand-Sparre et al. 2000). Notably, none Rubella of these fetuses was hydropic, and the authors suggest investigation for parvovirus B19 infection Background should be included in the investigation of all Rubella or German measles, also known as third intrauterine fetal deaths. Chronic congenital disease, is a benign, mild, self-limiting disease of anemia secondary to parvovirus B19 infection has childhood. In the fetus, in early gestation, infec- been reported (Brown et al. 1994). tion with rubella can cause profound morbidity and mortality: the congenital rubella syndrome Diagnosis (CRS). In 1941 Australian ophthalmologist Nor- Parvovirus B19 cannot be grown in standard cell man Gregg fi rst associated congenital cataract and cultures. Diagnosis of infection is made by dem- rubella infection in pregnancy (Gregg 1941). onstration of specifi c anti–parvovirus B19 antibodies. The presence of anti–parvovirus B19 IgM Virology is the best marker of recent/acute infection, and The family is Togaviride and the genus is Rubivi- seroconversion from anti–parvovirus IgG nega- rus. The rubella virus genome is composed of plus tive to IgG positive in paired acute and convales- sense, single-stranded, linear RNA, with an icoso- cent sera is also indicative of recent infection hedral capsid. The virion is spherical and is sur- (Koch 2001). Nucleic acid amplifi cation tests rounded by a lipid envelope that is covered with (NAATs) are available and are useful in tissue. glycoprotein peplomers. Rubella virus is relatively The NAATs are required for diagnosis of persis- unstable in the environment and is inactivated by tent infection where antibody production is absent disinfectants, solvents, extremes of pH and tem- or minimal (Young and Brown 2004). perature, and ultraviolet light (Maldonado 2003).

Treatment Epidemiology and Transmission Treatment of parvovirus B19 infection is symp- Rubella infection occurs worldwide and is endemic tomatic, as there is no specifi c antiviral therapy. in many areas. In temperate climates infection For pregnant women with confi rmed infection, occurs most commonly in late winter to early ultrasound screening for evidence of fetal edema spring. During the global rubella epidemic of 1962 may be done at 1- to 2-week intervals for 6 to 12 to 1965, there were an estimated 12.5 million cases weeks after infection (Schild et al. 1999). Fetal of rubella in the U.S. with 2000 cases complicated 16. The Impact of Infection During Pregnancy on the Mother and Baby 405 by encephalitis, 11,250 fetal deaths, 2100 neonatal a rash and lymphadenopathy of nasopharyngeal deaths, and 20,000 infants born with CRS. In 1969, and upper respiratory tract nodes. Complications live, attenuated rubella vaccines were fi rst licensed of rubella infection include arthropathy (in up in the U.S. and a vaccination program imple- to 70% women), and, rarely, thrombocytopenic mented aimed at preventing congenital infection. purpura (more common in children), encephali- Since then substantial declines in incidence in the tis, orchitis, and neuritis. U.S. have been reported and, in 2004, the CDC announced that rubella is no longer endemic in Infection in Pregnancy the U.S. (Centers for Disease Control and Preven- tion 2005a). Infection in the fi rst trimester of pregnancy has A recent survey of WHO member countries the most severe consequences for the fetus: mal- found that the number of countries incorporating formation, miscarriage, and intrauterine death. rubella-containing vaccine into their national Up to 90% of babies infected in the fi rst 11 weeks immunization schedule increased from 65 (33%) of gestation develop CRS, the risk declining in 1996 to 110 (57%) in 2003 (Centers for Disease rapidly after the fi rst trimester, becoming negli- Control and Prevention 2005a). Rubella vaccine gible after 16 weeks (Miller et al. 1982). Rubella use worldwide varies by level of economic devel- infection later in gestation does not result in CRS opment: 100% in industrialized countries, 71% in (Centers for Disease Control and Prevention countries with transitional economies, and 48% in 2001). developing countries (Robertson et al. 2003). The Rubella reinfection may occur. It is more estimated number of infants worldwide born with common after vaccination than is infection. The CRS each year is more than 100,000 (Robertson risk of CRS after rubella reinfection is extremely et al. 2003). small (Banatvala and Brown 2004). Infection is spread person to person via respiratory transmission. Humans are the only known Congenital Rubella Syndrome reservoir. The virus replicates in the nasopharynx Congenital rubella syndrome results from vertical and regional lymph nodes, with viremia occurring transmission of rubella and typically manifests in 5 to 7 days after infection. Transplacental trans- infancy. The CDC case defi nition for CRS is based mission of infection to the fetus occurs during on clinical and laboratory fi ndings (Centers for viremia. The incubation period is 12 to 23 days Disease Control and Prevention 1997). Infants (average 14 days). Infants infected with rubella in with CRS usually present with more than one of utero can shed the virus for up to 12 months or the following clinical fi ndings; however, they may longer (Cooper and Krugman 1967). have only a single defect, most commonly hearing impairment (Centers for Disease Control and Pre- Pathogenesis vention 1997): Maternal viremia infects the placenta, with sub- a. Cataracts/congenital glaucoma, congenital sequent fetal infection. Fetal infection can affect heart disease (most commonly patent ductus all organs; its impact is most severe in very arteriosus or peripheral pulmonary stenosis), early pregnancy, coincident with organogenesis. hearing impairment, pigmentary retinopathy Rubella is teratogenic and causes fetal damage b. Purpura, hepatosplenomegaly, jaundice, via two mechanisms: a generalized, progressive, microcephaly, developmental delay, meningo- necrotizing vasculitis, resulting in parenchymal encephalitis, radiolucent bone disease (Centers hypoplasia; and cellular deletion through mitotic for Disease Control and Prevention 1997). arrest and apoptosis (Plotkin 2001; Centers for Disease Control and Prevention 2005a). Congenital rubella syndrome is categorized as follows: Clinical Features 1. Suspected CRS: not meeting criteria for classi- Rubella is asymptomatic in up to 50% cases. Its fi cation as a probable case but having some commonest presentation in children and adults is consistent clinical fi ndings 406 H.E. Jeffery and M.M. Lahra

2. Probable CRS: any two fi ndings from entry “a” TABLE 16.5. Clinical features of congenital rubella syndrome (above) or one from “a” and one from category Type of defect Clinical feature “b” in the absence of any other etiology Ocular Cataracts (uni- or bilateral)** 3. Confi rmed CRS: clinically consistent and labo- Glaucoma** ratory confi rmed (Centers for Disease Control Pigmentary retinopathy** and Prevention 1997). Microphthalmia Iris hypoplasia Cases are further classifi ed by importation Cloudy cornea status, and these guidelines should be consulted Auditory Sensorineural deafness (uni- or for further details (Centers for Disease Control bilateral)** and Prevention 1997). Cardiovascular Persistent ductus arteriosus** Pulmonary artery stenosis** A global review of CRS sequelae from prospec- Ventricular septal defect** tive studies with laboratory-confi rmed infection Myocarditis found hearing impairment in 60%, congenital Central nervous system Microcephaly* heart disease in 45%, microcephaly in 27%, cata- Meningoencephalitis* racts in 25%, low birth weight (less than 2500 g) Psychomotor retardation Behavioral disorders in 23%, hepatosplenomegaly in 19%, purpura in Speech disorders 17%, mental retardation in 13%, and meningoen- Progressive rubella cephalitis in 10% of infants with CRS (Reef et al. panencephalitis 2000). The spectrum of clinical fi ndings, including Intrauterine growth restriction delayed manifestations that may not appear until Thrombocytopenia, with purpura* early adulthood or adulthood, are summarized in Hepatitis/hepatosplenomegaly* Table 16.5. Some developmental defects such as Bone lesions* hearing impairment may not become apparent for Pneumonitis months or even years (Banatvala and Brown Lymphadenopathy 2004). The most common delayed onset disease in Diabetes mellitus Thyroid disorders CRS is the development of type 1 diabetes mellitus in adulthood. Follow-up of a cohort of Australians *Commonly recognized in the neonatal period. with CRS at age 60 years found a higher preva- **Commonly recognized in early infancy. lence of type 2 diabetes, thyroid disorders, early Early transient features are italicized. Source: Adapted from Banatvala and Brown (2004). menopause, and osteoporosis compared with the Australian population (Forrest et al. 2002).

Diagnosis from the nearest rubella reference laboratory regarding specimen collection, transport and Rubella infection is subclinical in up to 50% cases. handling, and the applications and limitations of It is confi rmed serologically by detection of the tests available. rubella-specifi c IgM or demonstration of a signifi - Laboratory diagnosis of congenitally acquired cant rise in rubella-specifi c IgG in paired acute rubella and CRS can also be made serologically, and convalescent sera by standard serologic assay. by viral culture or by NAATs. Recommendations Rubella virus may be cultured from a clinical for testing and interpretation are available specimen (e.g., blood, nasopharyngeal fl uid, urine, (Centers for Disease Control and Prevention or CSF), with the best results from throat swabs. 2001). Rubella virus can also be detected by NAATs such as reverse-transcriptase PCR (Centers for Disease Treatment Control and Prevention 2001). Molecular typing There is no specifi c antiviral therapy for rubella. of rubella virus isolated in culture or NAAT products gives important epidemiological information Prevention about the virus. Diagnosis of rubella in pregnancy requires expert consultation given the gravity of Routine determination of immune status to the implications. Expert advice should be sought rubella in all women of childbearing age and 16. The Impact of Infection During Pregnancy on the Mother and Baby 407 vaccination of the nonimmune and nonpregnant lence in young adults in developing countries is recommended. There is a theoretical risk to the compared with approximately 50% seropreva- fetus after vaccination in pregnancy; women lence in early adulthood in middle and upper should be counseled prior to vaccination to avoid socioeconomic groups in developed countries, pregnancy for 3 months. Early antenatal screen- with higher rates in certain groups such as those ing for rubella immune status should be done in with lower socioeconomic status and those all pregnant women. The pregnant nonimmune working with young children (Griffi ths et al. 1985). should be advised to avoid persons with a rash Primary CMV infection in pregnancy may result illness and be vaccinated postpartum (Centers for in vertical transmission to the fetus. In the devel- Disease Control and Prevention 2001). Infants oping world, where seroprevalence of CMV is very with CRS can shed virus for up to 12 months or high, the impact of congenital CMV is unknown. more and thus pose an infectious risk. Thus congenital CMV infection is currently a problem of the developed world. Public Health issues Congenital CMV infection affects 0.2% to 2% of the 4 million infants born in the U.S. annually, Rubella and CRS are reportable diseases in the resulting in 10,000 to 80,000 congenitally infected U.S. The CDC recommendations for the elimina- children (Hollier and Grissom 2005). tion of rubella and the prevention of CRS include Transmission of CMV occurs after contact with maintenance of high immunization rates among infected body fl uids such as saliva, genital secre- children and the vaccination of women of child- tions, and urine. Acquisition of infection com- bearing age, in particular those born outside the monly occurs in infancy especially in a child care U.S. Other recommendations are continued sur- setting and, in young adulthood, transmitted by veillance and rapid response to any rubella out- infected saliva and urine during kissing and sexual break (Centers for Disease Control and Prevention activity. Cytomegalovirus infection can also be 2005a). transmitted via infected blood and tissue in transfusion and transplantation. Cytomegalovirus Vertical transmission of CMV is largely trans- Background placental. Less commonly, perinatal transmission of CMV occurs after contact with infected mater- Cytomegalovirus (CMV) infection is of particular nal genital secretions or infected breast milk. signifi cance in the immunocompromised, where Following resolution of initial infection CMV, it causes severe multisystem disease, and in the like all human herpes viruses, has the capacity to fetus, where CMV is now the commonest viral establish latency principally in the salivary glands cause of congenital abnormality since the intro- and renal tubules. Once infected, the host carries duction of widespread rubella vaccination. the virus for life and may intermittently shed virus in saliva, urine, semen, cervical secretions, or Virology breast milk (White and Fenner 1994a). Reactiva- tion of infection occurs both in healthy and immu- The family is Herpesviride, and the subfamily is nosuppressed individuals, and, in pregnancy, may Betaherpesvirine. Cytomegalovirus is the fi fth and lead to vertical transmission. the largest of the eight human herpes viruses. Primary CMV infection in pregnancy poses a It has a double-stranded DNA genome with risk of transmission to the fetus of 30% to 40% an icosohedral capsid, surrounded by a lipid (Stagno et al. 1986), whereas the risk of vertical envelope that is covered with glycoprotein transmission in recurrent CMV infection is peplomers. between 0.2% and 1.8% (Demmler 1991). Of those Epidemiology and Transmission infected, 10% to 15% will be symptomatic at birth. The mortality rate of symptomatic babies is 20% Cytomegalovirus is ubiquitous and infection is to 30%, and 90% of surviving babies will have endemic. Seroprevalence varies demographically severe neurological sequelae.169 More severe and geographically, with up to 100% seropreva- sequelae are seen in those children whose mothers 408 H.E. Jeffery and M.M. Lahra had primary CMV infection (Hollier and Grissom nitis, gastrointestinal disease, and retinitis, which 2005). have signifi cant morbidity and mortality. Children with congenital CMV who are asymptomatic at birth may have abnormalities evident Congenital Cytomegalovirus later in life in 10% to 15% cases, in particular sensorineural hearing loss (Reynolds et al. 1974). The early clinical fi ndings in symptomatic con- Infection in the fi rst half of pregnancy is more genital CMV may include intrauterine growth often associated with symptomatic disease in the restriction and preterm delivery, petechiae, hyper- newborn, whereas infection in the second half of bilirubinemia, hepatosplenomegaly, hepatitis, pregnancy is more often initially asymptomatic jaundice, microcephaly, chorioretinitis, ventricu- (Hollier and Grissom 2005). lomegaly, periventricular calcifi cations, and seizures. Late fi ndings include developmental delay, Pathogenesis mental retardation, seizures, and sensorineural hearing loss (Hollier and Grissom 2005). Cytomegalovirus replicates in the nucleus of host cells causing cytomegalic cells, the histological Diagnosis hallmark of CMV infection. Cytomegalic cells are swollen with an enlarged nucleus, which is dis- Congenital CMV is diagnosed by viral detection, tended by a huge inclusion separated from the for example, viral culture or NAAT of blood, nuclear membrane by a nonstaining halo, giving urine, or tissue, in the fi rst 3 weeks of life. In addi- them the appearance of “owl’s eyes.” The pres- tion, serology for anti-CMV specifi c IgM in the ence of these cells is indicative of active infection, neonate may be done. Prenatal diagnosis is pos- but they are not always found. sible but complex and, when indicated by mater- In pregnancy CMV is transmitted in infected nal serology or ultrasound fi ndings, includes leukocytes via the placenta, to the fetus (Trincado amniotic fl uid or chorionic villus sampling for and Rawlinson 2001). In the fetus, CMV replicates CMV detection (culture and NAATs) and quanti- in the epithelium of the renal tubules and is tation or percutaneous umbilical blood sampling excreted via urine into the amniotic fl uid, where for detection of virus or anti CMV IgM (Enright it is reingested by the fetus and the sequence and Prober 2004; Hollier and Grissom 2005). repeated (Hollier and Grissom 2005). Increased sensitivity of amniotic fl uid testing has The pathogenesis of fetal cellular injury in con- been reported when testing is done after 21 weeks’ genital CMV is not well understood. There is gestation or at least 6 weeks after maternal primary controversy over whether the virus is directly infection (Enders et al. 2001). Collection of fetal teratogenic or if its impact is a result of impaired blood, amniotic fl uid, or chorionic villus sampling perfusion after vascular injury, as the virus is is associated with a risk of pregnancy loss, and in known to infect endothelium (Schleiss 2005). The active maternal infection, a risk of iatrogenic fetal CNS is the major target for cellular injury, and this infection (Hollier and Grissom 2005). is refl ected in extensive neurodevelopmental sequelae. Treatment

Clinical Features Currently, no proven, effective treatment exists for CMV infection in pregnancy. Antiviral drug Generally a mild, or asymptomatic, nonspecifi c therapy with ganciclovir in symptomatic neonates illness in the otherwise well, CMV can cause a with CNS disease has been recently evaluated in a spectrum of clinical illnesses in the both the multicenter, randomized, controlled trial, and healthy and immunocompromised. In young fi ndings suggest this prevents hearing deteriora- adults CMV infection can cause a mononucleosis- tion, but many subjects were lost to follow-up like illness that may be diffi cult to distinguish (Kimberlin et al. 2003). Given the potential toxic- from Epstein-Barr virus infection. In the immu- ity of long-term ganciclovir therapy, the Com- nocompromised, CMV infection causes pneumo- mittee on Infectious Diseases of the American 16. The Impact of Infection During Pregnancy on the Mother and Baby 409

Academy of Pediatrics (CIDAAP) advises addi- Virology tional study before a recommendation be made The family is Herpesviride, and the subfamily/ (American Academy of Pediatrics 2003a). genus is Alphaherpesvirine/Varicellovirus. The Prevention Alphaherpesvirine subfamily includes herpes simplex virus 1 (HSV-1), HSV-2, and VZV. The Vaccines are in development though not in clini- VZV virion is spherical and enveloped with an cal use. The CDC recommendations for pregnant icosohedral capsid and linear double-stranded women include good personal hygiene, in parti- DNA genome. The envelope of VZV is studded cular hand washing with soap and water after with glycoproteins. The Alphaherpesvirine all contact with saliva or diapers. Pregnant women grow rapidly, cause lysis of infected cells, and who become ill with a mononucleosis-like illness establish latent infection in the ganglia of sensory should be evaluated for CMV infection and coun- nerves. Reactivation triggers replication and shed- seled regarding risks to the baby. Serology can be ding of infectious virus (herpes zoster), which is performed to determine immune status. Detec- less common than reactivation with HSV (White tion or recovery of CMV from urine or vaginal and Fenner 1994e). secretions is not an indication for operative delivery. Breast-feeding is not contraindicated in Epidemiology and Transmission maternal infection, and children should not be screened or excluded from school if they are shed- Varicella zoster virus is a common disease of ding CMV (Centers for Disease Control and Pre- childhood worldwide and 90% of cases occur in vention 2005c). children under 13 years of age. By the age of 15 years about 90% of people are immune (Whitely Public Health Issues 2000). The implementation of the varicella vacci- Women of childbearing age who work with infants nation program in the U.S. has achieved a reduc- and children, and who have not previously been tion in varicella infections in all ages, with the infected with CMV, are at potential risk of infec- most marked decrease in the 1 to 4 years age tion as CMV infection is common in children in group (Jumaan et al. 2005). day care centers. Since it may be contracted from Varicella zoster virus is a highly contagious contact with infected body fl uids, particularly infection that is transmitted person to person by saliva and urine, the CDC recommends education contact, aerosol, or droplet from vesicular fl uid of regarding CMV and its transmission, and prac- skin lesions, or by infected respiratory tract secre- tices such as hand washing, which reduce the risk tions. Varicella enters the body via the respiratory of infection (Centers for Disease Control and tract (Centers for Disease Control and Prevention Prevention 2005c). 1996). A large prospective study of 1373 women with varicella in the fi rst 36 weeks of pregnancy found Varicella Zoster Virus all cases of congenital varicella occurred at less Background than 20 weeks’ gestation with an overall risk of about 1%. The highest risk (2%) was observed Varicella zoster virus (VZV) is the third of the between 13 to 20 weeks (Enders et al. 1994). human herpes viruses. Infection with VZV causes varicella (chickenpox). Like all human herpes Pathogenesis viruses VZV remains latent after infection and reactivation causes herpes zoster (shingles). After infection occurs, VZV replicates initially in Primary VZV infection in pregnancy can have the respiratory and oropharyngeal mucosa. The severe consequences for both the mother and the virus then disseminates via the lymphatic system baby. Nosocomial transmission of varicella is well and the bloodstream and replicates in mononu- recognized (Centers for Disease Control and Pre- clear leukocytes and capillary endothelial cells. vention 1996). The rash is a result of viral replication in epithelial 410 H.E. Jeffery and M.M. Lahra cells of the skin (White and Fenner 1994e). The tality rate of about 30% (Preblud et al. 1985). This rash is pruritic and characterized by successive window of increased vulnerability is due to the crops of macules, papules, and vesicles. Virus is time required for the production and transplacen- abundant in the characteristic vesicles. The incu- tal passage of maternal VZV IgG antibodies to the bation period is typically 14 days. fetus (Miller et al. 1989).

Clinical Features Diagnosis Varicella is a rash illness usually acquired in Confi rmation of infection is possible by demon- childhood. Adults, adolescents, and the immuno- stration of seroconversion or serologic rises using compromised usually have more severe disease standard assays and acute and convalescent sera. and are at increased risk of complications Diagnosis can also be made by isolation of the (Centers for Disease Control and Prevention virus in cell culture, detection of viral nucleic 1996). Complications include secondary bacterial acid in CSF, and detection of viral antigen from infection of rash lesions, pneumonitis, hepatitis, scrapings of cutaneous lesions using a direct meningoencephalitis, cerebellar ataxia, and Reye’s fl uorescent antibody stain (Whitely 2000). syndrome. Treatment Varicella Pneumonitis The CIDAAP does not routinely recommend acy- Infection in pregnancy is associated with an clovir for pregnant women with uncomplicated increased risk of pneumonitis. Clinically, respira- varicella because the risks and benefi ts to the fetus tory symptoms develop about 4 to 5 days after the and mother are unknown. For the pregnant onset of the varicella rash and include tachypnea, patient with serious complications of varicella dyspnea, cough, and fever (Whitely 2000). Radio- intravenous acyclovir is recommended (American logically there are bilateral, diffuse, peribronchial Academy of Pediatrics 2003d). nodular infi ltrates (Hollier and Grissom 2005). Radiological and clinical fi ndings may be dispa- Prevention rate, with abnormal radiology in the absence of abnormal clinical fi ndings (Whitely 2000; Hollier Live attenuated varicella vaccines were intro- and Grissom 2005). Varicella pneumonitis can be duced in the U.S. in 1995, and widespread intro- life threatening when it occurs in the second or duction of childhood vaccination has led to a third trimester of pregnancy (Whitely 2000). reduction in the incidence of varicella. Varicella vaccine is contraindicated in pregnancy. Postex- Congenital Varicella posure prophylaxis with varicella-zoster immune globulin (VZIG) is recommended for nonimmune Clinical features of congenital varicella syndrome pregnant women within 96 hours of exposure include cutaneous and skeletal defects with cica- (Centers for Disease Control and Prevention tricial skin scarring and limb atrophy. Neurologi- 1996) and where VZV immune status is unknown cal and ocular defects also occur and include and unable to be determined within this time microcephaly and cortical atrophy, seizures, period (Hollier and Grissom 2005). The adminis- mental retardation, chorioretinitis, microphthal- tration of VZIG to nonimmune pregnant women mia, and cataracts. In severely affected infants, has not been shown to prevent viremia or vertical neurogenic bladder, hydroureter, hydronephro- transmission and its consequences, and is given sis, and severe gastroesophageal refl ux are to prevent complications in the mother (Centers common (Arvin 1996). for Disease Control and Prevention 1996). Rec- ommendations for administration of VZIG to Neonatal Varicella neonates include those whose mothers have signs Maternal varicella rash developing up to 5 days and symptoms of VZV infection 5 days before up before to 2 days after delivery has an attack rate to 2 days after delivery, neonates who are preterm in the newborn of approximately 20% with a mor- (less than 28 weeks), and neonates who weigh 16. The Impact of Infection During Pregnancy on the Mother and Baby 411

1000 g or less at birth regardless of maternal 2 is increasing worldwide but varies widely and history because these infants may not have is generally higher in developing countries. Prev- maternal antibody (Centers for Disease Control alence is higher in urban than in rural settings, and Prevention 1996). Guidelines should be and varies with age, gender (generally higher in consulted. females), ethnicity, sexual practices, and the presence of other sexually transmitted infections. Public Health Issues In the U.S. the overall seroprevalence of HSV-2 Infection control measures recommended for is 21% in adults, but is higher among African neonates born to mothers with varicella include Americans, who have a seroprevalence of more airborne and contact precautions in addition to than 45%, as compared to whites, who have a standard precautions. These should be main- seroprevalence of approximately 17% (Fleming tained until 21 days of age, or 28 days of age if they et al. 1997). Many European countries report a received VZIG. For exposed nonimmune patients seroprevalence of HSV-2 of less than 15%. In the precautions above are recommended for 8 developing countries there is a wide range (2% to to 21 days after onset of rash in the index patient 74%) of seroprevalence of HSV-2 reported and for 28 days in those who received VZIG (Nahmias et al. 1990; Wagner et al. 1994). In sub- (American Academy of Pediatrics 2003d). Saharan Africa and the Caribbean, many countries have seroprevalence rates of around 50% Herpes Simplex Viruses 1 and 2 (Weiss et al. 2001). Data are scarce from Asia and South American countries. Background Orolabial HSV-1 infection is a common infection of early childhood. Reactivation of orolabial Herpes simplex virus 2 and less commonly HSV-1 infection causes cold sores. Virus is shed in these cause genital herpes. Maternal herpes infection in lesions, which are infective. Herpes simplex virus pregnancy can be transmitted to the neonate to 1 genital infection can occur via autoinfection or cause neonatal herpes. The estimated annual inci- by orogenital sex. dence of neonatal HSV infection in the U.S. is 1 in 1400 to 1 in 30,000 deliveries, resulting in 1500 to 2200 infected babies per year (Enright and Prober Genital Herpes 2004). Genital herpes is caused by HSV-2 and HSV-1. Virology Genital herpes is transmitted sexually when virus- infected secretions come into contact with suscep- The family is Herpesviride, and the subfamily/ tible mucosal surfaces or breached epithelium. genus is Alphaherpesvirine/Simplexvirus. The The risk of infection is affected by age, race, Alphaherpesvirine subfamily includes HSV-1, number of lifetime sex partners, duration and fre- HSV-2, and VZV. The HSV virion is spherical and quency of sexual intercourse, and income (Mertz enveloped with an icosohedral capsid and a linear et al. 1992). double-stranded DNA genome. The envelope After infection, HSV may be intermittently contains many different glycoproteins. The Alpha- shed from the genital tract of both men and herpesvirine all grow rapidly, cause lysis of women in the absence of prodrome, symptoms, or infected cells, and establish latent infection in the lesions. In pregnancy, rates of HSV shedding at ganglia of sensory nerves. Reactivation triggers delivery have been reported at between 0.3% to replication and shedding of infectious virus 0.5% (Brown et al. 1986, 2003) with higher rates (White and Fenner 1994b). of 1.4% reported in women with a history of recur- Epidemiology and Transmission rent HSV infection (Arvin et al. 1986). Herpes simplex virus infections are defi ned Herpes simplex virus 2 is a sexually transmitted serologically as primary, nonprimary, and recur- disease and the most common cause of genital rent. Serological primary infection with HSV-1 or ulcer disease worldwide and the most common HSV-2 occurs in someone who is seronegative cause of neonatal herpes. The prevalence of HSV- to both. Nonprimary infection is defi ned as 412 H.E. Jeffery and M.M. Lahra confi rmed infection with HSV-1 or HSV-2 that transit of the virus by retrograde axonal fl ow up occurs in the presence of heterologous antibody the peripheral sensory nerve fi bers to the corre- (e.g., infection with HSV-2 in a HSV-2 seronega- sponding sensory ganglia in the brainstem or tive person who has antibody to HSV-1). Nonpri- spinal cord where, thereafter, the viral genome mary infection is generally clinically milder (Hill persists indefi nitely. Reactivation of infection and Roberts 2005). These classifi cations have occurs at any time and can be triggered by stress, implications for risk of vertical transmission. ultraviolet light, fever, nerve injury, or immuno- Primary HSV infection in pregnancy confers suppression. Following reactivation replication the highest risk of neonatal infection. The chance occurs in the latently infected neurons, and virus of vertical transmission is greatest when maternal is transported down the axon to the periphery infection with HSV-1 or HSV-2 occurs close to the where it multiplies in epithelial cells in the same time of labor, with a risk of 50% in primary infec- vicinity as those infected originally (White and tion and 33% when infection is a nonprimary fi rst Fenner 1994b). episode (Hill and Roberts 2005). Genital herpes infection acquired in the fi rst half of pregnancy or Clinical Features reactivation of genital HSV acquired prior to pregnancy is associated with a much lower risk Neonatal herpes is classifi ed into three subgroups, (1% to 5%) of vertical transmission (Hill and which have diagnostic, therapeutic, and prognos- Roberts 2005). tic implications: 1. Disease localized to the skin, eye, or mouth Neonatal Herpes (SEM) Maternal herpes simplex virus infection in preg- 2. Disease localized to the central nervous system nancy can be transmitted to the neonate. Maternal (CNS) HSV infection can be asymptomatic or symptom- 3. Disseminated disease with or without CNS atic, primary or recurrent disease, and the virus is involvement intermittently shed after infection. More than Neonatal HSV becomes symptomatic within the 85% of neonatal herpes infection occurs after fi rst month of life, a large proportion having onset perinatal exposure of the baby to HSV (HSV-2 in in the fi rst week (Hill and Roberts 2005). about 70%) in infected maternal genital secre- The largest study of neonatal HSV found that tions. In about 70% of cases this is a result of no single constellation of presenting symptoms asymptomatic HSV shedding near the time of and signs identifi ed all cases. Skin vesicles and, delivery (Whitely et al. 1988). in babies with CNS disease, seizures, were among The rate of recurrence of HSV is higher in preg- the most suggestive fi ndings of neonatal HSV nant women compared with nonpregnant women infection. Other common signs and symptoms and is more common with HSV-2 than HSV-1 were lethargy, fever, conjunctivitis, disseminated (Hill and Roberts 2005). intravascular coagulation, and pneumonia. Approximately 10% of neonatal herpes is Importantly, skin vesicles were absent in 17% of acquired postnatally after close contact with babies with SEM disease, 32% of babies with family or hospital staff with orolabial or cutane- CNS disease, and 39% of babies with dissemi- ous HSV infection (most commonly HSV-1) nated HSV disease (Kimberlin et al. 2001). (Enright and Prober 2004). Transplacental infec- Ocular involvement can affect the anterior or tion of herpes virus may rarely occur in women posterior orbit, can be unilateral or bilateral, and who have primary HSV infection in pregnancy can progress over several weeks and cause cortical but is extremely rare after recurrent disease (Hill blindness (Nahmias 2004). Disseminated disease and Roberts 2005). has the highest mortality and morbidity; CNS Pathogenesis disease has a lower mortality but signifi cant morbidity; and SEM has both low morbidity and low After transmission, HSV replicates locally in epi- mortality when specifi c antiviral therapy is used dermal cells of skin or mucous membrane before (Hill and Roberts 2005). 16. The Impact of Infection During Pregnancy on the Mother and Baby 413

Diagnosis been shown to prevent neonatal herpes (Brown et al. 2003). Prevention of primary infection in Herpes simplex virus infection must be consid- pregnancy is paramount. The CIDAAP recom- ered in a neonate with mucocutaneous vesicles, or mends that scalp monitoring be avoided if possi- evidence of clinical sepsis with negative cultures ble in infants of women suspected of having active at 48 hours with or without associated hepatitis, genital herpes (American Academy of Pediatrics or disseminated intravascular coagulation, sei- 2003b). zures, or pneumonitis (Freedman et al. 2004). Diagnosis is confi rmed by isolation of the virus in Public Health Issues viral cultures from skin vesicles, nose, throat, or conjunctival swabs or occasionally from CSF; by From a public health perspective, in developing detection of viral DNA using NAAT of CSF, blood, countries in particular, HSV-2 is implicated in or skin lesions; or by detection of viral antigen facilitating HIV transmission. In most regions using a direct fl uorescent antibody testing of cuta- with escalating HIV rates, HSV-2 is highly preva- neous lesions. Diagnosis of CNS HSV infection lent (WHO/UNAIDS/LSHTM 2001). may be diffi cult, as CSF pleocytosis is not always present and a negative NAAT does not exclude the Human Immunodeficiency Viruses diagnosis. Neurological imaging studies may be normal early in disease (Freedman et al. 2004). Human immunodefi ciency virus 1 (HIV-1) and HIV-2 are the causative agents of acquired immu- Treatment nodefi ciency syndrome (AIDS). The viruses are The CIDAAP recommends parenteral acyclovir as distinct with only 40% homology. the treatment of choice for all neonates with HSV Infection with HIV-2 accounts for a very small infection, regardless of manifestations and clinical proportion of the total HIV infections and is rare fi ndings. Management of asymptomatic infants in the developed world. exposed to HSV during delivery includes viral cul- Global data for 2004 show the number of people tures of urine and stool; rectal, oral, and nasopha- living with HIV has escalated to an estimated 39.4 ryngeal swabs; and close observation. Treatment million—the highest level ever (WHO 2004a). should be initiated if cultures are positive or in the This report shows the most marked increases in presence of clinical signs. Symptomatic, exposed infection in East Asia, Eastern Europe, and Central infants should be evaluated and treated immedi- Asia. In East Asia the incidence increased by 50% ately. Investigations include swabs, blood, and over the period 2002 to 2004, a fi gure that is largely CSF collected for culture and NAATs (see above). attributed to China’s expanding epidemic. Treatment should be initiated if virus is detected, Sub-Saharan Africa, however, remains the CSF fi ndings are abnormal, or HSV infection is worst affected region with an estimated 25.4 otherwise strongly suspected (American Academy million people (including 1.9 million children) of Pediatrics 2003b). Ophthalmologic opinion living with HIV, and 2.3 million attributable should be sought in any suspected or confi rmed deaths in adults and children in 2004. Women and case (Nahmias 2004).0 girls are increasingly affected and now account for just less than half the total estimate and 57% of Prevention the proportion infected in sub-Saharan Africa (WHO 2004a). Most HIV-infected children con- There is no vaccine in clinical use. The CDC rec- tract HIV from their mothers during pregnancy, ommendations include abstinence from sexual delivery, or lactation. activity when symptoms or lesions of herpes simplex infection are evident (Centers for Disease Control and Prevention 2005e). Use of condoms Human Immunodeficiency Virus 1 can reduce sexual transmission of infection Virology (Centers for Disease Control and Prevention 2005i). In the presence of active genital HSV The family is Retroviride, and the genus is Lenti- disease at time of delivery, cesarean section has virus. Retrovirus virions have a diploid, linear, 414 H.E. Jeffery and M.M. Lahra single-stranded RNA genome with three major and postnatally after exposure to the virus in structural genes (gag, env, and pol) as well as breast milk (Ahmad 2005). several other genes. The genome-nucleoprotein complex is closely associated with molecules of Clinical Features the viral enzymes: reverse transcriptase, integrase, Human immunodefi ciency virus disease in infants and protease. The virus is enveloped with glyco- progresses more rapidly than disease in adults, protein peplomers (White and Fenner 1994c). and most infants develop symptoms within the Transmission fi rst few months of life (Ahmad 2005). Clinical manifestations include failure to thrive, general- Human immunodefi ciency virus is transmitted ized lymphadenopathy, hepatomegaly, spleno- from person to person sexually via infected genital megaly, parotitis, oral candidiasis, recurrent secretions or blood in contact with the rectal, oral, diarrhea, cardiomyopathy, hepatitis, CNS disease or vaginal mucosa, via infected blood (direct (including developmental delay), recurrent bacte- contact with infected blood, transfusion of infected rial infections, opportunistic infections, and blood or blood products, or contaminated equip- malignancy (American Academy of Pediatrics ment). Transmission occurs vertically from 2003c). mother to baby and accounts for approximately Opportunistic infections with Pneumocystis jir- 90% of HIV infections in children. The estimated oveci (previously known as Pneumocystis carinii) rate of vertical transmission of HIV-1 is 30%, with (Stringer et al. 2002) causing Pneumocystis pneu- higher rates reported in women who are symp- monia or PCP, can occur as early as 4 to 6 weeks tomatic or who have previously delivered an of age. Other opportunistic infections include infected baby (Ahmad 2005). The importance of CMV infection, chronic or disseminated HSV or various modes of transmission of HIV-1 differs VZV infection, and candidal esophagitis. Less according to region; in most developing countries commonly mycobacterium infections and chronic the predominant mode of transmission is via het- enteritis and rarely disseminated CNS Toxoplas- erosexual sex, and vertical transmission is more mosis gondii or cryptococcal infections occur common than in industrialized countries (Grant (American Academy of Pediatrics 2003c). and De Cock 2001). The development of opportunistic infections, Multiple viral, immune, and clinical factors in wasting, progressive neurologic disease, high viral both mother and baby infl uence vertical transmis- load, a low CD4+ T-cell count, and the onset of sion. The strongest predictors of risk are maternal symptoms in the fi rst year of life are associated plasma viral load, obstetric factors, and breast- with a poor prognosis (American Academy of feeding (Moodley and Moodley 2005). Vertical Pediatrics 2003c). transmission of HIV can be interrupted and the incidence has been vastly reduced in the devel- Diagnosis oped world using intervention strategies. However, Defi nitive diagnosis of HIV infection in the in developing countries vertical transmission is neonate is made by detection of the virus by responsible for an estimated 90% of pediatric HIV nucleic acid testing or viral culture. U.S. guide- infections. In addition, the rapidly increasing lines for diagnosis of HIV infection in pregnancy incidence of HIV in women and girls tragically recommend testing within the fi rst 48 hours of forebodes that pediatric infections will escalate life, then at age 1 to 2 months and at 3 to 6 months. correspondingly. Exposed infants testing negative in the fi rst 48 Pathogenesis hours of life may be tested at 14 days, which may detect early infection acquired in the peripartum The specifi c mechanisms of mother-to-infant period (National Institutes of Health 2005). A transmission of HIV are not understood. However, positive test should be confi rmed by collecting it is known that transmission may occur transpla- and testing a second specimen. Human immuno- centally, during delivery through contact with defi ciency virus infection is diagnosed by two infected maternal blood and genital secretions, separate positive HIV virologic tests on two 16. The Impact of Infection During Pregnancy on the Mother and Baby 415 separate blood samples. Serological testing for Human Immunodeficiency Virus 2 diagnosis of HIV infection is not used in the neonate as transplacental passage of maternal Background antibody occurs. Serology is recommended after Human immunodefi ciency virus 2 (HIV-2) was 12 months to confi rm that maternal antibody has fi rst isolated from a patient with AIDS in West disappeared, and if still seropositive, the infant Africa in 1986 two years after the discovery of should be retested at 18 months of age (National HIV-1; both belong to the Lentoviride family. Institutes of Health 2005). Epidemiology and Transmission Treatment Infection with HIV-2 is concentrated in West Current guidelines for the treatment of HIV infec- Africa, Angola, and Mozambique and accounts tion in the U.S. are available online at http://www. for a very small proportion of total HIV infection. aidsinfo.nih.gov. Human immunodefi ciency virus 2 is rare in the developed world. It is transmitted in the same way Prevention as, but less commonly than, HIV-1. Co-infection with HIV-1 and HIV-2 occurs. Human immuno- There is no vaccine available. Strategies to prevent defi ciency virus 2 infection in children is rare, and vertical transmission are continually evolving. the rate of vertical transmission is reported to be The most recent guidelines for the U.S. are avail- approximately 1% (Grant and De Cock 2001). able online (National Institutes of Health 2005). Current recommendations include universal ante- Clinical Features natal counseling and screening with consent for HIV-1, the use of antiretroviral therapy for both Human immunodefi ciency virus 2 infection is the infected mother antepartum and intrapartum associated with opportunistic infection and AIDS, and her infant postpartum. In addition to antiret- although immunodefi ciency seems to develop roviral therapy for the exposed infant, prophy- more slowly and to be less severe (Centers for laxis against P. jiroveci commencing at 4 to 6 Disease Control and Prevention 2005f). The typical weeks of age is recommended (Centers for Disease course of HIV-2 infection from seroconversion is Control and Prevention 1995). Consideration unknown. A recent review of the literature on the should be given to delivery by elective cesarean natural history of HIV-1 and HIV-2 infections in section in certain circumstances. The CDC recom- adults in Africa concluded that, from the limited mends that HIV-positive mothers do not breast- studies available, those infected with HIV-2 feed to further minimize risk of infection. In the appeared to have a longer and possibly more vari- developing world, however, where children are at able survival than those with HIV-1 (Jaffar et al. increased risk of other infectious diseases and 2004). nutritional defi cit, the benefi ts of breast-feeding may outweigh the risks (U.S. Department of Diagnosis Health and Human Services 2000). Diagnosis of HIV-2 is made by confi rmation of a positive HIV-2 specifi c screening assay by one or Public Health Issues two different tests specifi c for HIV-2. Western blot is commonly used as a confi rmatory test, and Human immunodefi ciency virus infection is a guidelines for interpretation of Western blot public health crisis in the developing and the assays vary by organization. developed world. Optimal strategies for the prevention, diagnosis, and therapy of HIV infection Treatment are continually under review. Strategies for the prevention of mother-to-child transmission in The optimal therapeutic strategy for HIV-2 is both the developed and developing world are unknown. Genetic variation in the reverse tran- paramount and are the focus of global public scriptase and protease genes of HIV-1 and HIV-2 health initiatives. result in varying susceptibility to the different 416 H.E. Jeffery and M.M. Lahra classes of antiretroviral agents, in particular the Diseases, 26th ed. American Academy of Pediatrics, nonnucleoside reverse transcriptase inhibitors. Elk Grove Village, IL, pp. 672–686. http:// Recommendations from a recent review are, in aapredbook.aappublications.org/. the absence of large clinical trials of therapy for Anderson MJ, Higgins PG, Davis LR, et al. (1985) Exper- HIV-2, to combine the experience of management imental parvoviral infection in humans. J Infect Dis 152:257–65 strategies for HIV-1 with the available in vitro Arias F, Tomich P (1982) Etiology and outcomes of low susceptibility data for HIV-2 and the evidence birth weight and preterm infants. Obstet Gynecol from case series to guide management decisions 60:277–281. (Hightower and Kallas 2003). Arvin AM (1996) Varicella-zoster virus. Clin Microbiol Rev 9:361–381. Prevention Arvin AM, Hensliegh PA, Prober CG, et al. (1986) Failure of antepartum maternal cultures to predict Strategies aimed at preventing HIV-1 infection the infant’s risk of exposure to herpes simplex at should be effective in the prevention and control delivery. N Engl J Med 315:796–800. of HIV-2 infection (see above). Blood donations Austin N, Darlow B (2003) Prophylactic oral antifungal are screened for HIV-1 and HIV-2 virus. agents to prevent systematic Candida infection in preterm infants. Cochrane Database of Systematic Public Health Issues Reviews 4:CD003478. Bachman J, Heise R, Naessons J, et al. (1993) A study of The CDC recommends continued surveillance for various tests to detect asymptomatic urinary tract HIV-2 in the U.S. population, as there is the infections in an obstetric population. JAMA 270: potential for further spread of HIV-2, particularly 1971–1974. among intravenous drug users and those with Baker C, Edwards M (2003) Group B streptococcal con- multiple sex partners. jugate vaccines. Arch Dis Child 88:375–378. Banatvala JE, Brown DWG (2004) Rubella. Lancet 363:1127–1137. References Benitz W, Gould J, Druzin M (1999) Risk factors for early-onset group B streptococcal sepsis: estimation Ahmad N (2005) The vertical transmission of human of odds ratios by critical literature review. Pediatrics immunodefi ciency virus type 1: molecular and bio- 103. URL: http://www.pediatrics.org/cgi/content/full/ logical properties of the virus. Crit Rev Clin Lab Sci 103/6/e77. 42:1–34. Berkowitz K, LaSala A (1990) Risk factors associated American Academy of Pediatrics (2003a) Cytomegalo- with the increasing prevalence of pneumonia during virus infection. In: Pickering LK (ed) Red Book pregnancy. Am J Obstet Gynecol 163:981–985. Online 2003: Report of the Committee on Infectious Berman S (2004) Maternal syphilis: pathophysiology Diseases, 26th ed. American Academy of Pediatrics, and treatment. Bull WHO 82:433–438. Elk Grove Village, IL, pp. 259–262. http:// Bignell CJ (2001) European guidelines for the manage- aapredbook.aappublications.org/. ment of gonorrhea. Int J STD AIDS 12(suppl 12): American Academy of Pediatrics (2003b) Herpes 27–29. simplex. In: Pickering LK (ed) Red Book Online 2003: Bisharat N, Crook D, Leigh J, et al. (2004) Hyperinvasive Report of the Committee on Infectious Diseases, neonatal group B streptococcus has arisen from a 26th ed. American Academy of Pediatrics, Elk bovine ancestor. J Clin Microbiol 42:2161–2167. Grove Village, IL, pp. 344–353. http://aapredbook. Blackwell AL (1999) Vaginal bacterial phaginosis? Sex aappublications.org/. Transm Inf 75:352–353. American Academy of Pediatrics (2003c) Human Boyer K, Gotoff S (1986) Prevention of early-onset neo- Immunodefi ciency Virus. In: Pickering LK (ed) Red natal group B streptococcal disease with selective Book Online 2003: Report of the Committee on intrapartum chemoprophylaxis. N Engl J Med 314: Infectious Diseases, 26th ed. American Academy of 1665–1669. Pediatrics, Elk Grove Village, IL, pp. 360–382. http:// Brabin B, Romagosa C, Abdelgalil S, et al. (2004) The aapredbook.aappublications.org/. sick placenta—the role of malaria. Placenta 25:359– American Academy of Pediatrics (2003d) Varicella- 378. zoster infection. In: Pickering LK (ed) Red Book Bradshaw C, Morton A, Garland S, et al. (2005) Higher- Online 2003: Report of the Committee on Infectious risk behavioural practices associated with bacterial 16. The Impact of Infection During Pregnancy on the Mother and Baby 417

vaginosis compared with vaginal candidiasis. Obstet Centers for Disease Control and Prevention (2002a) Gynecol 106:105–114. Prevention of perinatal group B streptococcal disease. Brocklehurst P (1999) Update on the treatment of sexu- MMWR 51(RR-11):1–22. ally transmitted infections in pregnancy-1. Int J STD Centers for Disease Control and Prevention (2002b) AIDS 10:571–580. Sexually transmitted diseases treatment guidelines Brocklehurst P (2002) Antibiotics for gonorrhoea in 2002. MMWR 51(RR-6):1–84. pregnancy. Cochrane Database of Systematic Reviews Centers for Disease Control and Prevention (2004) 2:CD000098. Trends in Reportable Sexually Transmitted Diseases Brown KE, Anderson SM, Young NS (1993) Erythrocyte in the United States, 2004. National Data on Chla- P antigen: cellular receptor for B19 parvovirus. mydia, Gonorrhea and Syphilis. Atlanta, GA: U.S. Science 262:114–117. Department of Health and Human Services. Brown KE, Green SW, Antunez de Mayolo J, et al. (1994) Centers for Disease Control and Prevention (2005a) Congenital anemia after transplacental parvovirus Achievements in public health: elimination of rubella B19 infection. Lancet 343:895–896. and congenital rubella syndrome in the United States, Brown ZA, Benedetti J, Ashley R, et al. (1986) Neonatal 1969–2004. MMWR 54;279–282. herpes simplex virus infection in relation to asymp- Centers for Disease Control and Prevention (2005b) tomatic maternal infection at the time of labor. N Controlling tuberculosis in the United States. MMWR Engl J Med 315:796–800. 54(RR-12):1–81. Brown ZA, Wald A, Morrow RA, et al. (2003) Effect of Centers for Disease Control and Prevention (2005c) serologic status and cesarean delivery on transmis- Cytomegalovirus (CMV) infection. http://www.cdc. sion rates of herpes simplex virus from mother to gov/ncidod/diseases/cmv.htm. infant. JAMA 289:203–209. Centers for Disease Control and Prevention (2005d) Bryce J, Boshi-Pinto C, Shibuya K, et al. (2005) WHO Early-onset and late-onset neonatal group B strepto- estimates of the causes of death in children. Lancet coccal disease- United States, 1996–2004. MMWR 365:1147–1152. 54(RR-47):1205–1208. Carr P, Felsenstein D, Friedman R (1998) Evaluation Centers for Disease Control and Prevention (2005e) and management of vaginitis. J Gen Intern Med Genital herpes fact sheet. http://www.cdc.gov/std/ 13:335–346. Herpes/STDFact-Herpes.htm. Carrol S, Papaioannou S, Ntumazah I, et al. (1996) Centers for Disease Control and Prevention (2005f) Lower genital tract swabs in the prediction of intra- Human immunodefi ciency type 2. http://www.cdc. uterine infection in preterm prelabour rupture of the gov/hiv/pubs/facts/hiv2.htm. membranes. Br J Obstet Gynaecol 103:54–59. Centers for Disease Control and Prevention (2005g) Cassell G, Davis R, Waites K, et al. (1983) Isolation of Parvovirus B19 infection and pregnancy. http://www. Mycoplasma hominis and ureaplasma urealyticum cdc.gov/ncidod/dvrd/revb/respiratory/B19&preg. from amniotic fl uid at 16–20 weeks of gestation: htm. potential effect on outcome of pregnancy. Sex Transm Centers for Disease Control and Prevention (2005h) Dis 10(4 suppl):294–302. Reported Tuberculosis in the United States, 2004. Centers for Disease Control and Prevention (1995) Atlanta, GA: U.S. Department of Health and Human Guidelines for prophylaxis against Pneumocystis Services. carinii pneumonia for children infected with or peri- Centers for Disease Control and Prevention (2005i) natally exposed to human immunodefi ciency virus. STDs and Pregnancy—CDC Fact Sheet. http:// MMWR 44(RR-4). www.cdc.gov/std/STDFact-STDs&Pregnancy.htm Centers for Disease Control and Prevention (1996) Pre- (accessed December 6, 2005). vention of varicella: recommendations of Advisory Chaim W, Mazor M, Wiznitzer A (1992) The prevalence Committee on Immunization Practices (ACIP). and clinical signifi cance of intraamniotic infection MMWR 45(RR-11). with Candida species in women with preterm labour. Centers for Disease Control and Prevention (1997) Case Arch Gynecol Obstet 251:9–15. defi nitions for Infectious conditions under public Colditz G, Brewer T, Berkley C, et al. (1994) Effi cacy of health surveillance. MMWR 46(RR-10):30. BCG vaccine in the prevention of tuberculosis: meta- Centers for Disease Control and Prevention (2001) analysis of the published literature. JAMA 271: Control and prevention of rubella; evaluation and 698–702. management of suspected outbreaks, rubella in preg- Cooper LZ, Krugman S (1967) Clinical manifestations nant women, and surveillance for congenital rubella of postnatal and congenital rubella. Arch Ophthal- syndrome. MMWR 50(RR-12). mol 77:343–349. 418 H.E. Jeffery and M.M. Lahra

Corcoran A, Doyle S (2004) Advances in the biology, Fleming DT, McQuillan GM, Johnson RE, et al. (1997) diagnosis and host-pathogen interactions of parvovi- Herpes simplex virus type 2 in the United States, rus B19. J Med Microbiol 53:459–75. 1976–1994. N Engl J Med 337:1105–1111. Cossart YE, Field AM, Cant B, Widdows D (1975) Fletcher M (2001) Vaccine candidates in STD. Int J STD Parvovirus-like particles in human sera. Lancet AIDS 12:419–422. 1:72–73. Forrest JM, Turnbull FM, Sholler GF, et al. (2002) Cotch M, Pastorek J, Nugent R (1991) Demographic and Gregg’s congenital rubella patients 60 years later. behavioural predictors of Trichomonas vaginalis Med J Aust 177:664–667. infection among pregnant women. The vaginal infec- Foulon W, Pinon J-M, Stray-Pedersen B, et al. (1999) tions and prematurity study group. Obstet Gynecol Prenatal diagnosis of congenital toxoplasmosis: a 78:1087–92. multicenter evaluation of different diagnostic param- Cotch M, Pastorek J, Nugent R (1997) Trichomonas eters. Am J Obstet Gynecol 181:843–847. vaginalis associated with low birth weight and Foxman B (2003) Epidemiology of urinary tract infec- preterm delivery. Sex Transm Dis 24:353–360. tions: incidence, morbidity, and economic costs. Dis Danesh I, Stephen J, Gorbach J (1995) Neonatal Tricho- Mon 49:53–70. monas vaginalis infection. J Emerg Med 13:51–54. Fraser C, Norris S, Weinstock G (1998) Complete Dear K, Andrews R, Holden J, et al. (2003) Vaccines for genome sequence of Treponema pallidum, the syphi- preventing pneumococcal infection in adults. lis spirochete. Science 281:375–388. Cochrane Database of Systematic Reviews 4: Freedman E, Mindel A, Jones CA (2004) Epidemiologi- CD000422. cal, clinical and laboratory aids for the diagnosis of Demmler GJ (1991) Infectious Diseases Society of neonatal herpes—an Australian perspective. Herpes America and Centers for Disease Control: summary 11:38–40. of a workshop on surveillance for congenital cyto- Frieden T, Sterling T, Munsiff S, et al. (2003) Tubercu- megalovirus disease. Rev Infect Dis 13;315–29. losis. Lancet 362:887–899. DeVillard E, Burton J, Reid G (2005) Complexity of Garner P, Gülmezoglu AM (2002) Drugs for preventing vaginal microﬂ ora as analysed by PCR denaturing malaria-related illness in pregnant women and death gradient gel electrophoresis in a patient with recur- in the newborn. Cochrane Database of Systematic rent bacterial vaginosis. Infect Dis Obstet Gynecol Reviews 4:CD000169. 13:25–30. Gibbs R, Schrag S, Schuchat A (2004) Perinatal infec- Donovan B (2004) Sexually transmissible infections tions due to group B streptococci. Obstet Gynecol other than HIV. Lancet 363:545–556. 104:1062–1076. Duffy PE (2003) Maternal immunization and malaria in Goldenberg R, Andrews W, Mercer B, et al. (2000a) The pregnancy. Vaccine 21:3358–3361. preterm prediction study: granulocyte colony-stimu- Dunn D, Wallon M, Peyron F, et al. (1999) Mother-to- lating factor and spontaneous preterm birth. Am J child transmission of toxoplasmosis: risk estimated Obstet Gynecol 182:625–630. for clinical counselling. Lancet 353:1829–1833. Goldenberg R, Hauth J, Andrews W (2000b) Intrauter- Edwards J, Apicella M (2004) The molecular mecha- ine infection and preterm delivery. N Engl J Med nisms used by Neisseria gonorrhoeae to initiate 342:1500–1507. infection differ between men and women. Clin Micro Grant AD, De Cock KM (2001) ABC of AIDS. HIV infec- Rev 17:965–981. tion and AIDS in the developing world. Br Med J Enders G, Bader U, Lindemann L, et al. (2001) Prenatal 322:1475–1478. diagnosis of congenital cytomegalovirus infection in Gregg NM (1941) Congenital cataract following German 189 pregnancies with known outcome. Prenat Diagn measles in the mother. Trans Ophthalmol Soc Aust 21:362–377. 3:35–46. Enders G, Miller E, Craddock-Watson J, et al. (1994) Grifﬁ ths P, Baboonian C, Ashby D (1985) The demo- Consequences of varicella and herpes zoster in preg- graphic characteristics of pregnant women infected nancy: prospective study of 1739 cases. Lancet with cytomegalovirus. Int J Epidemiol 14:447–552. 343:1548–1552. Guerin P, Olliaro P, Nosten F, et al. (2002) Malaria: Enright AM, Prober CG (2004) Herpesviridae infections current status of control, diagnosis, treatment, and a in newborns: varicella zoster virus, herpes simplex proposed agenda for research and development. virus, and cytomegalovirus. Pediatr Clin North Am Lancet Infect Dis 2:564–573. 51:889–908. Gülmezoglu AM (2002) Interventions for trichomonia- Fischer PB (2003) Malaria and newborns. J Trop Pediatr sis in pregnancy. Cochrane Database of Systematic 49:132–134. Reviews 3:CD000220. 16. The Impact of Infection During Pregnancy on the Mother and Baby 419

Guyatt H, Snow R (2001) Malaria in pregnancy as an Jordon JA (1996) Identifi cation of human parvovirus indirect cause of infant mortality in sub-Saharan infection in idiopathic nonimmune hydrops fetalis. Africa. Trans Royal Soc Trop Med Hygiene 95: Am J Obstet Gynecol 174;37–42. 569–576. Jumaan AO, Yu O, Jackson LA, et al. (2005) Incidence Guyatt H, Snow R (2004) Impact of malaria during of herpes-zoster, before and after varicella- pregnancy on low birth weight in sub-Saharan Africa. vaccination-associated incidence decreases in the Clin Micro Rev 17:760–769. incidence of varicella 1992–2002. J Infect Dis 191: Haberland C, Benitz W, Sanders G, et al. (2002) Perina- 2002–2007. tal screening for group B streptococci: cost-benefi t Kimberlin DW, Lin C-Y, Jacobs RF, et al. (2001) Natural analysis of rapid polymerase chain reaction. Pediat- history of neonatal herpes simplex virus infections in rics 110:471–480. the Acyclovir era. Pediatrics 108:223–229. Haile M, Kallenius G (2005) Recent developments in Kimberlin DW, Lin Cy, Sanchez PJ, et al. (2003) Effect tuberculosis vaccines. Curr Opin Infect Dis 18:211– of ganciclovir therapy on hearing impairment in 215. symptomatic congenital cytomegalovirus disease Hedges S, Mayo M, Mestecky J, et al. (1999) Limited involving the central nervous system: a randomized, local and systemic antibody response to Neisseria controlled trial. J Pediatr 143:16–25. gonorrhoeae during uncomplicated genital infec- Kiss H, Petricevic L, Husslein P (2004) Prospective ran- tions. Infect Immun 67:3937–3946. domized controlled trial of an infection screening Heegaard ED, Laub Peterson B (2000) Parvovirus B19 programme to reduce the rate of preterm delivery. Br transmitted by bone marrow. Br J Haematol 111:659– Med J 329:371–375. 661 Klebanoff M, Carey C, Hauth J, et al. (2001) Failure of Heine P, McGregor J (1993) Trichomonas vaginalis: a metronidazole to prevent preterm delivery among remerging pathogen. Clin Obstet Gynecol 36:137– women with asymptomatic Trichomonas vaginalis 144. infection. N Engl J Med 345:487–493. Hightower M, Kallas EG (2003) Diagnosis, antiretrovi- Koch WC (2001) Fifth (human parvovirus) and sixth ral therapy, and emergence of resistance to antiret- (herpes virus 6) diseases. Curr Opin Inf Dis 14: roviral agents in HIV-2 infection: a review. Brazi J Inf 343–356. Dis 7(1):7–15. Koch WC, Harger JH, Barnstein B, et al. (1998) Sero- Hill J, Roberts S (2005) Herpes simplex virus in preg- logic and virologic evidence for frequent intrauterine nancy: New concepts in prevention and manage- transmission of human parvovirus B19 with a ment. Clin Perinatol 32:657–670. primary maternal infection during pregnancy. Hollier LM, Grissom H (2005) Human herpes viruses Pediatr Infect Dis J 17:489–494. in pregnancy: cytomegalovirus, Epstein-Barr virus, Kotiw M, Zhang G, Daggard G, et al. (2003) Late-onset and varicella zoster virus. Clin Perinatol 32:671– and recurrent neonatal group B streptococcal disease 696. associated with breast-milk transmission. Pediatr Holmes K, Levine R, Weaver M (2004) Effectiveness of Dev Pathol 6:251–265. condoms in preventing sexually transmitted infec- Kravetz J, Federman D (2005) Toxoplasmosis in preg- tions. Bull World Health Organ 82:454–457. nancy. Am J Med 118:212–216. Jaffar S, Grant AD, Whitworth J, et al. (2004) The Lahra M, Jeffery HE (2004) A fetal response to chorio- natural history of HIV-1 and HIV-2 infections in amnionitis is associated with early survival after adults in Africa: a literature review. Bull WHO preterm birth. Am J Obstet Gynecol 190:147–151. 82:462–469. Laibl V, Sheffi eld J (2005a) Tuberculosis in pregnancy. Jeffery HE (1996) Perinatal group B streptococcal infec- Clin Perinatol 32:739–747. tion: a signifi cant public health problem. Semin Laibl V, Sheffi eld J (2005b) Infl uenza and pneumonia Neonatal 1:77–89. in pregnancy. Clin Perinatol 32:727–738. Jeffery HE, Lahra M (1998) Eight-year outcome of uni- Lamont R, Duncan S, Mandal D, et al. (2003) Intravagi- versal screening and intrapartum antibiotics for nal clindamycin to reduce preterm birth in women maternal group B streptococcal carriers. Pediatrics with abnormal genital tract fl ora. Obstet Gynecol 101e2. URL: http://www.pediatrics.org/cgi/content/ 101:516–22. full/101/1/e2. Lamont RF (2005) Vaginal markers of preterm birth. Jones J, Kruszon-Moran D, Wilson M, et al. (2001) Acta Obstet Gynecol Scand 84:537–538. Toxoplasma gondii infection in the United States: Le J, Briggs G, McKeown A, et al. (2004) Urinary tract seroprevalence and risk factors. Am J Epidemiol infections during pregnancy. Ann Pharmacotherapy 154:357–365. 38:1692–1701. 420 H.E. Jeffery and M.M. Lahra

Lengeler C (2004) Insecticide-treated bed nets and cur- group-B-streptococcal disease on the incidence and tains for preventing malaria. Cochrane Database of ecology of early-onset neonatal sepsis. Lancet Infect Systematic Reviews 2:CD000363. Dis 3:201–13. Leviton A, Paneth N, Reuss L, et al. (1999) Maternal Morel C, Lauer J, Evans D (2005) Cost effectiveness infection, fetal infl ammatory response, and brain analysis of strategies to combat malaria in develop- damage in very low birth weight infants. Pediatr Res ing countries. Br Med J 331:1299. 46:566. Mylonakis E, Paliou M, Hohmann E, et al. (2002) Liste- Lim W, Macfarlane J, Colthorpe C (2001) Pneumonia riosis during pregnancy: a case series and review of and pregnancy. Thorax 56:398–405. 222 cases. Medicine 81:260–69. Lindsay S, Ansell J, Selman C, et al. (2000) Effect of Nahmias AJ (2004) Neonatal HSV infection. Part 1: con- pregnancy on exposure to malaria mosquitoes. tinuing challenges. Herpes 11:33–37. Lancet 355:1972. Nahmias AJ, Lee FK, Beckman-Nahmias S (1990) Sero- Lockwood CJ (2002) Predicting premature delivery— epidemiological and sociological patterns of herpes no easy task. N Engl J Med 346:282–284. simplex virus infection in the world. Scand J Infect Lopez A, Dieta V, Wilson M, et al. (2000) Preventing Dis S69:19–36. congenital toxoplasmosis. MMWR 49 RR-2:59–69. National Institutes of Health (2005) Guidelines for the Maldonado YA (2003) Rubella virus. In: Long SS use of antiretroviral agents in pediatric HIV therapy. (ed) Principles and Practice of Pediatric Infectious http://aidsinfo.nih.gov/ContentFiles/PediatricGuide- Diseases, 2nd ed. Churchill Livingstone, New lines_PDA.pdf. York. Neralla S, Glassroth J (2003) Mycobacterium tubercu- Martin C (2005) The dream of a vaccine against tuber- losis: the treatment of active disease. Semin Respir culosis; new vaccines improving or replacing BCG? Infect 18:292–306. Eur Respir J 26:162–167. Newman RD, Hailemariam A, Jimma D, et al. (2003) McDonald H, Brocklehurst P, Parsons J (2005) Antibi- Burden of malaria during pregnancy in areas otics for treating bacterial vaginosis in pregnancy. of stable and unstable transmission in Ethiopia Cochrane Database of Systematic Reviews 1: during a nonepidemic year. J Infect Dis 187:1765– CD000262. 1772. Mertz GJ, Benedetti JK, Selke Sa, et al. (1992) Risk Newnham J, Shub A, Jobe A, et al. (2005) The effects of factors for the sexual transmission of genital herpes. intra-amniotic injection of periodontopathic lipo- Ann Intern Med 116:197–202. polysaccharides in sheep. Am J Obstet Gynecol Miller E, Cradock-Watson JE, Pollock TM (1982) Con- 193:313–321. sequences of confi rmed maternal rubella at succes- Nicolle L, Bradley S, Colgan R, et al. (2005) Infectious sive stages of pregnancy. Lancet 2:781–794. disease society of America guidelines for the diagno- Miller E, Cradock–Watson JE, Ridehalgh MK (1989) sis and treatment of asymptomatic bacteruria in Outcome of newborn babies given anti-varicella- adults. Clin Infect Dis 40:643–654. zoster immunoglobulin after perinatal infection with Nigro G, Bastianon V, Colloridi V, et al. (2004) Human varicella- zoster virus. Lancet 2:371–373. parvovirus B19 infection in infancy associated with Miller E, Fairley CK, Cohen BJ, Seng C (1998) Immedi- acute and chronic lymphocytic myocarditis and high ate and long term outcome of human parvovirus cytokine levels: report of three cases and review. Clin B19 infection in pregnancy. Br J Obstet Gynaecol Infect Dis 31:65–69. 105:174–178. Offenbacher S, Katz V, Fertik G, et al. (1996) Periodon- Mittal P, Wing D (2005) Urinary tract infections in tal infections as a possible risk factor for preterm low pregnancy. Clin Perinat 32:749–764. birth weight. J Periodontal 67:1103–1113. Montoya J (2002) Laboratory diagnosis of Toxoplasma Ogunmodede F, Jones JL, Scheftel J, Kirkland E, Schul- gondii infection and toxoplasmosis. Infect Dis kin J, Lynfi eld R (2005) Listeriosis prevention knowl- 185(suppl 1):s73–82. edge among pregnant women in the USA. Infect Dis Montoya J, Rosso F (2005) Diagnosis and management Obstet Gynecol 13:11–5. of toxoplasmosis. Clin Perinatol 32:705–726. Olliaro P (2004) Congenital toxoplasmosis. Clin Evi- Moodley J, Moodley D (2005) Management of dence 12:1058–1061. human immunodefi ciency virus infection in preg- Ormerod P (2001) Tuberculosis in pregnancy and the nancy. Best Pract Res Clin Obstet Gynaecol 19:169– puerperium. Thorax 56:494–499. 183. Orton L, Garner P (2005) Drugs for treating uncompli- Moore M, Schrag S, Schuchat A (2003) Effects of intra- cated malaria in pregnant women. Cochrane Data- partum antimicrobial prophylaxis for prevention of base of Systematic Reviews 3:CD004912. 16. The Impact of Infection During Pregnancy on the Mother and Baby 421

Pacora P, Chaiworapongsa T, Maymon E, et al. (2002) Romero R, Chaiworapongsa T, Espinoza J (2003) Micro- Funisitis and chorionic vasculitis: the histological nutrients and intrauterine infection, preterm birth counterpart of the fetal infl ammatory response and the fetal infl ammatory response syndrome. syndrome. J Matern Fetal Neonatal Med 11:18– J Nutr 133:1668s–1673s. 25. Romero R, Gomez R, Chaiworapongsa T, et al. (2001) Pastore L, Savitz D, Thorp J (1999) Predictors of urinary The role of infection in preterm labour and delivery. tract infection at the fi rst prenatal visit. Epidemiol- Paediatr Perinatal Epidemiol 15(suppl 2):41–56. ogy 10:282–287. Rouse D, Andrews W, Goldenberg R, et al. (1995) Peeling R, Ye H (2004) Diagnostic tools for preventing Screening and treatment of asymptomatic bacteruria and managing maternal and congenital syphilis: an of pregnancy to prevent pyelonephritis: a cost-effec- overview. Bull WHO 82:439–446. tiveness and cost-benefi t analysis. Obstet Gynecol Peipert JF (2003) Genital chlamydial infections. N Engl 86:119–123. J Med 349:2424–2430. Rupp R, Stanberry L, Rosenthal S (2004) New biomedi- Petersen E (2004) Malaria chemoprophylaxis: when cal approaches for sexually transmitted infection should we use it and what are the options? Expert Rev prevention: vaccines and microbicides. Adolesc Med Antiinfect Ther 2:119–32. Clin 15:393–407. Peyron F, Wallon M (2001) Options for the pharmaco- Russell P (1979) Infl ammatory lesions of the therapy of toxoplasmosis during pregnancy. Exp human placenta: I, clinical signifi cance of acute Opin Pharmacol 2:1269–1274. chorioamnionitis. Am J Diagn Gynecol Obstet Peyron F, Wallon M, Liou C, et al. (1999) Treatments 1:127–137. for toxoplasmosis in pregnancy. Cochrane Database Sachs J, Malaney P (2002) The economic and social of Systematic Reviews 3:CD001684. burden of malaria. Nature 415:680–685. Planche T, Krishna S (2005) The relevance of malaria Saloojee H, Velaphi S, Goga Y, et al. (2004) The pre- pathophysiology to strategies of clinical manage- vention and management of congenital syphilis: an ment. Curr Opin Infect Dis 18:369–375. overview and recommendations. Bull WHO 82: Plotkin SA (2001) Rubella eradication. Vaccine 19: 424–430. 3311–3319. Schild RL, Bald R, Plath H, et al. (1999) Intrauterine Polizzotto M (2005) Prevention of sexually transmitted management of fetal parvovirus B19 infection. Ultra- diseases. Clin Fam Prac 7:1–12. sound Obstet Gynecol 13:161–166. Preblud SR, Bregman DJ, Vernon LL (1985) Deaths Schleiss MR (2005) Cytomegalovirus infection. www. from varicella in infants. Pediatr Infect Dis J 4:503– emedicine.com/MED/topic504.htm. 507. Schmid G (2004) Policy and practice. Economic and Puopolo K, Madoff L, Eichenwald E (2005) Early-onset programmatic aspects of congenital syphilis preven- group B streptococcal disease in the era of maternal tion. Bull WHO 82:402–409. screening. Pediatrics 115:1240–1246. Silver HM (1998) Listeriosis during pregnancy. Obstet Reef SE, Plotkin S, Cordero JF, et al. (2000) Preparing Gynecol Surv 53:737–740. for elimination of congenital rubella syndrome Skjoldebrand-Sparre L, Tolfvenstam T, Papadogianna- (CRS): summary of a workshop on CRS elimination kis N, et al. (2000) Parvovirus B19 infection: associa- in the United States. Clin Infect Dis 31:85–95. tion with third-trimester intrauterine death. Br J Reynolds DW, Stagno S, Stubbs KG, et al. (1974) Inap- Obstet Gynaecol 107:476–480. parent congenital cytomegalovirus infection with Smaill F (1996) Intrapartum antibiotics for group B elevated cord IgM levels; causal relationship with streptococcal colonization. Cochrane Database of auditory and mental defi ciency. N Engl J Med Systematic Reviews 1:CD000115. 290:291–296. Smaill F (2001) Antibiotics for asymptomatic bacter- Risser W, Bortot A, Benjamins L, et al. (2005) The epi- uria in pregnancy. Cochrane Database of Systematic demiology of sexually transmitted infections in ado- Reviews 2:CD000490. lescents. Semin Pediatr Infect Dis 16:160–167. Smith K (2002) Congenital tuberculosis: a rare manifes- Robertson SE, Featherstone DA, Gacic-Dobo M (2003) tation of a common infection. Curr Opin Infect Dis Rubella and congenital rubella syndrome: global 15:269–274. update. Pan Am J Public Health 14:306–315. Soper D (2004) Trichomoniasis: Under control or Rodis JF, Quinn DL, Gary GW Jr, et al. (1990) Manage- undercontrolled? Am J Obstet Gynecol 190:281–90. ment and outcomes of pregnancies complicated by Southwick F, Purich D (1996) Mechanisms of disease, human parvovirus B19 infection: a prospective study. Intracellular pathogenesis of listeriosis. N Engl J Med Am J Obst Gynecol 163:1168–1171. 334:770–776. 422 H.E. Jeffery and M.M. Lahra

Spigarelli M, Biro F (2004) Sexually transmitted disease African Cities. The epidemiology of HSV-2 infection testing: evaluation of diagnostic tests and methods. and its association with HIV infection in four urban Adolesc Med Clin 15:287–299. African populations. AIDS 15(suppl 4):S97–S108. Stagno S, Pass R, Cloud G, et al. (1986) Primary cyto- White DO, Fenner FJ (1994a) Cytomegalovirus in Her- megalovirus infection in pregnancy: incidence, trans- pesviridae In: Medical Virology, 4th ed. Academic mission to fetus, and clinical outcome. JAMA Press, San Diego, pp. 334–341. 256:1904–1908. White DO, Fenner FJ (1994b) Herpes simplex viruses in Steketee R, Nahlen B, Parise M, et al. (2001) The burden Herpesviridae. In: Medical Virology, 4th ed. Aca- of malaria in pregnancy in malaria-endemic areas. demic Press, San Diego, pp. 323–330. Am J Trop Med Hyg 64S:28–35. White DO, Fenner FJ (1994c) Human immunodefi - Steketee RW (2003) Pregnancy, nutrition and parasitic ciency virus in Retroviridae In: Medical Virology, 4th diseases. J Nutr 133:1661S–1667S. ed. Academic Press, San Diego, pp. 538–561. Stevens-Simon C, Sheeder J (2005) Chlamydia tracho- White DO, Fenner FJ (1994d) Parvoviridae In: Medical matis: common misperceptions and misunderstand- Virology, 4th ed. Academic Press, San Diego, pp. ings. J Pediatr Adolesc Gynecol 18:231–243. 285–293. Stringer JR, Beard CB, Miller RF, Wakefi eld AE (2002) White DO, Fenner FJ (1994e) Varicella-Zoster virus in A new name (Pneumocystis jiroveci) for pneumocys- Herpesviridae In: Medical Virology, 4th ed. Aca- tis from humans. Emerg Infect Dis 8. http://www.cdc. demic Press, San Diego, pp. 333–334. gov/ncidod/EID/vol8no9/02–0096.htm. Whitely RJ (2000) Varicella-zoster virus. In: Mandell ter Kuile F, Parise M, Verhoeff F, et al. (2004) The GL, Bennett JE, Dolin R (eds) Principles and Practice burden of co-infection with human immunodefi - of Infectious Diseases, 5th ed. Churchill Livingstone, ciency virus type 1 and malaria in pregnant women New York, pp. 1580–1586. in sub-Saharan Africa. Am J Trop Med Hyg 71(suppl Whitely RJ, Corey L, Arvin A, et al. (1988) Changing 2):41–54. presentation of herpes simplex virus infection in Thomsen AC, Morup L, Brogaard Hansen K (1987) neonates. J Infect Dis 158:109–116. Antibiotic elimination of group B streptococci in Workowski K, Levine W, Wasserheit J (2002) U.S. urine in prevention of preterm labour. Lancet 1: Centers for disease control and prevention guide- 591–593. lines for the treatment of sexually transmitted dis- Trincado DE, Rawlinson WD (2001) Congenital and eases: an opportunity to unify clinical and public perinatal infections with cytomegalovirus. J Paediatr health practice. Ann Intern Med 137:e255–262. Child Health 37:187–192. World Health Organization (2004a) AIDS Epidemic U.S. Department of Health and Human Services (2000) update. http://.whqlibdoc.who.int/unaids/2004/a Blueprint for action on breastfeeding. http://www. 62410. womenshealth.gov/Breastfeeding/bluprntbk2.pdf. World Health Organization (2004b) A strategic Frame- van Geertruyden J-P, Thomas F, Erhart A, et al. (2004) work for Malaria Prevention and Control During The contribution of malaria in pregnancy to perina- Pregnancy in the African Region. Brazzawille: WHO tal mortality. Ann Trop Med Hyg 71(suppl 2):35– Regional Offi ce for Africa. 40. WHO/UNAIDS/LSHTM (2001) Herpes simplex virus Vazquez JC, Villar J (2003) Treatments for symptomatic type 2 programmatic and research priorities in devel- urinary tract infections during pregnancy. Cochrane oping countries. Report of a WHO/UNAIDS/LSHTM Database of Systematic Reviews 4:CD002256. Workshop 2001. http://www.who.int/docstore/hiv/ Villar J, Widmer M, Lyon-Rochelle MT, et al. (2000) herpes meeting/. Duration of treatment for asymptomatic bacteruria Yaegashi N, Niinuma T, Chisaka H, et al. (1999) Sero- during pregnancy. Cochrane Database of Systematic logic study of human parvovirus B19 in pregnancy in Reviews 2:CD000491. Japan. J Infect 38:30–35. Volmink J, Garner P (2003) Directly observed therapy Yaegashi N, Okamura K, Yajima A, et al. (1994) for treating tuberculosis. Cochrane Database of Sys- The frequency of human parvovirus B19 infection in tematic Reviews 1:CD003343. nonimmune hydrops fetalis. J Perinat Med 22:159– Wagner HU, Van Dyck E, Roggan E, et al. (1994) Sero- 163. prevalence and incidence of sexually transmitted Yoon B, Romero R, Park J, et al. (2000) The relationship diseases in a rural Ugandan population. Int J STD among infl ammatory lesions of the umbilical cord AIDS 5:322–327. (funisitis), umbilical cord plasma interleukin 6 con- Weiss HA, Buve A, Robinson NJ, et al. (2001) Study centration, amniotic fl uid infection, and neonatal group on the heterogeneity of HIV epidemics in sepsis. Am J Obstet Gynecol 183:1124–1129. 16. The Impact of Infection During Pregnancy on the Mother and Baby 423

Yost N, Bloom S, Richey S, et al. (2000) An appraisal of Young NS, Brown KE (2004) Mechanisms of disease: treatment guidelines for antepartum community- parvovirus B19. N Engl J Med 350:586–597. acquired pneumonia. Am J Obstet Gynecol 183: Yudin MH (2005) Bacterial vaginosis in pregnancy: 131–135. diagnosis, screening and management. Clin Perinatol Young G, Jewell D (2001) Topical treatment for vaginal 32:617–627. candidiasis (thrush) in pregnancy. Cochrane Data- Zeltser R, Kurban A (2004) Syphilis. Clin Dermatol base of Systematic Reviews 4:CD000225. 22:461–468.