Over 300,000 maternal deaths occur each year, 11% of which are thought to be due to infectious causes, and approximately one million newborns die within the first week of life annually due to infectious causes. Infections in pregnancy may result in a variety of adverse obstetrical outcomes, including preterm delivery, pre-labor rupture of membranes, stillbirth, spontaneous abortion, congenital infection, and anomalies. This paper reviews the burden of disease due to key infections and their contribution to maternal, perinatal, and newborn morbidity and mortality, as well as key interventions to prevent maternal and newborn deaths related to these infections. Research needs include more accurate clinical and microbiologic surveillance systems, validated risk stratification strategies, better point-of-care testing, and identification of promising vaccine strategies.
Highlights
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Lifelong antiretroviral therapy is recommended for pregnant women with human immunodeficiency virus (HIV) in low-resource settings.
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HIV+ pregnant women should be screened at each visit for tuberculosis-related symptoms.
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Intermittent preventive treatment and use of insecticide-treated bed nets are important malaria-preventive measures in pregnancy.
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Intrapartum antibiotic prophylaxis for Group B Streptococcus colonization and with other risk factors decreases risk of early neonatal sepsis.
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Accurate, rapid, point-of-care diagnostic tests for syphilis are now available.
Scope of the Problem
Over 300,000 maternal deaths occur each year, 11% of which are thought to be due to infectious causes, and approximately one million newborns die within the first week of life annually due to infectious causes . Furthermore, around 2.6 million stillbirths occur each year worldwide, with major causes being infections, including chorioamnionitis, syphilis, and malaria . Over 98% of all of these deaths occur in low- and middle-income countries (LMIC).
Infections in pregnancy may result in a variety of adverse obstetrical outcomes, including preterm delivery, pre-labor rupture of membranes, spontaneous abortion, congenital infection, and anomalies. The types of infections span the microbial spectrum, including bacterial, viral, and parasitic diseases. The aims of this review are to (1) discuss what is known about the contributions of key individual infections to maternal, perinatal, and newborn mortality and morbidity and (2) review interventions to prevent maternal and newborn deaths related to these infections and their effectiveness.
Human Immunodeficiency Virus (HIV)
Burden of Disease
The estimated number of pregnant women living with HIV globally exceeds 1.5 million , the majority in sub-Saharan Africa. The health of a woman with HIV in pregnancy and beyond depends on her sustainable access to antiretroviral therapy (ART), as well as other medications for treatment and prevention of opportunistic infections. A recent population-based open cohort study in rural Uganda found that life expectancy in women living with HIV increased by 22.9 years between 2000 and 2002 and 2009 and 2012, coinciding with introduction of ART in 2004 . Perinatal transmission from an HIV-infected woman to her fetus or infant is the leading cause of pediatric HIV infections, with approximately 220,000 new HIV infections among children in 2014; however, this is a reduction of 58% from the number of infections in 2000, largely due to increased access to antiretroviral medications during and after pregnancy: as of June 2015, 73% (68–79%) of pregnant women living with HIV had access to antiretroviral medicines to prevent transmission of HIV to their babies .
Mother-to-child transmission
Mother-to-child transmission (MTCT) can occur during pregnancy, labor, delivery, or with breastfeeding and in the absence of any intervention transmission rates ranging from 15% to 45%. In high-resource settings, MTCT rates as low as 0.46% have been achieved with the use of effective combination of ART started early in pregnancy or prior to conception, attainment of undetectable HIV viral load, and avoidance of breastfeeding . Cesarean section is recommended at 38 weeks of gestation only if the HIV viral load is >1000 copies/mL near the time of delivery . In the US, it is now recommended that all individuals with HIV initiate ART regardless of the CD4 cell count, based on increasing evidence that earlier initiation of ART reduces morbidity due to the number of non-acquired immune deficiency syndrome (AIDS)-defining conditions, improves survival, and substantially reduces sexual transmission .
In lower-resource countries, perinatal transmission can be reduced below 5% with currently available interventions. In 2013, World Health Organization (WHO) released Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection in limited resource settings . All pregnant women should have HIV testing and counseling on the first antenatal visit and retesting should be considered in the third trimester or peripartum, especially in settings of generalized epidemics. Key recommendations relevant to treatment of pregnant women are summarized below:
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All pregnant and breastfeeding women with HIV should initiate triple antiretroviral drugs (ART), with those meeting the treatment eligibility criteria continuing with lifelong ART. For programmatic and operational reasons, particularly in generalized epidemics, lifelong ART is preferred for all pregnant and breastfeeding women, regardless of the CD4 count (Option B+). With Option B+, ART is stopped after cessation of breastfeeding in women who do not meet the eligibility for treatment.
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The recommended first-line regimen is a combination of efavirenz (EFV) + lamivudine (3TC) or emtricitabine (FTC) + tenofovir. Recent evidence from systematic reviews is reassuring regarding the safety and efficacy of EFV in pregnancy .
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HIV-exposed infants should be exclusively breastfed for the first 6 months of life, with introduction of complementary foods thereafter, and continued to be breastfed for the first 12 months of life; breastfeeding should stop only when there is an adequate and safe diet. The benefits of breastfeeding in preventing diarrhea, pneumonia, and malnutrition have been shown to outweigh the risk of HIV transmission in low-resource settings.
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With Option B+, infants who are breastfeeding should receive 6 weeks of infant prophylaxis with nevirapine once daily; infants receiving replacement feeding should receive 4–6 weeks of nevirapine or azidothymidine.
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Cesarean section is recommended in resource-limited settings only for standard obstetric and other medical indications.
Pregnancy may also be a time of increased risk for HIV acquisition , and acute infections in pregnancy carry a greater risk for perinatal transmission, both because of missed opportunities for diagnosis and because of higher HIV viral loads with acute infection . Providers should have a high index of suspicion for acute infection with compatible clinical signs and symptoms and in women known to be at increased risk.
Tuberculosis (TB) and HIV
TB is the leading cause of HIV-associated mortality globally, accounting for one out of every five HIV-related deaths. The risk of developing TB is 30 times higher among people living with HIV than among people who do not have HIV infection and can occur at any CD4 count .
Pregnant women living with HIV who have TB are three times more likely to die than women who have TB alone . When a pregnant woman is co-infected with HIV, TB also doubles the risk of vertical transmission of HIV to the unborn child and co-infection may increase the risk of congenital TB or postpartum TB transmission through airborne exposure . Other adverse outcomes include increased risk for preterm delivery, low-birth weight (LBW), and a six-fold increase in perinatal deaths .
All pregnant women living with HIV in TB-endemic areas should be screened at each antenatal visit using the WHO-recommended symptom algorithm: current cough, fever, night sweats, or weight loss (or poor weight gain in pregnancy) . Women with any one of these symptoms should be evaluated for TB. Xpert MTB/RIF on sputum should be used as the initial diagnostic test in individuals suspected of having HIV-associated TB or multidrug-resistant TB . Smear-negative pulmonary TB is common in HIV-infected pregnant women and therefore smear microscopy alone has limitations in diagnosis. Extrapulmonary TB is more common in pregnancy and should be considered when women have atypical signs or symptoms, such as enlarged lymph nodes .
TB treatment consists of a standardized regimen of antibiotics taken for at least six months, irrespective of HIV status. Completing TB treatment is critical to reducing mortality and avoiding the development and spread of drug-resistant TB. ART should be initiated as soon as possible, no later than eight weeks after initiation of TB treatment .
Isoniazid preventive treatment (IPT) and ART given together can reduce the risk of TB among people living with HIV by up to 97% . Pregnant women who do not report any of the symptoms on screening are unlikely to have active TB and should be offered IPT for at least six months .
Human Immunodeficiency Virus (HIV)
Burden of Disease
The estimated number of pregnant women living with HIV globally exceeds 1.5 million , the majority in sub-Saharan Africa. The health of a woman with HIV in pregnancy and beyond depends on her sustainable access to antiretroviral therapy (ART), as well as other medications for treatment and prevention of opportunistic infections. A recent population-based open cohort study in rural Uganda found that life expectancy in women living with HIV increased by 22.9 years between 2000 and 2002 and 2009 and 2012, coinciding with introduction of ART in 2004 . Perinatal transmission from an HIV-infected woman to her fetus or infant is the leading cause of pediatric HIV infections, with approximately 220,000 new HIV infections among children in 2014; however, this is a reduction of 58% from the number of infections in 2000, largely due to increased access to antiretroviral medications during and after pregnancy: as of June 2015, 73% (68–79%) of pregnant women living with HIV had access to antiretroviral medicines to prevent transmission of HIV to their babies .
Mother-to-child transmission
Mother-to-child transmission (MTCT) can occur during pregnancy, labor, delivery, or with breastfeeding and in the absence of any intervention transmission rates ranging from 15% to 45%. In high-resource settings, MTCT rates as low as 0.46% have been achieved with the use of effective combination of ART started early in pregnancy or prior to conception, attainment of undetectable HIV viral load, and avoidance of breastfeeding . Cesarean section is recommended at 38 weeks of gestation only if the HIV viral load is >1000 copies/mL near the time of delivery . In the US, it is now recommended that all individuals with HIV initiate ART regardless of the CD4 cell count, based on increasing evidence that earlier initiation of ART reduces morbidity due to the number of non-acquired immune deficiency syndrome (AIDS)-defining conditions, improves survival, and substantially reduces sexual transmission .
In lower-resource countries, perinatal transmission can be reduced below 5% with currently available interventions. In 2013, World Health Organization (WHO) released Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection in limited resource settings . All pregnant women should have HIV testing and counseling on the first antenatal visit and retesting should be considered in the third trimester or peripartum, especially in settings of generalized epidemics. Key recommendations relevant to treatment of pregnant women are summarized below:
- •
All pregnant and breastfeeding women with HIV should initiate triple antiretroviral drugs (ART), with those meeting the treatment eligibility criteria continuing with lifelong ART. For programmatic and operational reasons, particularly in generalized epidemics, lifelong ART is preferred for all pregnant and breastfeeding women, regardless of the CD4 count (Option B+). With Option B+, ART is stopped after cessation of breastfeeding in women who do not meet the eligibility for treatment.
- ○
The recommended first-line regimen is a combination of efavirenz (EFV) + lamivudine (3TC) or emtricitabine (FTC) + tenofovir. Recent evidence from systematic reviews is reassuring regarding the safety and efficacy of EFV in pregnancy .
- ○
- •
HIV-exposed infants should be exclusively breastfed for the first 6 months of life, with introduction of complementary foods thereafter, and continued to be breastfed for the first 12 months of life; breastfeeding should stop only when there is an adequate and safe diet. The benefits of breastfeeding in preventing diarrhea, pneumonia, and malnutrition have been shown to outweigh the risk of HIV transmission in low-resource settings.
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With Option B+, infants who are breastfeeding should receive 6 weeks of infant prophylaxis with nevirapine once daily; infants receiving replacement feeding should receive 4–6 weeks of nevirapine or azidothymidine.
- •
Cesarean section is recommended in resource-limited settings only for standard obstetric and other medical indications.
Pregnancy may also be a time of increased risk for HIV acquisition , and acute infections in pregnancy carry a greater risk for perinatal transmission, both because of missed opportunities for diagnosis and because of higher HIV viral loads with acute infection . Providers should have a high index of suspicion for acute infection with compatible clinical signs and symptoms and in women known to be at increased risk.
Tuberculosis (TB) and HIV
TB is the leading cause of HIV-associated mortality globally, accounting for one out of every five HIV-related deaths. The risk of developing TB is 30 times higher among people living with HIV than among people who do not have HIV infection and can occur at any CD4 count .
Pregnant women living with HIV who have TB are three times more likely to die than women who have TB alone . When a pregnant woman is co-infected with HIV, TB also doubles the risk of vertical transmission of HIV to the unborn child and co-infection may increase the risk of congenital TB or postpartum TB transmission through airborne exposure . Other adverse outcomes include increased risk for preterm delivery, low-birth weight (LBW), and a six-fold increase in perinatal deaths .
All pregnant women living with HIV in TB-endemic areas should be screened at each antenatal visit using the WHO-recommended symptom algorithm: current cough, fever, night sweats, or weight loss (or poor weight gain in pregnancy) . Women with any one of these symptoms should be evaluated for TB. Xpert MTB/RIF on sputum should be used as the initial diagnostic test in individuals suspected of having HIV-associated TB or multidrug-resistant TB . Smear-negative pulmonary TB is common in HIV-infected pregnant women and therefore smear microscopy alone has limitations in diagnosis. Extrapulmonary TB is more common in pregnancy and should be considered when women have atypical signs or symptoms, such as enlarged lymph nodes .
TB treatment consists of a standardized regimen of antibiotics taken for at least six months, irrespective of HIV status. Completing TB treatment is critical to reducing mortality and avoiding the development and spread of drug-resistant TB. ART should be initiated as soon as possible, no later than eight weeks after initiation of TB treatment .
Isoniazid preventive treatment (IPT) and ART given together can reduce the risk of TB among people living with HIV by up to 97% . Pregnant women who do not report any of the symptoms on screening are unlikely to have active TB and should be offered IPT for at least six months .
Malaria
Malaria is caused by an infection with protozoan parasites of the genus Plasmodium ( P. falciparum (cause of most maternal illness), P. malariae , P. ovale , P. vivax, and P. knowlesi ) and transmitted by female Anopheles mosquito vectors in tropical and subtropical areas. The highest transmission occurs in sub-Saharan Africa. In areas where populations are continuously exposed to a high frequency of malarial inoculation, partial immunity to clinical disease and a reduced risk of developing severe malaria are generally acquired in early childhood. In other areas, such as much of Asia and Latin America, the intensity of malaria transmission fluctuates widely by season and year, which retards the development of immunity so that people of all ages suffer from acute clinical malaria, with a significant risk for progression to severe malaria if untreated. Maternal mortality attributable to malaria is as high as 17.6–23% in hospital and community studies and 75,000–200,000 neonatal deaths yearly are attributable to malaria .
In sub-Saharan Africa, there are 50 million women living in malaria-endemic areas, who become pregnant each year , and the median prevalence of maternal malaria is 28 percent .
Malaria and Pregnancy
The incidence of malaria is higher during pregnancy compared with before or after pregnancy . Where levels of acquired immunity are high, malaria in pregnancy is usually asymptomatic or with mild nonspecific symptoms, but parasites may be present in the placenta and contribute to maternal anemia and adverse fetal effects, even in the absence of documented peripheral parasitemia. In these settings, the adverse effects of malaria in pregnancy are most pronounced in the first pregnancy . In lower transmission settings, where there is little acquired immunity, malaria in pregnancy is associated with anemia, increased risk of severe malaria in the mother, and increased risk of severe adverse fetal effects and can affect women regardless of the number of pregnancies.
Effective treatment in the early stages of malaria should result in rapid and full recovery; however, if treatment is inadequate or delayed, severe malaria can develop quickly, and if untreated it is fatal in the majority of cases. Compared with nonpregnant women, pregnant women experience more severe disease, more hypoglycemia, and more respiratory complications (pulmonary edema, acute respiratory distress syndrome) .
In endemic regions, maternal malaria may account for one-quarter of LBW infants, and this risk is highest in the first pregnancy . Placental malaria increases the odds of both LBW and stillbirth twofold and maternal malaria increases the risk of miscarriage up to threefold . Congenital malaria from transplacental transmission can occur but is lower in mothers with immunity from prior exposure. Infants with congenital malaria generally present at 2–8 weeks of age with irritability, fever, vomiting, diarrhea, and poor feeding. Anemia, thrombocytopenia, and hyperbilirubinemia are common .
Pregnant women with HIV may be at higher risk for malaria acquisition, placental malaria, higher parasite densities, and more severe clinical disease, and after delivery women with HIV and malaria are at increased risk for anemia compared with HIV-seronegative women with or without malaria. Co-infection with HIV and malaria is also associated with an increased risk of adverse perinatal outcomes and may increase the risk of perinatal HIV infection .
Diagnosis
Malaria should be suspected clinically primarily based on fever or temperature ≥37.5 °C with no other obvious cause. Unfortunately, the signs and symptoms of malaria are nonspecific (e.g., headache, myalgias, fatigue, nausea, vomiting, abdominal pain, and worsening malaise), and there is no combination of signs and symptoms that increases specificity. Suspected malaria should be confirmed with a parasitological test (microscopy or rapid diagnostic test) and the results should be available within a short time (<2 h) to reduce over-treatment with antimalarial drugs and improve the diagnosis of other febrile illnesses. However, in settings where timely diagnosis is not possible, antimalarial treatment should be started promptly when a diagnosis of malaria is likely. (WHO) IPT can suppress or clear existing asymptomatic infections and provide prophylaxis against possible new infections; antimalarial treatment should be started promptly when a diagnosis of malaria is likely .
Treatment
Resistance to antimalarial drugs is a major threat to control and eliminate malaria and is likely related to widespread inappropriate use of antimalarial drugs, inappropriate dosing, or treatment, with greatest resistance seen with P. falciparum . Resistance can be prevented or slowed by combining antimalarial drugs with different mechanisms of action and full adherence to correct dose regimens. Current WHO recommendations for treatment of uncomplicated P. falciparum malaria are to use quinine + clindamycin in the first trimester and a recommended artemisinin-based combination therapy (ACT) in later pregnancy; although there are limited data on ACT exposure early in pregnancy, inadvertent exposure is not considered an indication for pregnancy termination . P. vivax is the dominant malaria species outside Africa malaria and, unlike P. falciparum, has a dormant liver stage that causes relapses; weekly chloroquine chemoprophylaxis has been shown to substantially reduce recurrent P. vivax malaria in pregnancy . Severe malaria should be treated with recommended parenteral artesunate without delay.
Prevention
In malaria-endemic areas in Africa, the WHO recommends implementation of intermittent preventive treatment (IPT) for all pregnant women in their first or second pregnancy with monthly sulfadoxine–pyrimethamine (SP) beginning in the second trimester, with the goal of at least three doses being received . A systematic review showed reduction of LBW and placental and maternal parasitemia with three or more doses compared with two doses across a wide range of resistance to SP .
However, currently only around one-quarter of pregnant women in Africa receive IPT-m . HIV-positive women who are taking co-trimoxazole for OI prophylaxis should not receive additional prophylaxis with SP .
A second preventive approach is the use of insecticide-treated bed nets (ITN); a Cochrane review of ITNs showed reduced risk of placental malaria (RR 0.79), LBW (RR 0.77), stillbirth, and miscarriage (RR 0.67) compared with the control group . In a survey of pregnant women in 37 malaria-endemic countries, only 33% of the women reported having slept under an ITN the previous night .
Sepsis
Maternal Sepsis
Epidemiology
Several terms are used synonymously with maternal sepsis, including puerperal sepsis and maternal peripartum infection; these are defined by WHO as infection of the genital tract or surrounding tissues occurring between the onset of rupture of membranes or labor and the 42nd day postpartum in which two or more of the following are present: pelvic pain, fever, abnormal vaginal discharge, foul-smelling discharge, or delay in uterine involution .
The factors associated with increased risk of maternal sepsis can be categorized into preexisting maternal conditions and conditions occurring during labor and childbirth. Preexisting maternal conditions include malnutrition, diabetes, obesity, severe anemia, bacterial vaginosis, and Group B Streptococcus (GBS) infections. Conditions during labor and childbirth are prolonged labor, prolonged membrane rupture, internal fetal or uterine monitoring, presence of genital tract pathogens, multiple vaginal examinations, manual removal of the placenta, operative vaginal birth, and cesarean section . Cesarean section is an important risk factor, with a five- to eightfold increased risk compared with vaginal birth . Frequency is highest in preterm delivery and with preterm membrane rupture .
The three most important causes of maternal sepsis include pyelonephritis, chorioamnionitis, and endometritis . The other causes include wound infection, mastitis, and pneumonia. The causative microorganisms causing maternal sepsis usually are polymicrobial, including aerobic (e.g., GBS, Escherichia coli , Klebsiella pneumoniae , etc.) and anaerobic bacteria (e.g., Bacteroides fragilis , Peptostreptococcus spp , etc.) .
Chorioamnionitis
Chorioamnionitis is the most common obstetric cause of maternal sepsis. It is an acute inflammation of fetal membranes, amniotic fluid, and/or placenta and is associated with 20–40% of early neonatal sepsis and pneumonia . It is most often caused by ascending infection from the lower genital tract and less commonly through hematogenous/transplacental spread or direct inoculation through invasive procedures.
The key clinical findings include fever, uterine tenderness, maternal tachycardia (>100/min), fetal tachycardia, and purulent or foul amniotic fluid . Fever is present in almost all cases of clinical chorioamnionitis and is considered the essential criterion for clinical diagnosis . Maternal tachycardia (>100/min) and fetal tachycardia (>160/min) are also common, reported 40–80% of cases . Chorioamnionitis may also be subclinical, which may manifest as preterm labor (PTL) or premature rupture of membrane (PROM), especially when preterm. Chorioamnionitis is associated with increased risk of labor abnormalities, uterine atony, postpartum hemorrhage, and endometritis . Leukocytosis is very common but nonspecific as an isolated finding. Amniotic fluid culture, although considered the “gold standard,” is of limited value because of the length of time for results, difficulty in obtaining sterile specimens, and high frequency of negative results . Inflammatory markers hold promise for early and more rapid diagnosis .
Treatment
Broad-spectrum antibiotics should be started promptly when a diagnosis of chorioamnionitis is made, which have been associated with significantly reduced maternal and neonatal morbidity .
Antibiotics should be effective against beta-lactamase-producing aerobes and anaerobes; the most common regimen is ampicillin and gentamicin, but the combination of gentamicin and clindamycin has been shown to be superior to penicillins in the treatment of postpartum endometritis . The optimal duration for continuing antibiotic therapy postpartum has not been determined conclusively, although data from small randomized and observational studies suggest that only one additional dose is needed . There is no evidence that oral antibiotics are needed after discontinuation of parenteral therapy . Cesarean section is not indicated for chorioamnionitis unless there are other obstetric indications. Maternal fever has been shown to have an independent association with neonatal encephalopathy , supporting the adjunctive use of antipyretics.
Neonatal Sepsis
Neonatal sepsis is a systemic infection due to a microbial pathogen in the first 28 days of life and is an important cause of morbidity and mortality among newborns. Early-onset sepsis is generally defined as the onset of symptoms before 7 days of age and late-onset sepsis is defined as the onset of symptoms at ≥7 days of age. Neonatal sepsis may include meningitis, which occurs in an many as 15% of neonates with bacteremia, pneumonia, or involvement of other organs. Important risk factors for early-onset infection include maternal chorioamnionitis , intrapartum maternal fever > or = 38 °C, preterm delivery (<37 weeks gestation), maternal group B streptococcal colonization, and membrane rupture ≥ 18 h, which increases the risk 10-fold . Early-onset infection is usually due to vertical transmission by contaminated amniotic fluid or during vaginal delivery from bacteria in the mother’s lower genital tract . Late-onset infections may be caused by initial neonatal colonization evolving into infection or from direct contact with care providers or environmental sources. Metabolic factors (e.g., hypoxia, hypothermia, acidosis) may increase risk and severity of neonatal sepsis by disrupting the neonate’s immunologic responses .
Epidemiology
The overall incidence of neonatal sepsis ranges from one to five cases per 1000 live births in the US . In South Asia, sub-Saharan Africa, and Latin America in 2010, there were 1.7 million cases of neonatal sepsis ; approximately half a million neonatal deaths annually are due to neonatal sepsis . Infection rates increase with decreasing gestational age. The incidence of early-onset sepsis has decreased in settings where intrapartum antibiotic prophylaxis (IAP) is used, primarily related to a reduction in GBS infections .
GBS and Escherichia coli ( E. coli ) are the most common causes of both early- and late-onset sepsis; . In a recent systematic review, Africa was estimated to have the highest incidence of GBS in infants worldwide . E. coli , K. pneumoniae , and Staphylococcus aureus are also commonly reported pathogens in early-onset neonatal sepsis in developing countries .
Diagnosis and Management
Signs and symptoms of sepsis are nonspecific and can be subtle; therefore, recognition of risk factors and having a high index of suspicion is important. Fetal distress in labor, fetal tachycardia, meconium-stained amniotic fluid, and Apgar score ≤ 6 may be early indicators of sepsis. In the newborn, temperature instability, irritability, lethargy, respiratory symptoms, poor feeding, seizures, tachycardia, jaundice, poor perfusion, and hypotension may be seen.
In low-resource countries, diagnoses are often made by health care workers without specialist training. To support a diagnosis of possible severe bacterial infections and to guide treatment, clinical algorithms have been developed and are included in the Integrated Management of Childhood Illness (IMCI) . Seven clinical signs (respiratory rate >60/min, severe chest in-drawing, temperature >37.5 °C or <35.5 °C, no movement or movement only on stimulation, convulsions, poor feeding) had 85–87% sensitivity and 62–75% specificity for serious possible bacterial infection in the first week of life, as compared with an experienced pediatrician’s diagnosis (in some cases with supporting laboratory data) as the gold standard .
Neonates with signs and symptoms of sepsis require prompt clinical and laboratory evaluation (cultures, complete blood count, lumbar puncture) and initiation of empiric antibiotic therapy . A definitive diagnosis of neonatal sepsis is established by a positive blood culture, but blood culture may be negative by up to 38 percent in infants with meningitis . Molecular techniques may improve diagnostic ability; in addition, they have a more rapid turnaround time, require smaller volumes of blood, and are not affected by the administration of antepartum antibiotics .
Infants of mothers with chorioamnionitis should receive empiric treatment with antibiotics while under observation . Infants appearing well with identified risk factors for sepsis should be observed for a minimum of 48 h, with consideration of more limited diagnostic evaluation based on the nature of the risk factor(s) and maternal receipt of IAP.
Infants who present with signs or symptoms of infection later than 7 days of age should also have appropriate cultures and be started on empiric antibiotic therapy. The antibiotic regimen should be started pending the culture results and should include agents active against GBS and other organisms that cause neonatal sepsis. In the US, ampicillin and gentamicin are generally the preferred regimen for both early-onset disease and community-acquired late-onset sepsis; however, local antibiotic resistance patterns must be considered and regimens may require alteration based on culture results or specific site(s) of infection.
In lower-resource settings, empirical treatment for neonatal sepsis with intravenous (IV)/intramuscular (IM) ampicillin (or penicillin) plus gentamicin for 7–10 days is recommended by WHO. Injectable coxacillin is an alternative if staphylococcal infection is suspected and a third-generation cephalosporin is a second-line therapy if there is no response after 48–72 h of therapy. In neonates born to mothers with PROM ≥ 18 h, maternal fever ≥ 38 °C before delivery, and foul-smelling amniotic fluid, neonatal treatment is recommended for 48 h with close observation . IAP is recommended for women in PTL rupture of membranes (WHO, Recommendations on interventions to improve preterm birth outcomes, WHO, Geneva, 2015). There is evidence for reduced antimicrobial susceptibility in pathogens causing both hospital- and community-acquired infections, threatening current empiric treatment strategies . However, recently completed community-based clinical trials in Africa and Asia where referral was not feasible have shown that a large proportion of community-acquired infections responded clinically to gentamicin and amoxicillin . WHO has recently launched guidelines to manage possible serious bacterial infection in neonates and young infants when referral is not possible with simplified antibiotic regimens on outpatient basis. However, critically ill neonates and young infants were not recommended to be treated on an outpatient basis .
Supportive care is an essential part of management, including maintaining adequate oxygenation, IV fluids, temperature and glucose regulation, normal fluid and electrolyte balance, and prevention of metabolic acidosis. Simple bedside tests are available in low-resource settings for testing glucose levels, and temperature regulation can be improved by Kangaroo Mother Care. Severely ill infants may require mechanical ventilation and vasopressor support.
Survivors of neonatal sepsis may have long-term sequelae. Approximately 20% of survivors of neonatal meningitis have severe disability and another 35% have mild-to-moderate disability .
Prevention of maternal and neonatal sepsis
Prevention of maternal and neonatal sepsis in all settings includes good infection control, including hand hygiene. Data from a systematic review demonstrated that there was a reduction in neonatal death, cord infection, and neonatal tetanus when the birth attendant washed her hands . Topical application of chlorhexidine to the umbilical cord was associated with a 12% reduction in neonatal mortality in the community setting in a recent meta-analysis; current WHO guidelines recommend daily application of chlorhexidine to the umbilical cord stump in the first week of life for newborns who are born at home in settings with high neonatal mortality (30 or more neonatal deaths per 1000 live births) . The use of vaginal chlorhexidine during labor was not found effective in preventing maternal and neonatal infections in a systematic review .
The use of prophylactic antibiotics with C-section has been associated with a decreased incidence of wound infection (RR 0.40, 95% CI 0.35–0.46), endometritis (RR 0.38, 95% CI 0.34–0.42), and serious infectious maternal complication (RR 0.31, 95% CI 0.20–0.49) . There is evidence from a meta-analysis that reveals that antibiotic prophylaxis for Cesarean delivery given before skin incision, rather than after cord clamping, decreases the incidence of postpartum endometritis (RR 0.47, 95% CI 0.26–0.85) and total infectious morbidities (RR 0.50, 95% CI 0.33–0.78) . The American College of Obstetricians and Gynecologists recommends that prophylaxis should be given within 60 min before the start of the cesarean delivery with a single dose of a first-generation cephalosporin or a combination of clindamycin with gentamicin in penicillin-allergic patients. Obese patients having excessive blood loss may require additional or altered dosing. No data exist to support using prophylactic antibiotics in the manual removal of placenta during cesarean or vaginal delivery .
In the US, the primary intervention to prevent early-onset neonatal sepsis is screening pregnant women for GBS colonization and administering IAP with GBS colonization and other risk factors. The Center for Disease Control and Prevention (CDC) recommends that all pregnant women should be screened for GBS colonization with a swab of the lower vagina and rectum at 35–37 weeks of gestation, except women who have had GBS bacteriuria during the current pregnancy or a prior infant with GBS disease, who should always receive IAP. IAP should also be given to women whose GBS culture status is unknown if delivery is at <37 weeks of gestation, amniotic membranes have ruptured for ≥18 hours, intrapartum temperature ≥100.4 F (≥38 °C) is documented, or intrapartum nucleic acid amplification test (NAAT) is positive for GBS. Adequate IAP is defined as IV penicillin, ampicillin, or cefazolin given id a prior to delivery. A recent meta-analysis found that IAP was associated with a significant reduction in chorioamnionitis and endometritis in women who had term or near-term membrane rupture >12 h . In women with preterm premature rupture of membranes, data from recent meta-analysis found that use of antibiotic prophylaxis was associated with prolonged pregnancy, reduction in chorioamnionitis (RR 0.66, 95% CI 0.46–0.96), and neonatal infection (RR 0.67, 95% CI 0.52–0.85) .
Respiratory Syncytial Virus (RSV)
Epidemiology
RSV is the most common cause of lower respiratory tract infections (LRTI) in children worldwide, with 22% of LRTI due to RSV. A systematic epidemiologic review of data estimated 33.8 million RSV-LRTI worldwide in 2005 in children <5 years of age, with 3.4 million requiring hospitalization . LRTI caused by RSV result in an estimated 41,000–199,000 deaths yearly, with >99% of these occurring in low-income countries . High-risk groups for RSV include premature infants, very low birth-weight infants, and HIV-infected or other immunocompromised children ; however, most children admitted to the hospital with RSV-LRTI were previously healthy .
Clinical Presentation
RSV is transmitted through direct or close contact with contaminated secretions and there is a latent period of 4–6 days before clinical symptoms. The first signs in infants include nasal discharge and congestion, cough, fever, and decreased appetite; in up to 30% of infants <2 years, a LRTI develops, varying in severity. As the infection progresses, other symptoms, including tachypnea, wheezing, persistent cough, increased respiratory effort, and feeding difficulties, develop with the typical clinical picture of bronchiolitis. Although most cases are not severe, a subgroup of children develops acute respiratory failure, requiring ventilator support. RSV results in potential increased risk of longer-term respiratory problems, such as asthma. Nonrespiratory manifestations of RSV have been described, including acute otitis media, central nervous system (CNS), cardiovascular, and liver .
Management
Most RSV infections are self-limiting and resolve in up to 21 days after symptom onset. However, if there is respiratory distress or dehydration, IV fluids and supplemental oxygen are needed. Electrolyte imbalance, such as hyponatremia, may be seen in seriously ill infants. Cochrane reviews support the absence of efficacy of systemic corticosteroids and bronchodilators . Antibiotics are recommended only if there is evidence of bacterial co-infection. Frequent hand washing and isolation of RSV-infected patients has proven effective in reducing nosocomial RSV infections .
Prevention
Palivizumab is a monoclonal antibody that targets the RSV F protein and has been approved by the FDA and European Medicines Agency for immunoprophylaxis in high-risk infants. A Cochrane systematic review of randomized clinical trials comparing palivizumab prophylaxis with placebo found that children at a higher risk of severe RSV infection were less often hospitalized or admitted to intensive care units and had fewer days on oxygen . However, it is expensive and requires monthly IV infusion, which makes it inaccessible to populations with the highest burden of disease. Patent expiration for palivizumab is expected soon and this may be associated with increased opportunities for lower pricing and greater access.
Active pediatric and passive immunizations via maternal vaccination are potential strategies for prevention and several vaccine approaches are in development. Transmission dynamics studied at the community level in Kenya show that transmission mainly occurs through introduction of RSV via siblings in school, supporting the potential effectiveness of vaccinating older siblings to provide indirect immunity in the household . Several antiviral drugs for RSV are also being investigated in clinical trials.
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