Antepartum Infections

Etiology

Pregnancy results in a state of immune alteration, which is necessary to prevent the maternal immune system from destroying the fetus. Infections acquired during pregnancy can be passed vertically to the developing fetus through the placenta and the birthing process. The etiology of antepartum infections is multifactorial and varies based on the pathogen, maternal health status, and environmental factors.

Infections can arise from ascending genital tract colonization, hematogenous spread, or direct exposure to contaminated food, water, or vectors. Maternal factors such as immunosuppression, poor nutritional status, and preexisting medical conditions increase susceptibility. Additionally, socioeconomic determinants, including inadequate prenatal care and limited access to sanitation, further contribute to the risk of antepartum infections, particularly in resource-limited settings.

Bacterial Infections

• Group A and B Streptococcus
• Chlamydia trachomatis
• Listeria monocytogenes
• Treponema pallidum (syphilis)

Common bacterial causes of chorioamnionitis include the following:

• Escherichia coli
• Ureaplasma urealyticum
• Ureaplasma pyogenes
• Mycoplasma hominis
• Gardnerella vaginalis

Viral Infections

• Herpes simplex virus 
• Cytomegalovirus
• Zika virus
• Chikungunya
• Rubella
• Hepatitis A, B, C, D, and E
• Human immunodeficiency virus (HIV)
• SARS-CoV-2 virus (COVID)
• Parvovirus
• Monkeypox
• Coxsackievirus

 Protozoal Infections:

• Toxoplasmosis gondii
• Malaria

Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes Simplex Virus; TORCH:

• The TORCH organisms are causes of congenital infections that may be acquired through vertical transmission.[5] 
• These organisms are responsible for roughly 35.7% of neonatal deaths, 15.6% of neonatal infections, and 10.5% of congenital abnormalities.[6]
• Ideally, serologic screening of biological women should be completed before pregnancy to establish an individual's serologic status, which is crucial for managing infections that occur through vertical transmission.

Epidemiology

Low- and middle-income countries (LMICs) continue to face challenges with preventing and managing maternal infections, as limited resources and restricted access to healthcare heighten the risk of adverse pregnancy outcomes. According to a systematic analysis by the World Health Organization (WHO), direct obstetric infections remain a significant cause of maternal mortality, responsible for approximately 10.7% of maternal deaths. This mortality rate is notably higher in LMICs compared to high-income countries (HICs), where the rate stands at 4.7%.[7]

Worldwide, sepsis is a leading cause of maternal morbidity and mortality, as there is frequently a delay in diagnosis and suboptimal medical management.[8] To address this issue, the WHO launched the Global Maternal Sepsis and Neonatal Initiative in collaboration with its partners in 2016. This initiative led to the implementation of the GLOSS (Global Maternal Sepsis Study) in 2017, aiming to reduce the burden of maternal sepsis and related infections. While some progress has been made in alleviating the impact of maternal sepsis and maternal infections (MSMI) across 131 LMICs, the disease burden remains significantly higher in low-income countries compared to lower-middle- and upper-middle-income countries. Factors such as socioeconomic status and access to universal health coverage play a crucial role in shaping the severity of MSMI in these regions.[7] 

Infections during pregnancy pose a significant global public health concern. However, many of these infections are preventable.[9] Vertically transmitted infections, in particular, are disproportionately prevalent in regions with developing economies. For instance, the prevalence of toxoplasmosis varies significantly by region, with 11% of women of childbearing age in Europe testing seropositive compared to 77% in a comparable population in South America. Certain infections are notably more common in specific geographic areas, including high rates of syphilis in Central Africa, HIV in Southern Africa, cytomegalovirus (CMV) in South America, hepatitis B in West Sub-Saharan Africa, hepatitis C in the Middle East and East Asia, hepatitis E in India, Southeast Asia, the Middle East, and Africa.[10]

Antepartum infections can significantly impact maternal and fetal outcomes, including risks such as preterm birth, growth restriction, and fetal loss. Understanding the types, implications, and management is essential for optimizing prenatal care. The following discussion explores the various specific types of antepartum infections.

Antepartum Infections

Gonorrhea and chlamydia

In 2022, there were 2.5 million cases of gonorrhea, chlamydia, and syphilis reported to the Centers for Disease Control and Prevention (CDC), with chlamydia being one of the most common sexually transmitted infections, even in more developed countries.[11][12] Gonorrhea is the second most commonly reported sexually transmitted bacterial disease in the United States, with an estimated over 820,000 new Neisseria gonorrhoeae infections occurring each year.[13] Gonorrhea in pregnancy has been associated with chorioamnionitis, premature rupture of membranes, preterm labor, low birth weight, and small for gestational age infants.[14]

Perinatal transmission of gonorrhea can lead to ophthalmia neonatorum, which can cause blindness. Systemic neonatal infections such as sepsis, arthritis, and meningitis are rare complications of gonorrhea in pregnancy.[15][16] Similar complications of pregnancy are seen with chlamydia infection, including preterm birth, preterm prelabor rupture of membranes, low birth weight, and stillbirth.[14][17] Neonates exposed to chlamydia may develop conjunctivitis and chlamydial pneumonitis, occurring in up to 30% of exposed infants.[18]

Parvovirus B19

Primary infection with parvovirus B19 occurs through exposure to respiratory droplets or infected blood products. Congenital infection is transplacental.[10] When parvovirus B19 infection occurs in the first half of pregnancy, the rate of intrauterine transmission is 24% to 39%, with a risk of fetal hydrops and death of 4% to 10%.[6] There is no vaccine or medical treatment available for parvovirus.

Herpes simplex virus

Primary herpes simplex virus (HSV) infection occurs through sexual contact; vertical transmission occurs primarily through contact with active lesions in the maternal birth canal during parturition. Less common modes of transmission include transplacental infection and postnatal infection.[19] The highest risk of vertical transmission (30% to 50%) is when the primary infection with HSV occurs near term. Alternatively, the risk of vertical transmission in the first half of pregnancy is less than 1%.[6]

Syphilis

The microaerophilic, gram-negative spirochete Treponema pallidum causes syphilis. Maternal infection occurs through sexual contact, and congenital infection is transmitted transplacentally with increased risk in mothers with high spirochete titers, an early stage of infection at the time of pregnancy, and late or incomplete treatment.[10] Many neonates are born with no symptoms, but symptoms manifest after 3 months of age. Due to the hypoxemia caused by placental damage, 30% of fetuses with congenital syphilis are stillborn.[20] From 2015 to 2018, syphilis cases increased by 30%, with congenital syphilis cases rising as well.[6]

Zika virus

Zika virus is a significant infectious disease due to its impact on fetal neurodevelopment. Initially identified in tropical and subtropical regions, such as certain areas of South America, Zika has since spread to various parts of the world where Aedes mosquitoes are prevalent, as these mosquitoes serve as the primary vectors for the transmission of the disease. The peak incidence of Zika virus infections occurred in 2016. Prenatal exposure to the virus can lead to a spectrum of complications, ranging from severe microcephaly to more subtle neurodevelopmental delays that may not become apparent until later in childhood, even in the absence of obvious defects at birth.[21] 

The mosquitoes in the Aedes genus spread the Zika virus, and an unknown primate reservoir is theorized to exist.[22] The virus has been found in the semen and vaginal secretions of infected individuals and sexual transmission of the virus has been documented.[23] Nonsexual human-to-human transmission has also been reported, although the mechanism of infection in these cases has not been elucidated.[24][25] Vertical transmission occurs in utero through infection or injury of the placenta, resulting in the transplacental transmission of the virus to the fetal brain.[26]

Chikungunya virus

Chikungunya virus (CHIKV), a member of the Togaviridae family, is another mosquito-borne virus transmitted by Aedes mosquitoes. Alongside dengue and Zika viruses, CHIKV has now spread worldwide. Due to overlapping symptoms, distinguishing among these viral infections can be challenging.[27][28] CHIKV infection can cause an acute febrile illness accompanied by rash and joint pain, with potential consequences for both maternal and neonatal health. Maternal-to-fetal transmission has been associated with severe neonatal complications, including enterocolitis, encephalitis, seizures, and even mortality. Additionally, cases of early fetal loss before 22 weeks of gestation have been reported among pregnant individuals with antepartum CHIKV infection, suggesting intrauterine transmission as a possible contributing factor.[28]

Malaria

According to the WHO, there are 85 countries in which malaria is endemic, mostly in sub-Saharan Africa. In 2020, there were 241 million cases of malaria. Over 11 million patients were thus exposed to malaria during pregnancy. Plasmodium falciparum malaria is most commonly related to pregnancy morbidity, followed by Plasmodium vivax, and some patients have both strains. Both placental malaria and gestational malaria infections can occur during pregnancy, resulting in abortion, premature delivery, maternal anemia, fetal growth restriction, stillbirth, and low birth weight. Approximately 100,000 infants die each year due to low birth weight in areas of Africa where malaria is endemic.[29]

Cytomegalovirus

Cytomegalovirus (CMV) is the leading cause of congenital viral infections, affecting approximately 1 in 150 live births, or 0.67% of all neonates. However, only about 10% of affected newborns exhibit symptoms at birth.[30] Primary CMV is acquired through contact with infected bodily fluids, including saliva, urine, cervical or vaginal secretions, semen, blood, and breast milk. The risk of vertical transmission is estimated to be approximately 35% and can occur transplacentally or during birth. Infection early in gestation is less common but associated with more severe manifestations.[30] 

Primary infection with CMV is usually asymptomatic, making the diagnosis in pregnant women difficult. Symptoms can include a prolonged febrile illness resembling mononucleosis, sore throat, rash, and transaminitis. Cerebral manifestations of congenital CMV infection include periventricular calcifications, microcephaly, parenchymal echogenic foci, cerebral pseudocysts, hypoplastic corpus callosum, and abnormal gyri. These findings are often visible on fetal ultrasound before delivery.[31] Common systemic manifestations in neonates include intrauterine growth restriction (IUGR), thrombocytopenic purpura, microcephaly, hepatosplenomegaly, and pneumonia. Long-term complications are common, with up to 90% of symptomatic infants and 5% to 15% of asymptomatic cases developing conditions such as hearing impairment, neurological abnormalities (including structural brain defects, hydrocephalus, and seizures), and developmental delays.[30]

Rubella

Infection during pregnancy occurs when a non-immune individual is exposed to aerosolized viral particles. Primary infection with rubella in adults is often asymptomatic. Still, this condition can manifest with low-grade fevers, sore throat, conjunctivitis, and a macular rash that starts on the face and spreads downward. Transmission to the fetus is transplacental, and the highest risk of transmission is with maternal infection in the first trimester.[10][32] Congenital rubella syndrome (CRS) can include deafness, cardiac defects, and a variety of ophthalmic and ocular findings, including microphthalmia, cataracts, and glaucoma.[10]

Toxoplasma gondii

Toxoplasmosis is one of the most prevalent zoonotic diseases worldwide. This vector is a protozoan that can cause human infection through ingestion of raw or undercooked meat or contaminated products, contact with cat feces or contaminated food or soil, transfusion of infected blood products or donor organs. Vertical transmission of toxoplasmosis is through transplacental infection. The protozoan first infects maternal leukocytes, then invades trophoblasts, and lastly, the fetal vasculature.[20] The risk of congenital infection increases linearly with gestational age at the time of primary maternal infection.[10]

Maternal primary toxoplasmosis is frequently asymptomatic; approximately 70% to 90% of congenitally-infected infants are likewise asymptomatic at birth. Chorioretinitis, hydrocephalus, and periventricular calcifications are the classic, but rare, triad of symptoms (see Image. Congenital Toxoplasmosis). More common early manifestations of congenital toxoplasmosis include anemia and thrombocytopenia, hepatosplenomegaly, seizures, and jaundice. Late manifestations in untreated disease include hearing loss, microcephaly, seizures, motor and cerebellar dysfunction, and intellectual disability.[10] 

Hepatitis viruses

While the hepatitis A virus has been documented in perinatal transmission, serious complications are uncommon, and chronic infection does not occur. Worldwide, perinatal transmission of hepatitis B virus (HBV) is the largest cause of chronic infection and can occur in up to 90% of cases when maternal antiviral treatment and neonatal prophylaxis are not used. In 2019, only 217 perinatal hepatitis C virus infection cases were reported. Hepatitis C (HCV) is associated with an increased risk of IUGR, intrahepatic cholestasis of pregnancy, and preterm labor and delivery.

Hepatitis D is usually transmitted through blood, and being an incomplete virus, hepatitis D only causes disease when the hepatitis B virus is also present. Hepatitis E virus (HEV) can cause severe effects on pregnant individuals. Although rarely seen in the United States (US), the hepatitis E virus is a waterborne disease, and poor sanitation promotes transmission. The mean incubation period is 40 days, with a higher risk to pregnant people and maternal mortality as high as 20% to 30%. Vertical transmission is as high as 50%, with fetal mortality as high as 35% in Asia and Africa.[33] 

Primary infection with HBV is through contact with infected bodily fluids, with sexual contact being the most common cause of primary infection in the US.[34] Vertical transmission accounts for approximately a third of HBV infections worldwide and results primarily from contact with contaminated bodily fluids during labor and delivery. Transplacental infection accounts for a minority of congenital HBV infections.[10]

Primary HCV is transmitted through contact with infected body fluids, and the mechanism of its vertical transmission remains unclear.[10] Primary infection with HEV occurs through contaminated food and water or contact with infected blood. HEV is notable for its severity in pregnant individuals, with high mortality during the third trimester.[35] In endemic areas, it is a major contributor to maternal death, fulminant hepatic failure, and fetal loss.[36]

Human immunodeficiency virus

HIV infection occurs through contact with infected body fluids, including through sexual contact, needle sticks, or blood transfusions. Vertical transmission is most common in utero but can also occur intrapartum. High maternal viral plasma load, low maternal CD4 count, and acute maternal infection during pregnancy increase the risk of in-utero transmission.[10]

Listeria monocytogenes

A gram-positive bacterium, this vector is obtained through the consumption of contaminated food products. Chorioamnionitis is subsequently caused by the hematogenous transplacental spread of infection from the mother to the fetus.[37] Chorioamnionitis occurs in the setting of intact fetal membranes.[38] Placental pathology typically reveals abscesses, with organisms visible within these abscesses. The US has a low incidence of Listeria, which is commonly an asymptomatic disease.[20]

Monkeypox

Similar to smallpox, monkeypox has recently experienced a surge, prompting the WHO to declare a Public Health Emergency of International Concern on August 14, 2024. Monkeypox, a zoonotic disease that has now been shown to have human-to-human transmission, can be vertically transmitted to the fetus by intrauterine transmission. Like smallpox, monkeypox increases the risks of miscarriage, stillbirth, and severe disease in pregnant persons.[39] 

Group B streptococci

Infections of the female urogenital tract can impact birth outcomes, even though they are not always vertically transmitted to the newborn. Such infections include group B streptococci (GBS), which may colonize the genitourinary tracts in many people but can cause significant fetal morbidity and mortality if prophylaxis is not used during labor. Neonatal infection can occur through ascending vaginal infection or contact during parturition.[40]

Group A streptococcus

Worldwide, group A Streptococcus (GAS, eg, Streptococcus pyogenes) infection is the third leading cause of mortality in pregnant individuals. This bacterium normally resides on human skin and mucus membranes. Ascending infection from the genital tract can cause multiorgan failure and septic shock. In pregnant individuals, there is a 20-fold increased risk of invasive GAS infection as compared to nonpregnant patients. This is a significant cause of miscarriage and morbidity from sepsis in pregnant people. Recently, the virulence of group A streptococcus has increased due to the predominance of certain genotypes and the rise in patient risk factors for infection, such as obesity.[41]

Coxsackievirus

Hand, foot, and mouth disease is caused by coxsackievirus, a type of enterovirus that causes painful, red, blister-like lesions on the hands, feet, and mouth. While some people remain asymptomatic, others may experience symptoms such as high fever, muscle aches, headache, sore throat, conjunctivitis, abdominal pain, and nausea. The fecal-oral route is the primary mode of transmission for this virus. During pregnancy, it can cause preterm labor, encephalitis, fetal growth restriction, and myocarditis. Long-term outcomes for the fetus may include cardiac anomalies and type 1 diabetes.[42]

Ureaplasmas

Ureaplasmas are mycoplasmas that colonize the urogenital tract of 40% to 80% of sexually active women.[20] Most cases of chorioamnionitis occur secondary to ascending infection with maternal urogenital organisms in the setting of ruptured fetal membranes. Other commonly implicated organisms in chorioamnionitis include GBS, Escherichia coli, Gardnerella vaginalis, and Mycoplasma hominis.[37][43] The association between ascending urogenital infection and ruptured membranes remains uncertain—whether due to opportunistic infection by these organisms following the loss of the anatomic barrier, or because infection itself weakens the fetal membranes and leads to premature rupture.     [37]

Pathophysiology

Pregnancy alters immune and physiological functions, impacting the replication of infectious organisms, disease severity, and the risk of transmission to the fetus. The placenta serves as a protective barrier against infections and a site of immune tolerance for the developing fetus. While some viruses, such as CMV, Zika, and rubella, can bypass these defenses and infect the fetus, others, like influenza and SARS-CoV-2, may cause placental inflammation and damage without direct infection.[44]

Additionally, the hormonally-mediated physiologic changes of pregnancy increase maternal risk for certain infections and may likewise increase the severity of disease in pregnant patients.[45] Vertical transmission to the fetus can occur through transplacental migration of the organism prenatally or contact with maternal blood and vaginal secretions during labor.[10] As discussed, the mechanism of initial maternal infection varies with the etiologic agent.

The risk of chorioamnionitis is highest in pregnancies that end at earlier gestational ages, with neonates delivered during the periviable period having a 94% likelihood of developing the infection. Several maternal factors increase the risk of chorioamnionitis, including nulliparity, immunocompromised conditions, bacterial vaginosis, GBS or ureaplasma colonization, and substance use such as tobacco, alcohol, or drugs. In the US, 15% to 35% of women of childbearing age carry GBS in the vagina or rectum.[46]

Being a member of the Black population is also associated with an increased risk due to a combination of biological, socioeconomic, and healthcare-related factors. Labor-related factors that contribute to a higher risk of chorioamnionitis include preterm labor and prolonged preterm prelabor rupture of membranes.[37] Rare mechanisms of infection due to chorioamnionitis include direct iatrogenic inoculation of the amniotic fluid during invasive procedures such as amniocentesis or chorionic villous sampling, and the spread of peritoneal infection to the fetal membranes through the fallopian tubes. Patients with chronic liver and kidney disease are at particular risk for the spread of infection from the peritoneum through the fallopian tubes.[37] 

Histopathology

Recognizing the source of the inflammatory response in antepartum infections is crucial, as it may originate from the mother, the fetus, or both. Maternal inflammatory responses include chorioamnionitis, deciduitis, and inflammation of the chorionic plate (see Image. Deciduitis). In contrast, fetal inflammatory responses involve choriositis and inflammation of the umbilical cord and chorionic vessels on the chorionic plate. Fetal inflammatory responses are associated with an increased risk of neurologic impairment in offspring.

Results from clinical studies have shown that chorioamnionitis is strongly linked to low birth weight and cerebral palsy, suggesting a causal relationship between prematurity, inflammation, and adverse outcomes. Severe fetal inflammation, characterized by the presence of neutrophils and eosinophils, is predictive of poor neonatal outcomes, particularly in preterm infants. Current pathogenic models propose that fetal premyelinating oligodendrocytes are especially vulnerable to cytokine-mediated inflammation, which contributes to a strong association between neonatal infection and sensorineural auditory impairment.[47][48][49][50][51][52] 

There are specific grading and staging systems for the maternal and fetal inflammatory response (eg, Amsterdam [53] and Redline [49] criteria).

• Stage of inflammatory response refers to the anatomical progression of the process.
  • Stage 1: The presence of neutrophils in the chorion or subchorionic space
  • Stage 2: The presence of neutrophils in the chorionic connective tissue or amnion 
  • Stage 3: Necrotizing chorioamnionitis and epithelial necrosis of the amnion
• Grade of inflammatory response refers to the intensity of the acute inflammation.
  • Grade 1: Small clusters of maternal neutrophils, found in the chorion laeve, chorionic plate, subchorionic fibrin, and amnion 
  • Grade 2: Three or more confluent groups of 10 to 20 neutrophils (microabscesses)

Subchorial inflammation is the earliest form of inflammation and is defined by the presence of neutrophils between the decidua and chorion leave. This inflammation does not necessarily imply the presence of chorioamnionitis. In the early phases, a patchy accumulation of leukocytes and fibrin occurs at the choriodecidual interface. Extension of the infection into the chorionic layer is called chorionitis and can be followed by the involvement of the amniotic layer (chorioamnionitis).

Chorioamnionitis refers to the presence of inflammation in the chorion and amnion. This is usually the result of ascending microbial infection from the lower genital tract to the sterile amniotic cavity, potentially endangering the fetus.[54] Neutrophils migrate from the decidua in cases of ascending or blood-borne infection. Chorioamnionitis is diagnosed by microscopic examination of placental sections, with the typical findings of acute neutrophilic inflammation. In acute chorioamnionitis, the leukocytes are of maternal origin.

Acute villitis is a specific gross and histologic feature of acute inflammation of the placental villi. This condition is diagnosed histologically with the presence of neutrophilic abscesses in the placental parenchyma, often associated with neutrophilic chorioamnionitis. Acute villitis is a typical feature of bacterial infections, such as those caused by Listeria or Streptococcus species.

Funisitis is the inflammatory response occurring in the umbilical cord. Topographically, this condition can present with neutrophils in the umbilical vein, in the umbilical arteries, or infiltration into the Wharton jelly. Acute funisitis usually begins with inflammation of the umbilical vein. Arteritis is evidence of an advanced inflammatory response.

Congenital neonatal infection refers to microbial colonization of the amniotic cavity, which can result in fetal invasion of the respiratory tract, gastrointestinal tract, skin, or the ear through the auditory canal to the middle ear. The fetal examination can reveal severe dermatitis, pneumonitis, and encephalitis. The progression of the microbial agent to fetal circulation can lead to systemic disease. The rate of congenital neonatal sepsis is higher in preterm neonates than in term neonates, likely due to bacterial infection following preterm rupture of membranes.[55]

History and Physical

A thorough history and physical examination are essential first steps in evaluating suspected antepartum infections. These assessments help identify risk factors, detect early signs of infection, and guide the selection of appropriate diagnostic testing and management.

History

• Maternal risk factors
  • Previous sexually transmitted infection
  • Immunocompromised state
  • Poor prenatal care
  • History of preterm birth
• Symptoms
  • Fever
  • Chills
  • Myalgias and arthralgias
  • Pharyngitis with nasal congestion and cough
  • Fatigue
  • Shortness of breath
  • Pelvic pain
  • Painful urination
  • Nausea
  • Loss of smell and taste
• Travel history (eg, malaria or Zika virus in endemic areas)

Physical Examination Findings

• May be asymptomatic
• Hepatosplenomegaly
• Abnormal vaginal discharge
• Bilateral nontender cervical lymphadenopathy (toxoplasmosis)
• Abdominal or uterine tenderness
• Uterine contractions
• Abnormal fetal heart rate tracing or other signs of fetal distress
• Maculopapular rash with conjunctivitis
• Genital lesions
• Leukocytosis
• Thrombocytopenia
• Transaminitis
• Anemia

Key Fetal Ultrasound Findings

• Zika virus
  • Microcephaly 
  • Partially collapsed skull with overlapping sutures and redundant skin folds
•  Varicella, HSV, and Zika
  • Limb hypoplasia or contractures
• Toxoplasmosis and varicella
  • Intrahepatic calcifications
• Toxoplasmosis, CMV, Zika, and Listeria
  • Intracranial calcifications
• Varicella and Rubella
  • Cataracts
• Syphilis, parvovirus, malaria, and Zika
  • Anemia causing abnormal MCA dopplers

Fetal Loss

• Untreated syphilis: 40% 
• Zika: 5% to 10%
• Toxoplasmosis: 1.5%

When discussing the history and physical examination findings of antepartum infections, it is crucial to distinguish between the findings in primary (maternal) infections and those in congenital infections. Also note that the manifestations of congenital infection may not be present immediately following birth. Several findings are common to many congenital infections. These include hepatomegaly, splenomegaly, thrombocytopenia, and a violaceous macular or papular rash, commonly referred to as a "blueberry muffin rash," which results from extramedullary hematopoiesis (see Image. Congenital Rubella).[10] Other manifestations may include ascites, hepatosplenomegaly, hydrops, pericardial effusion, and placental enlargement.[31]

Primary infection with HIV is usually asymptomatic, although acute infection can present with a flu-like illness. Similarly, congenital infection is usually asymptomatic in the acute phase. Failure to thrive, oral candidiasis, developmental delay, and frequent opportunistic infections are common presenting complaints.[56] Noncongenital syphilis infection has 3 stages: primary, secondary, and tertiary. The primary stage is characterized by the development of a painless genital or rectal ulcer, known as a chancre.[57] A rash involving the palms and soles is the most characteristic symptom of secondary syphilis and can be macular, papular, ulcerating, or pustular. Other symptoms of secondary syphilis are nonspecific and can include constitutional symptoms, gastrointestinal ulcerations, musculoskeletal inflammation, and ocular complaints.[57]

Tertiary syphilis can manifest with cardiovascular complications such as aortitis and neurological abnormalities like tabes dorsalis or paresis.[58] Early manifestations of congenital syphilis include hepatosplenomegaly, nasal secretions (called "snuffles"), osteochondritis, pseudoparalysis, rash, anemia, and thrombocytopenia. Untreated congenital syphilis progresses to involve the central nervous and musculoskeletal systems, resulting in developmental abnormalities as well as abnormalities of the bones, joints, teeth, eyes, and skin.[10]

Active herpes infection is characterized by grouped, painful vesicular lesions. Congenital HSV can present with low birth weight, microcephaly, chorioretinitis, and hydrocephalus.[59] Characteristic vesicular lesions may also be present in neonatal infections. The feared manifestation of HSV in neonates is viral encephalitis, which can result in significant and permanent blindness, neurodevelopmental delay, and death.[60]

Maternal infection with parvovirus can be asymptomatic or may present with a distinctive "slapped cheeks" rash, preceded by a flu-like illness characterized by fever, malaise, arthralgias, and myalgias.[10] Manifestations of congenital infection include nonimmune hydrops fetalis secondary to high-output heart failure and viral myocarditis, severe anemia and thrombocytopenia, and maternal mirror syndrome.[10]  

Acute manifestations of primary HBV include subclinical (anicteric) or icteric hepatitis, as well as fulminant hepatitis and cirrhosis. Symptoms of congenital HBV are usually absent at birth. A minority of affected neonates develop clinical hepatitis in the first few months of life and can present with jaundice, failure to thrive, and vomiting. More commonly, congenital HBV results in subclinical hepatitis and an immune-tolerant carrier state, and progression to chronic infection is uncommon.[10]

Acute primary HCV infection presents similarly to acute primary HBV infection. Most cases of congenital infection are asymptomatic, but, in contrast to congenital HBV infection, the majority of cases of congenital HCV result in chronic infection.[10] Primary HEV infection usually results in mild, subclinical hepatitis in the general population. Still, it has a high risk of progression to fulminant hepatitis and death in pregnant women, particularly in the third trimester.[36] Vertical transmission has been documented but is rare.[61] Primary infection with the Zika virus, an arbovirus, can be asymptomatic or present with a "dengue-like" syndrome of nonpurulent conjunctivitis, arthralgias, headache, maculopapular rash, extremity edema, and gastrointestinal upset.[22] Congenital Zika syndrome is characterized by severe microcephaly and neurological abnormalities.[62] 

Monkeypox presents clinically with a characteristic rash accompanied by fever and lymphadenopathy. Mucosal lesions can be highly painful and lead to dehydration as well as hospitalization for pain control. The illness progresses in 2 phases: a prodromal phase lasting up to 5 days, characterized by fever (most common), headache, fatigue, muscle and back pain, and swollen lymph nodes, followed by a rash phase that appears 1 to 3 days after the onset of fever. The rash has a distinctive presentation, beginning as painful and/or pruritic maculopapular lesions that progress into a vesiculopustular rash. A secondary fever may indicate worsening. Severe cases can result in encephalitis, sepsis, or acute respiratory distress, which contribute to mortality. Most reported cases involve sexual contact, including anal and oral sex.[63]

While definitionally, intraamniotic infection is reserved for cases where there is evidence of pathogens in the amniotic fluid along with intraamniotic inflammation, the diagnosis of clinical chorioamnionitis is usually made based on clinical findings.[43] Unfortunately, the symptoms of chorioamnionitis are nonspecific and poorly sensitive for diagnosis; therefore, attention to the complete clinical picture is critical for making this diagnosis. Findings suggestive of chorioamnionitis include maternal fever, uterine tenderness, maternal or fetal tachycardia, and purulent or malodorous discharge.[37] 

In July 2024, the American College of Obstetricians and Gynecologists (ACOG) issued a Clinical Practice Update stating that a suspected intraamniotic infection is diagnosed when a maternal temperature reaches 39 °C (102.2 °F) or higher. This condition can also be identified if the maternal temperature falls between 38.0 °C (100.4 °F) and 38.9 °C (102 °F), and at least 1 additional clinical risk factor is observed. In some cases, the diagnosis may be made even without maternal fever if other relevant clinical signs and symptoms are present.

Evaluation

Current guidelines by ACOG recommend universal screening for hepatitis B, hepatitis C, syphilis, gonorrhea, chlamydia, and asymptomatic bacteriuria at the first prenatal visit, which should occur at 8 to 10 weeks of gestation.[64] Universal recommendations also include an HIV screen at the first visit using an "opt-out" approach, where testing is done unless the patient declines it. All pregnant women should have a rectovaginal swab for GBS at 35 to 37 weeks of gestation; patients at high risk for preterm labor should be tested before 35 weeks.[65]

Additional recommended screening for antepartum infections includes repeat testing for HIV, chlamydia, and gonorrhea in the third trimester in populations at high risk for the acquisition of these infections, including adolescents and younger people.[64] These infections may be missed if repeat screenings are not performed in the third trimester.[66] ACOG also supports additional recommendations for syphilis screening 3 times during pregnancy, regardless of the patient's risk and the population prevalence.[12]

Pregnant individuals who test positive for hepatitis B surface antigen should have quantitative testing for hepatitis B virus deoxyribonucleic acid and maternal antiviral treatment during pregnancy when the viral load is over 200,000 IU/mL to help prevent perinatal transmission of hepatitis B. Infants born to HIV-positive mothers or mothers with unknown HIV status should be tested for the disease using nucleic acid tests. The recommended schedule includes testing within 48 hours of birth, at 2 weeks of age, between 4 and 6 weeks of age, and between 4 and 6 months of age.[10]

Chorioamnionitis is a pathologic diagnosis made by examination of the fetal membranes for a neutrophilic infiltrate.[37] However, this diagnosis is usually made on a clinical basis, and treatment should not be delayed for the postpartum pathologic examination of the placenta. Maternal leukocytosis supports the diagnosis of chorioamnionitis but is neither sensitive nor specific. Infants exposed to chorioamnionitis who meet criteria on sepsis calculators should have blood cultures, a complete blood count, and a C-reactive protein (CRP) drawn at birth to evaluate for neonatal sepsis, for which they are at increased risk.[37]

The United States Preventive Services Task Force (USPSTF) and ACOG recommend against routine screening for bacterial vaginosis in asymptomatic pregnant patients.[67] In symptomatic patients, testing is best done by vaginal pathogen swabbing, although microscopic evaluation of vaginal discharge obtained through a vaginal swab may be performed. The presence of clue cells is diagnostic of bacterial vaginosis.[68] USPSTF also recommends against routine serologic screening for HSV in asymptomatic individuals, including pregnant persons.[69]

According to ACOG, routine CMV serologic screening during pregnancy is not advised. Most positive immunoglobulin M (IgM) results, nearly 90%, are false positives, often caused by cross-reactivity with non–CMV antibodies. Additionally, maternal immunity does not fully protect against fetal infection. The absence of an approved vaccine or an effective treatment to prevent congenital transmission further reduces the benefits of universal screening.[70] With a known maternal exposure, serum CMV IgM and IgG may be tested. If all are negative, repeat testing of IgM and IgG may help identify seroconversion.[70] At least 6 weeks after maternal CMV infection is confirmed, an amniocentesis for CMV polymerase chain reaction (PCR) is recommended if at least 21 weeks of gestation.

However, a consensus recommendation from the European Congenital Infection Initiative advises conducting CMV serology testing as early as possible during the first trimester of pregnancy. For women who test seronegative, follow-up testing should be performed every 4 weeks until 14 to 16 weeks of gestation. Routine CMV serology is not recommended beyond 16 weeks unless ultrasound findings suggest a CMV-related anomaly.[71]

Treatment / Management

Effective treatment of antepartum infections is critical to minimizing risks to both mother and fetus. Management strategies should be guided by the specific pathogen involved, gestational age, and current evidence-based recommendations to ensure optimal outcomes.

Medical Interventions

• Antibiotics for GBS, chlamydia, and other bacterial infections
• Antiviral therapy for HSV (eg, acyclovir) and CMV (eg, valganciclovir in severe cases)
• Antimalarial drugs for malaria

Surgical Interventions

Cesarean delivery for active genital HSV or other severe maternal infections with risk to the fetus

National and International Guidelines

• CDC guidelines for GBS screening and treatment during pregnancy (see Image. Intrapartum Antibiotic Prophylaxis, Indications and Nonindications)
• WHO guidelines for preventing and managing maternal infections (eg, malaria, HIV)
• Guidelines for Zika virus management, including travel restrictions and testing

Toxoplasmosis

In toxoplasma seropositive pregnant individuals diagnosed before 18 weeks of gestation, treatment should begin with spiramycin until ultrasonography and PCR can evaluate for the presence of congenital fetal infection.[10] If fetal infection is present, spiramycin should be continued, and pyrimethamine, sulfadiazine,[8] and folinic acid should be added to the regimen. Observational data suggest a decrease in fetal infection and less severe neurologic sequelae with these regimens, although there is no trial data on the topic.[10](B2)

Rubella

There is no specific therapy for rubella in primary or congenital infections. The cornerstone of management is, therefore, prevention. All children and adolescents without contraindications to the measles, mumps, rubella (MMR) vaccine should receive it. MMR administration is contraindicated in pregnancy, however. Pregnant women found to be nonimmune to rubella should be counseled on the importance of vaccination and vaccinated upon completion of the pregnancy.[72] Women of childbearing age who receive the MMR vaccine should be cautioned to avoid becoming pregnant within 28 days of vaccine administration.[10]

Human immunodeficiency virus

Antiretroviral prophylaxis should be given to all infants born to HIV-positive mothers.[10] A 4- or 6-week course of zidovudine can be used for infant prophylaxis in cases where the mother was adherent with prepartum combination antiretroviral therapy (cART) and had effective viral suppression throughout the pregnancy.[10] In cases where prenatal cART was not used, infants should receive a 6-week course of zidovudine as well as 3 total doses of nevirapine within 8 hours after birth, at 48 hours following the first dose, and 96 hours following the second dose. 

The cART should be immediately initiated in HIV-positive infants. Early cART initiation is associated with reduced mortality and improved developmental milestones and gross motor skills in these infants.[10] Vaginal delivery can be considered if the risk of transmission to the fetus is low, as evidenced by low maternal viral loads; otherwise, cesarean section is recommended to reduce the risk of intrapartum HIV transmission to the infant. HIV-positive mothers should not breastfeed.[73](B3)

Syphilis

The only treatment for syphilis in pregnant women is intramuscular penicillin.[10] Penicillin-allergic patients should be desensitized before treatment. Treatment for congenital syphilis is 10 days of parenteral penicillin.[74]

Herpes simplex virus

A primary HSV outbreak in pregnancy should be treated with acyclovir, famciclovir, or valacyclovir. Oral therapy is typically sufficient, but parenteral treatment may be needed in severe or disseminated cases. Oral HSV suppressive therapy should be offered at 36 weeks to women with genital herpes. Cesarean section should only be performed if genital lesions are present at the time of delivery.[75] Infants suspected or confirmed to have congenital HSV should receive intravenous acyclovir.[76]

Hepatitis E

Treatment, both for the primary infection in pregnant people and congenital cases, is supportive.[77]

Hepatitis B

In cases of high maternal hepatitis B viral load, the recommended strategy for preventing mother-to-child transmission involves initiating maternal antiviral therapy at 28 weeks' gestation, in conjunction with administering a full hepatitis B vaccination series and hepatitis B immune globulin (HBIG) to the neonate immediately after birth.[78] At the beginning of the third trimester, if viral loads exceed 200,000 IU/mL of hepatitis B virus deoxyribonucleic acid, tenofovir disoproxil fumarate should be initiated to prevent neonatal hepatitis B infection.(A1)

Infants should be encouraged to breastfeed, and cesarean delivery should be done only for obstetrical indications.[33] In areas with limited access to hepatitis B immune globulin (HBIG), results from a recent randomized controlled trial showed that initiating tenofovir therapy at 16 weeks, combined with infant hepatitis B vaccination, was not inferior to standard treatment for patients with high viral loads.[78] Additionally, ACOG recommends vaccination against the hepatitis A and B viruses during pregnancy if necessary. Prepregnancy screening and treatment are ideal.(A1)

Hepatitis C

Although direct antiviral agents for HCV are now available, due to a lack of data on their safety in pregnant patients, the Society for Maternal-Fetal Medicine and ACOG do not recommend medical treatment for Hepatitis C with antivirals during pregnancy or lactation.[79] A 12- to 24-week course of antiviral medications for virologic cure should be completed before pregnancy when possible.[33] Treatment of HCV should be deferred in children until at least 3 years of age to allow for potential spontaneous resolution and avoid the adverse effects of the treatment medications in the infant.[80] (A1)

Parvovirus B19

Treatment of primary parvovirus infection in pregnant individuals is supportive. Treatment of congenital infection is likewise primarily supportive, and in utero fetal transfusions have become a cornerstone of therapy in the management of the associated severe fetal anemia.[10] 

Zika virus

Treatment of both primary and congenital Zika virus infection is supportive, so prevention is vital. Several vaccines are in development. Pregnant people and people desiring to become pregnant should avoid visiting countries where the Zika virus is circulating. Although the transmission of the Zika virus is predominantly vector-borne, sexual transmission has been described.[81]

Chorioamnionitis

Patients with preterm rupture of membranes should receive antibiotics targeting the most common organisms implicated in chorioamnionitis.[37] With preterm rupture of membranes, antenatal antibiotics are associated with a decreased risk of neonatal sepsis, respiratory distress syndrome, and necrotizing enterocolitis.[37] In these patients, antibiotic use is also associated with an increase in latency time until delivery; recommended antibiotic regimens include ampicillin and gentamicin.[37]

If signs of chorioamnionitis develop, urgent delivery is indicated regardless of gestational age. Neonates exposed to chorioamnionitis should be started on empiric antibiotics pending the results of the blood cultures and laboratory testing described above. The duration of antibiotic use in these neonates has not been delineated. However, experts suggest that, in the setting of reassuring laboratory results and negative blood cultures, antibiotics can be discontinued after 48 hours.[37]

Group B Streptococcus

Pregnant individuals colonized with GBS should receive intrapartum antibiotics, with penicillin G being the medication of choice in nonallergic patients.[65] Cefazolin can be used in patients having a non-life-threatening penicillin allergy. In contrast, clindamycin should be used in patients with a history of urticaria, angioedema, respiratory distress, or anaphylaxis with penicillin administration, assuming the bacteria are sensitive to clindamycin.[65](B3)

Group A Streptococcus

Blood and vaginal cultures should be considered if GAS is in the differential diagnosis. GAS remains highly sensitive to penicillins, and treatment includes intravenous penicillin plus clindamycin. GAS infection plus organ dysfunction should be surgically managed, commonly requiring a hysterectomy, to control the source of infection.[41](A1)

Monkeypox

Tecovirimat, an antiviral therapy that is US Food and Drug Administration (FDA)-approved for the treatment of smallpox, is recommended for pregnant people who have severe monkeypox disease. Monkeypox can result in severe disease in pregnant people and their newborns. The WHO recommends administration of the smallpox vaccine, eg, modified vaccinia Ankara–Bavarian Nordic (MVA-BN), which contains live, nonreplicating virus, to pregnant people who are at high risk of monkeypox. Smallpox is another orthopox virus, and cross-immunity to monkeypox is expected with vaccination. Further research is needed before clinical guidelines and policies for monkeypox in pregnancy are developed.[39] 

Cytomegalovirus

In cases of maternal primary infection with CMV occurring around conception or during the first trimester, the European Congenital Infection Initiative consensus recommendation supports oral valacyclovir at a dosage of 8 g/day, starting as soon as the infection is diagnosed and continuing until CMV PCR results from amniocentesis are available. For fetuses confirmed to be infected, fetal ultrasound and magnetic resonance imaging (MRI) evaluation in the third trimester are recommended to assess CMV-related abnormalities and provide prognostic insights.[71](B3)

In contrast, the FDA has not approved any treatments for maternal or fetal CMV infection. Antiviral drugs like ganciclovir, valganciclovir, and foscarnet are FDA-approved solely for managing CMV infections in individuals with acquired immunodeficiency syndrome (AIDS) or those who have undergone organ transplantation. Valacyclovir to prevent fetal infection after maternal primary infection is not FDA-approved and not recommended by ACOG at this time.[70]

Chlamydia and Gonorrhea

Since doxycycline is contraindicated in pregnancy, azithromycin is the preferred treatment for chlamydia in pregnancy.[82] A test of cure is recommended 4 weeks after treatment.[16] For gonorrhea, the CDC and ACOG recommend the use of ceftriaxone as the first-line regimen for the treatment of gonorrhea in the United States.[13] Pregnant people with antenatal gonococcal infection should have a test of cure in 4 weeks and also be retested in the third trimester.(A1)

Coxsackievirus

While there is no current treatment for coxsackievirus, therapies are emerging with promising results. Infection control and hygiene measures to decrease transmission rates are highly recommended during coxsackievirus outbreaks.[42]

Maternal sepsis

With sepsis in pregnancy, broad-spectrum antibiotics should be administered within the first hour of recognition. Aggressive fluid resuscitation is required with a target mean arterial blood pressure greater than 65 mm Hg. Hypotension should be managed with vasopressors when necessary, with norepinephrine as first-line therapy since it is more effective than phenylephrine in pregnant individuals. Intravenous immunoglobulin (IVIG) should be considered for use in severe cases of streptococcal or staphylococcal infections that are resistant to other therapies.[8](B2)

Differential Diagnosis

High maternal temperature has a broad differential diagnosis that, in addition to antepartum infections, includes infections common to the general population. Differential diagnoses that should be considered in patients with fever from prenatal infection include the following:

• Respiratory infection or pneumonia
• Cellulitis
  • Soft tissue infection from mastitis, Bartholin gland, or other skin injury
• Urinary tract infections
• Pulmonary embolism
• Sepsis
• Gastroenteritis
• Hyperthermic toxidromes
• Placental abruption
• Sexually transmitted infections
• Appendicitis

Prognosis

Antenatal infections can lead to serious complications that affect both the mother and the developing fetus. Recognizing these potential outcomes is crucial for timely intervention and improving pregnancy outcomes.

Maternal Prognosis

Maternal prognosis following antenatal infections varies widely, influenced by the type of infection, its severity, and the timing during pregnancy. While many infections are mild and manageable, some can lead to serious complications. For instance, infections like influenza can increase the risk of pneumonia and hospitalization, especially in the second trimester, and may lead to preterm labor or even maternal death in severe cases. Chorioamnionitis is associated with risks such as preterm birth, postpartum complications, hemorrhage, and sepsis. Severe infections during pregnancy are linked to higher odds of complications, with sepsis being a leading cause of maternal mortality.

With the notable exception of HEV, the antepartum infections discussed above have a favorable prognosis for the mother in immunocompetent individuals. Maternal sequelae from toxoplasmosis, rubella, CMV, parvovirus, and Zika virus infection are rare.[10] Progression of acute hepatitis B and C to chronic infection is possible and increases the risk for hepatic failure and hepatocellular carcinoma in these patients.[10][83] The risk of fulminant liver failure and mortality in pregnant patients with HEV ranges from 30% to 100%.[5] Finally, with appropriate antiviral therapy, individuals with HIV infection have a comparable life expectancy to their noninfected counterparts.[84] 

Fetal Prognosis

The severity of the antenatal infection and the timing of intervention play crucial roles in fetal outcomes. Some infections may have minimal effects, while others can lead to serious complications such as miscarriage, stillbirth, preterm birth, or long-term developmental issues. Certain infections, like CMV, rubella, syphilis, and toxoplasmosis, are known to cross the placenta and affect fetal development. These infections can result in conditions such as hearing loss, vision problems, intellectual disabilities, or growth restriction. The severity often depends on when the infection occurs during pregnancy; earlier infections can be more detrimental.

Bacterial infections, such as GBS and chorioamnionitis, can also pose risks. GBS can lead to neonatal sepsis, pneumonia, or meningitis, particularly if not identified and managed during labor. Since chorioamnionitis is associated with preterm birth, this may increase the risk of cerebral palsy in the newborn.

Complications

Complications of antenatal infections can significantly impact both maternal and fetal health, leading to increased morbidity and mortality. Understanding these potential outcomes is vital for timely intervention and the prevention of long-term adverse events.

Maternal complications include the following:

• Sepsis, postpartum hemorrhage, uterine rupture, and disseminated intravascular coagulation 
• Increased risk of preterm labor and delivery

Fetal complications include the following:

• Premature birth, low birth weight, and developmental delays
• Congenital effects (eg, microcephaly, congenital heart defects, vision or hearing loss in CMV, Zika)
• Neonatal infection and mortality in severe cases

The most severe fetal complication of congenital infection is fetal demise and spontaneous abortion, but the incidence of this is difficult to estimate. Congenital toxoplasmosis, Rubella, CMV, and HSV can result in low birth weight, failure to thrive, and significant neurodevelopmental and motor delays in affected infants.[10] HSV encephalitis is also associated with blindness. Congenital parvovirus is associated with fetal myocarditis and heart failure.[10] 

Complications of congenital HBV include progression to fulminant hepatitis or, rarely, chronic HBV infection. Congenital HCV carries a high risk of progression to chronic HCV, leading to cirrhosis and an increased risk of hepatocellular carcinoma.[10] HEV infection is associated with a significant risk of fulminant hepatic failure and death in pregnant women compared to the general population.[10] Untreated bacterial vaginosis is associated with an increased risk of preterm birth, chorioamnionitis, and endometritis.[67] 

Chorioamnionitis is associated with an increased risk of preterm birth, neonatal sepsis, intraventricular hemorrhage, periventricular leukomalacia, and cerebral palsy.[37] Data regarding the relationship between chorioamnionitis and bronchopulmonary dysplasia or respiratory distress syndrome is mixed.[37] Maternal complications from chorioamnionitis include a 2- to 3-fold increase in the risk of cesarean section and its associated complications, as well as increased risk of endometritis, wound infection, postpartum hemorrhage, bacteremia and sepsis, and postpartum hemorrhage.[85][86]