Fever in Pregnancy - Introduction

               Any acute or chronic infectious diseases may be contracted during the course of pregnancy, and conception may occur in women already subject to infection. The coexistence of pregnancy may aggravate the risk to maternal life of the more serious of these diseases. In pregnancy most infections are no more common, nor more serious than in non-pregnant women of similar age. Besides affecting the mother, some infections may be transmitted to the fetus in utero, during the intrapartum period or, postnatal, with potentially serious consequences. Infectious illnesses and fevers in the mother must be treated as any other serious illness. The effects on pregnancy depend on the extent of temperature elevation, its duration, and the stage of fetal development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in miscarriage, premature labor, growth restriction, and stillbirth.

               Hyperthermia also causes a wide range of fetal structural and functional defects, with the central nervous system (CNS) being most at risk. While there is a greater incidence of neonatal morbidity and mortality with transmitted infections, not all maternal infections lead to transmission to the fetus, nor does transmission to the fetus lead to disease or sequelae. During the puerperium, parturient women are particularly susceptible to serious infections of the genital tract and childbed fever remains one of the most important causes of maternal death. This chapter will deal with fevers and infections during pregnancy, rather than the puerperium. While attempts have been made to list the more important causes of fever in pregnancy (Tables 1, 2, 3), the lists are by no means complete.

               Infections in pregnancy may be viral, bacterial or protozoan, affecting both mother and fetus. The purpose of this document is to describe these infections, their modes of transmission, and their maternal and fetal effects, and to offer guidelines for counseling and management of these infections during pregnancy. Some of the infections cause fevers, while others may not; this chapter will concentrate on infections resulting in maternal pyrexia, and some other infections which may not result in maternal pyrexia, but have important implications for the pregnancy and the fetus (Table 1). A differential diagnosis of fever in pregnancy, including both infectious and non-infectious etiologies, may be found in Table 2.

Pathogenesis

               Persistent elevation of body temperature above normal levels in an individual is defined as fever. The normal body temperature usually lies between 37.0 and 37.5◦C with diurnal variations. Disturbances of temperature regulation in disease can be explained by shifts in body water, inadequate hydration, and changes in metabolism. The pattern of febrile response may be intermittent (falling to normal each day), remittent (falling each day, but still remaining above the normal), sustained (without significant diurnal variation), or relapsing (alternating with periods of one to several days of normal temperatures). The underlying sequence of events seems to be the removal of endotoxins from the circulation by fixed phagocytes of the reticuloendothelial system, followed by margination of polymorphonuclear leukocytes along the margins of the vessels. These two types of cells undergo activation to release endogenous pyrogen in to the circulation. The pyrogen produced in response to toxic, immunological or infectious stimuli, is induced through the release of lymphocytic lymphokines arising in response to antigenic recognition, and acts on the hypothalamic thermoregulatory center, transmitting information to the vasomotor center, possibly through production of prostaglandin. The release of endogenous pyrogen by phagocytic cells appears to be the common factor in the pathogenesis of fever, irrespective of its cause (Table 2).

               The immune status of an individual may be innate or acquired. Innate immunity is genetically or constitutionally determined, and is not a function of cells of the immune system or antibodies, but of physiological, biochemical or anatomical differences between species. The response of adults to antigen stimulation consists of production of IgM, followed by production of IgG. The pattern of response in the neonate is different; IgM is produced as a first response, and persists for several weeks before IgG is released. The fetus elaborates IgM in response to antigen exposure in utero, and it is the detection of the specific antibody in the IgM fraction of cord blood that is used for detection of congenital infections. The poor response of newborns to certain infections are not clearly understood, however, there is evidence that in addition to physiological dysglobinemia, the cellular response to infection varies, and the phagocytes are less active. Further, there is a lack of antigen-presenting macrophages. Immunity acquired either passively or actively, follows the transfer of immune antibody of the IgG class from mother to fetus by the transplacental route, and the ingestion of IgA antibody in colostrum. Artificially acquired passive immunity follows injection of immune products such as antitoxins, antisera, or immune globulin.

               Somatic cell proliferation is adapted to, and proceeds optimally at the normal body temperature range of the species, and the deleterious effects of higher levels on meiotic and mitotic cell proliferation and survival are widely recognized. A hyperthermic episode during pregnancy can result in embryonic death, abortion, growth retardation, and defects of development. It has been proposed that defects following a maternal fever might be caused by metabolic changes in the mother due to the infection and fever, and not due to the associated elevation of temperature. The Collaborative Perinatal Study of the National Institute of the Neurological Diseases and Stroke found that children of mothers who experienced kidney-urinary tract infections (UTIs) with fever were nearly twice as likely to have neurological problems requiring institutional care as children whose mothers had the infection without fever. The association between maternal influenza, and fever, in the second trimester of pregnancy, and the later onset of schizophrenia in the offspring raises the possibility of hyperthermia being one of the initiating factors in this condition, and perhaps, a number of other neurological conditions of uncertain etiology such as cerebral palsy and autism. Inflammation (leukocytic invasion) of the chorioamnion (chorioamnionitis) and/or umbilical cord (funisitis) marks the maternal and fetal immune responses, respectively. While these histologic markers may result from numerous insults (hypoxic injury, trauma, meconium or allergens), by far the most common is the immune response to subclinical or clinical infection.

               There are several ways in which maternal infection might lead to inflammation within the fetal tissue and the loss of vulnerable cell populations. Bacterial products could cross to the fetal circulation, bind specific cell-membrane receptors, such as CD-14 and toll-like receptors, on inflammatory cells within the systemic circulation initiating a cascade of intracellular events. They activate transcription factors such as nuclear factor κ-B and production of proinflammatory cytokines. These proinflammatory cytokines, such as granulocyte colony-stimulating factor, tumor necrosis factor-α, interleukin-1β, C-reactive protein and interferon γ, have a variety of effects. These include a direct toxic effect on neurones and vulnerable oligodendrocyte precursor populations, gliosis with release of nitric oxide and mitochondrial dysfunction, as well as microglial activation in the brain. Animal studies describe the direct correlation between increasing temperature and susceptibility to a variety of neurotoxic factors. Hypothermia can be neuroprotective after hypoxia–ischemia in neonatal animals, while hyperthermia increases brain injury after ischemia in adult rats. Maternal pyrexia, resulting from both microbial infection as well as non-infective causes such as epidural anaesthesia, could therefore augment the deleterious effects of hypoxia on the fetal brain, possibly by increasing the cerebral metabolic rate and demand for oxygen. Systemic fetal hypotension, endothelial injury and leukocyte aggregation may all contribute to local tissue ischemia, especially in vulnerable areas. Many of these mechanisms could lead directly to cell death. They may also have an indirect neurotoxic effect by sensitizing the brain and lowering the threshold at which hypoxia triggers apoptosis.

               Modes of transmission of infective agents include transplacental transfer via the umbilical blood flow or by direct spread to the amniotic fluid, ascending transmission from the cervix and uterus to the amniotic fluid, intrapartum exposure to maternal vaginal secretions and blood, or by postpartum exposure to maternal respiratory secretions or breast milk.

Table 1. Causative Agents, Transmission, and Effects on Mother and Fetus/Neonate

Infecting Agent	Transmission	Potential Effects on Mother	Potential Effects on Fetus/Newborn
VIRAL
Coxsackie A & B	Mostly intrauterine	Herpangina; hand, foot, mouth disease; myocardiopathy, aseptic meningitis, Bornholm disease	Abortion,stillbirth, neonatal sepsis, myocarditis-meningoencephalitis.   ?gastrointestinal, cardiac and urogenital defects
Cytomegalovirus	Mostly intrauterine. 50% in primary maternal infection (25% symptomatic)	Usually asymptomatic. Sometimes moderate to high fever in primary infection	Deafness,microcephaly, hepatosplenomegaly, hydrops fetalis
Echovirus		Rash may resemble rubella; mimics appendicitis and abruption placenta	Neonatal Sepsis, disseminated infection (hepatic necrosis), late stillbirth
Enteroviruses		Non-specific febrile illness, abdominal pains	Neonatal sepsis
Hepatitis B	Intrauterine, postnatal, mostly perinatal. Risk of perinatal infection if mother HBAg +ve is 90%	Asymptomatic chronic carrier state, acute hepatitis	Chronic carrier, rarely acute fulminant neonatal hepatitis
Hepatitis C	Intrauterine, mostly perinatal. 0%-6.2% depending on HCV RNA-titres. Up to 19.4% in HCV/HIV +ve patients	Acute hepatitis, cirrhosis, hepatocellular carcinoma.	Unknown effects
Herpes Simplex	Intrauterine & perinatal. 40-50% risk of severe neonatal infection after primary maternal genital infection, and 8% risk  after secondary infection	Oral or genital papular eruptions; more severe in pregnancy	Abortion after primary infection, fatal disseminated infection, prematurity, congenital malformations, stillbirth, intrauterine growth restriction
Human Immunodeficiency viruses (HIV-1&2)	Intrauterine, postnatal, mostly perinatal. 2%-40% transmission depending on treatment, and breastfeeding	Asymptomatic, unless had AIDS	? Infantile disease, viremia
Influenza	Intrauterine & postnatal	Up to 54% mortality in pandemics	Uncertain. ? CNS malformations, neural tube defects, ? circulatory malformations, ? cleft lip, ? reductive deformities
Lymphocytic choriomeningitis virus	Mostly intrauterine	Meningitis/meningo-encephalitis	Congenital disease
Measles	Mostly intrauterine	May be complicated by pneumonia & CCF. More severe. May be fatal	Congential measles, ? increased mortality
Mumps	Intrauterine	Nonspecific effects	? increased mortality, ? endocardial fibroelastosis
Poliomyelitis		Increased severity, mortality	Stillbirth, neonatal disease
Rubella (German measles)	Mostly intrauterine, postnatal. 40%-60% risk of severe defects in months 1&2, 30%-35% in month 3, 10% in month 4. rare fetal damage after 20 weeks	Mild nonspecific symptoms	Congenital malformations, abortions, fetal death, chronic infection
Parvovirus B19	Intrauterine	Asymptomatic “slapped-cheek” rash, erythema infectiosum (Fifth disease)	Second rimester abortions, hydrops fetalis due to severe anemia, ?myocarditis, ?hepatitis, haematological effects in late pregnancy,
Varicella zoster (Chickenpox)	Intrauterine & perinatal. No accurate figures; estimated 0.7%-2.2% transmission	More severe; maternal death	Varicella embryopathy, congenital varicella syndrome, infantile zoster, microcephaly, focal brain calcification, optic atrophy, skin scarring, limb atrophy
Bacterial
Treponema pallidum	Intrauterine.0.02%–4.5%, but varies in regions	Primary (asymptomatic, chancre, lymphadenopathy), secondary (rash, condylomata, alopecia, arthritis, periostitis, optic neuritis, intersitial keratitis, iritis, uveitis, meningitis) & tertiary (cardiovascular, neurological, joint disorders, gummas, dementia)	Abortion, stillbirth, premature birth, non-immune hydrops, intrauterine growth restriction, perinatal death, congenital disease
Mycobacterium tuberculosis	Mostly intrauterine, postnatal.	9% of all deaths of women of reproductive age. Malaise, night sweats, weight loss,  usually respiratory symptoms	>Abortion,premature birth, stillbirth
Listeria moncytogenes	Mostly intrauterine, Perinatal. Soil, food, animals	Headache, myalgia, fever, loin pains, pharyngitis,  gastrointestinal symptoms	Fetal death, chronic intrauterine, congenital or perinatal infection, prematurity, meningoencephalitis
Borrelia burgdorferi(Lyme disease)	Intrauterine	3 stages: early localized, early disseminated, and late disease. Erythema migrans, rash, palsies of the cranial nerves, meningitis, conjunctivitis, carditis, arthritis, Meningoradiculoneuritis (Bannwarth syndrome). Systemic symptoms, such  as arthralgia, myalgia, headache, fatigue	Miscarriage, stillbirth, neonatal deaths, congenital Lyme disease hydrocephalus, cardiovascular anomalies, neonatal respiratory distress, hyperbilirubinemia, intrauterine growth restriction, cortical blindness
Protozoal
Toxoplasma gondii	Intrauterine. 15% -40%. Acquired through eating raw or undercooked meat or ingesting soil contaminated with toxoplasma oocysts, which are excreted in the faeces of infected cats.	Usually asymptomatic or mild, non-specific symptoms. Posterior cervical lymphadenopathy	Hydrocephalus, intracranial calcification, chorioretinitis. Jaundice, anemia, hepatosplenomegaly, lymphadenopathy
Plasmodium Species		Increased susceptibility. Maternal death, anemia	Abortion, stillbirth, premature delivery, intrauterine growth restriction, low birth weight.

Table 2. Infectious and Non-infectious Causes of Fever in the Mother

Systemic diseases	Bacterial infections	Non-infectious diseases
1. Tuberculosis   2. Gall bladder cholecystitis cholangitis empyema   3. Abscesses su bphrenic hepatic pelvic cerebral dental breast   4. Gastrointestinal appendicitis diverticulitis   5. Urinary tract infections   6. Retroperitoneal infection   7. Septicemia   meningococcal streptococcal staphylococcal gonococcal listeriosis vibriosis brucellosis   8. Endocarditis   9. Breast mastitis   10. Other Q-fever amebiasis leptospirosis	1. Gonococcal septicaemia salpingitis arthritis 2. Secondary syphilis 3. Gas gangarene 4. Tetanus 5. Opportunistic – associated with immune deficiency syndrome – candidiosis cryptococcosis histoplasmosis aspergillosis  coccidiomycosis	1. Neoplasms Lymphoma Leukemia Melanoma Metastasis Retroperitoneal sarcoma Tumors of the lung, kidney, pancreas, liver 2. Connective tissue disease Rheumatic fever Systemic lupus erythematosis Rheumatoid arthritis 3. Other Drug fever Thromboembolism Sarcoidosis Hemolytic disease

Table 3. Investigation of Symptomatic Infective Illness During Pregnancy

Diagnosis	Diagnostic tests	Clinical Scenario
Primary CMV infection, primary toxoplasmosis	IgG & IgM (paired sera)	Mono-like illness
Listeriosis	Culture of faeces, blood and/or urine	Meningitis
Other viral infections	Culture, serology	Nonspecific fever
Rubella, Parvovirus infection	Culture, serology	Rash, exposure
Enterovirus infection	Throat swab or faecal culture	Non-specific fever, respiratory symptoms
Varicella	Lesion swab & serology	Rash
Urinary tract infection(cystitis, pyelonephritis)	Urine microscopy & culture	Any fever, dysuria
Genital herpes	First episode: lesion swab, HSV1 & HSV2 IgG & IgM (paired with stored serum if available)	Genital lesions
Chlamydia, gonorrhoea	Cervical swab, Gram stain &culture; urine PCR (if positive, check syphilis, HBV& HIV serology)	Vaginal discharge, diagnosis of other STI
Chorioamnionitis	Vaginal Gram stain & culture (for group B streptococci or abnormal vaginal flora associated with bacterial vaginosis)	Abdominal pain
Pneumonia	Chest x-ray, sputum for stain & culture	Cough, dyspnea
Malaria	Peripheral blood smearPeripheral blood smear, antigen detection techniques(PfHPR-2),fluorescent staining, PCR based assay, antibody test	Fever after returning from an endemic country
Typhoid	Antigen detection	Fever after returning from an endemic country.
Hepatitis	HBsAg,HBeAg, Hepatitis C-RNA (PCR)	Fever and abdominal pain,abnormal LFT’s