Fever in pregnancy

Fever in pregnancy is a maternal temperature of 38.0°C or more, measured by an oral, tympanic or axillary thermometer on repeat measurement, occurring at any time from conception to birth. A temperature of 37.5 to 37.9°C is low grade and is only meaningful when it persists or comes with symptoms.

Key clinical points:

• Look for maternal sepsis at once.
• Separate obstetric sources (intra amniotic infection, septic abortion, pyelonephritis, endometritis after a procedure) from non obstetric sources.
• Test for malaria in any woman who lives in or has travelled to an endemic area.
• Treat serious infection without delay, because pregnancy lowers the threshold for deterioration.
• Some infections (listeriosis, influenza, malaria, varicella) are more severe in pregnancy, and some harm the foetus directly.

Clinical relevance. Sepsis is a leading cause of direct and indirect maternal death. Fever in the first trimester is linked to neural tube and other congenital defects, and high maternal temperature in labour raises neonatal complications. Infection can cause miscarriage, preterm labour, stillbirth and neonatal sepsis.

Physiology. Pregnancy shifts the immune response away from cell mediated immunity, which raises susceptibility to intracellular organisms (listeria, malaria, viruses, tuberculosis). Heart rate rises by 10 to 20 beats/min and respiratory rate is unchanged. The lower blood pressure of pregnancy can hide early shock.

The white cell count rises to 6 to 16 x 10^9/L in pregnancy and up to 20 to 30 x 10^9/L in labour, so a raised count has low specificity. Baseline body temperature rises by about 0.3 to 0.5°C in the luteal phase and early pregnancy.

Mechanisms. Fever follows pyrogenic cytokines (interleukin 1, interleukin 6, tumour necrosis factor) released after infection, inflammation, tissue injury, thrombosis, drugs or malignancy. In pregnancy, microorganisms can ascend the genital tract into the membranes, or spread haematogenously across the placenta (listeria, malaria, syphilis, cytomegalovirus, parvovirus, toxoplasma). They can also arise from the urinary, respiratory or gastrointestinal tract.

Classification.

• By duration: acute (under 7 days), prolonged (7 days or more), and fever of unknown origin (over 3 weeks with no cause after investigation).
• By source: obstetric (intra amniotic infection, septic abortion, endometritis, pelvic abscess, retained products) and non obstetric (urinary, respiratory, gastrointestinal, skin, central nervous system, blood borne).
• By pattern: continuous, remittent, intermittent (tertian or quartan in malaria), relapsing.
• By severity: fever alone, sepsis, severe sepsis, septic shock.

Key distinctions.

• Fever with rigors and loin pain suggests pyelonephritis.
• Fever with contractions, uterine tenderness or foul discharge suggests intra amniotic infection or septic abortion.
• Fever with flu like illness in an endemic area is malaria until proved otherwise.
• Fever with a mild flu like illness after unpasteurised dairy or processed meat suggests listeriosis.
• Fever with a rash needs exposure history for varicella, rubella, measles, parvovirus and syphilis.

History

• Fever: onset, pattern, peak, rigors, night sweats, response to antipyretics, duration.
• Gestation, plurality, obstetric history, recent procedures (amniocentesis, cerclage, miscarriage management, termination, surgery), membranes, contractions, vaginal loss, bleeding, foetal movements.
• Source symptoms: dysuria, frequency, loin pain; cough, sputum, chest pain, breathlessness; sore throat, ear pain; abdominal pain, diarrhoea, vomiting; headache, neck stiffness, photophobia; rash; joint pain; jaundice; wound or skin changes; breast pain; dental pain.
• Exposure: travel, malaria prophylaxis taken, mosquito bites, unpasteurised cheese, raw milk, deli meats, undercooked food, contaminated water, sick contacts (influenza, COVID-19, varicella, rubella, measles, tuberculosis), animals (toxoplasma, brucella, Q fever), occupational exposure, sexual exposure.
• Medical: HIV, diabetes, sickle cell disease, immunosuppression, valvular heart disease, asthma, chronic kidney disease, tuberculosis contact.
• Vaccination: influenza, COVID-19, tetanus, pertussis, rubella, varicella, hepatitis B, typhoid.
• Drugs: antibiotics already taken, antipyretics, drugs causing fever (beta lactams, antiepileptics, methyldopa), recent steroids.

Examination

• Temperature, heart rate (over 100 beats/min abnormal in pregnancy), respiratory rate (over 20 breaths/min abnormal), blood pressure, oxygen saturation, capillary refill, mental state, urine output.
• General: pallor, jaundice, dehydration, rash (petechiae, maculopapular, vesicles), lymph nodes, splenomegaly, mouth and teeth, tonsils, ears, sinuses.
• Chest: crackles, bronchial breathing, pleural rub, effusion. Heart: murmurs, new regurgitation. Spine: tenderness.
• Abdomen: uterine tenderness and tone, fundal height, loin tenderness, right upper quadrant and right iliac fossa tenderness (appendix may sit higher in pregnancy), hepatosplenomegaly.
• Speculum examination when membranes are in doubt or bleeding or discharge is present: foul liquor, cervical dilatation, retained products.
• Neurology: neck stiffness, Kernig and Brudzinski signs, focal deficit.
• Breasts and wound sites, calf swelling, intravenous cannula sites.
• Foetal assessment: foetal heart rate (tachycardia over 160 beats/min), cardiotocography from viability.
• Bedside tests: urine dipstick, capillary glucose, rapid malaria test where available.

Red flags

• Systolic blood pressure under 90 mmHg, heart rate over 120 beats/min, respiratory rate over 25 breaths/min, oxygen saturation under 94%, new confusion, or urine output under 0.5 mL/kg/h (sepsis).
• Lactate over 2 mmol/L, non blanching rash, mottled skin, or capillary refill over 3 seconds.
• Neck stiffness, photophobia, seizure, or reduced consciousness.
• Fever with contractions, ruptured membranes, uterine tenderness, foul discharge, or bleeding.
• Fever with recent travel to a malaria area, or any fever with jaundice and altered mental state.
• Severe localised pain with systemic illness (appendicitis, necrotising soft tissue infection, pyelonephritis with obstruction).
• Fever in early pregnancy with vaginal bleeding after a recent miscarriage or termination (septic abortion).
• Immunosuppression, HIV with low CD4 count, sickle cell disease, asplenia.
• Persistent foetal tachycardia or reduced foetal movements.
• Fever for 7 days or more, weight loss, night sweats (tuberculosis, lymphoma, brucellosis).

Special groups. Women with HIV need earlier testing for tuberculosis, cryptococcus and opportunistic infection. Women with sickle cell disease have functional asplenia and need broad cover and early review. Women from malaria endemic areas have partial immunity that may mask symptoms, though parasitaemia in pregnancy is still dangerous. Region specific: malaria, typhoid, dengue and tuberculosis dominate the causes of fever in many settings; test early and treat on suspicion in unwell women.

Organised by source. Each cause is common unless marked serious or uncommon.

Obstetric and genital tract

• Serious: intra amniotic infection (chorioamnionitis).
• Serious: septic abortion and retained products with infection.
• Serious: group A streptococcal infection (puerperal sepsis, toxic shock, necrotising fasciitis).
• Infected fibroid with degeneration, adnexal or tubo ovarian abscess, pelvic inflammatory disease.
• Wound or cerclage related infection, infection after amniocentesis.
• Placental infection (malaria, syphilis, listeria, cytomegalovirus, toxoplasma).

Urinary

• Acute pyelonephritis (the commonest serious bacterial cause).
• Cystitis, asymptomatic bacteriuria progressing to pyelonephritis.
• Renal or perinephric abscess, obstructing stone with infection.

Respiratory and head and neck

• Upper respiratory tract infection, pharyngitis, sinusitis, otitis media.
• Influenza and COVID-19.
• Pneumonia (pneumococcal, Mycoplasma, viral, varicella pneumonitis).
• Pulmonary tuberculosis.
• Dental abscess, tonsillar abscess.

Gastrointestinal and hepatobiliary

• Gastroenteritis, typhoid and paratyphoid fever, Salmonella, Campylobacter.
• Serious: listeriosis (bacteraemia, meningitis).
• Serious: appendicitis, cholecystitis, cholangitis, pancreatitis, intra abdominal abscess.
• Viral hepatitis (A, B, E; hepatitis E is severe in pregnancy), amoebic liver abscess.

Blood borne and systemic

• Serious: malaria (falciparum is the most dangerous in pregnancy).
• Dengue, chikungunya, Zika, yellow fever, viral haemorrhagic fevers.
• HIV seroconversion illness, cytomegalovirus, Epstein Barr virus, toxoplasmosis, parvovirus B19, rubella, measles, varicella.
• Syphilis, brucellosis, leptospirosis, Q fever, rickettsial infection.
• Infective endocarditis (injecting drug use, valve disease).
• Tuberculosis (miliary or extrapulmonary).

Central nervous system

• Serious: bacterial meningitis, viral meningitis and encephalitis (herpes simplex), tuberculous meningitis, cryptococcal meningitis.
• Cerebral abscess, cerebral malaria.

Skin and soft tissue

• Cellulitis, erysipelas, abscess, herpes zoster.
• Serious: necrotising soft tissue infection.
• Mastitis (late pregnancy and lactation).

Non infectious

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism, septic pelvic thrombophlebitis).
• Drug fever, transfusion reaction, serum sickness.
• Autoimmune disease flare (systemic lupus erythematosus), vasculitis.
• Thyroid storm, phaeochromocytoma, adrenal insufficiency.
• Malignancy (lymphoma, leukaemia), haemolysis, sickle cell crisis.
• Dehydration and heat illness, epidural related fever in labour.
• Hyperthermia from exercise, saunas or hot tubs.

Stepwise reasoning

1. Assess airway, breathing and circulation and decide whether sepsis is likely; if so, start the first hour actions at once.
2. Take a focused history and examination for source, gestation, exposures and travel.
3. Send cultures and first line tests before antibiotics when this does not delay treatment beyond 1 hour.
4. Test for malaria in anyone with exposure.
5. Assess the foetus, then refine the diagnosis with targeted tests and imaging.

First line tests

• Full blood count with differential, C reactive protein (trend; procalcitonin where available), urea, creatinine, electrolytes, liver function tests, glucose, lactate, blood gas.
• Blood cultures (two sets) before antibiotics.
• Midstream urine dipstick and culture; a negative dipstick does not exclude infection in pregnancy.
• Malaria: rapid antigen test and thick and thin blood films, repeated every 12 hours for 48 hours if negative and suspicion remains.
• Coagulation screen with fibrinogen when septic or bleeding.
• High vaginal swab, low vaginal and rectal swab for group B streptococcus, endocervical nucleic acid amplification tests for chlamydia and gonorrhoea when genital source is suspected.
• Throat swab and nasopharyngeal swab for influenza and COVID-19 by polymerase chain reaction.
• Cardiotocography and obstetric ultrasound (foetal viability, liquor volume, placenta, retained products).

Targeted tests

• Chest radiograph with abdominal shielding when respiratory symptoms or signs are present (foetal dose is negligible); sputum culture; Xpert MTB/RIF testing for suspected tuberculosis.
• Renal tract ultrasound if pyelonephritis does not respond within 48 to 72 hours, or stone is suspected.
• Abdominal ultrasound, then MRI for suspected appendicitis, cholecystitis or abscess; contrast CT when MRI is not available and the diagnosis threatens life.
• Lumbar puncture after imaging when meningitis or encephalitis is suspected; start antibiotics first if the delay exceeds 30 minutes.
• Blood cultures for typhoid (the most sensitive test, positive in about half of cases in the first week); stool culture; Widal test is unreliable.
• Dengue: non structural protein 1 antigen in the first 5 days, then IgM; platelets and haematocrit daily.
• Serology as indicated: HIV, hepatitis A, B and E, syphilis, cytomegalovirus, toxoplasma IgG and IgM with avidity, parvovirus B19 IgM, rubella IgG, varicella IgG, brucella.
• Listeria: blood cultures (specific request), and cerebrospinal fluid culture when meningeal signs are present.
• Echocardiography and repeated blood cultures for suspected endocarditis.
• Autoimmune and malignancy screen (antinuclear antibodies, complement, lactate dehydrogenase, blood film) in prolonged fever.

Limitations. Procalcitonin and C reactive protein rise in labour and after steroids. White cell count is raised by steroids and labour. Lactate is raised in labour. Malaria tests can be falsely negative at low parasitaemia. Imaging must be chosen with the foetal radiation dose in mind, but a needed investigation is never withheld because of pregnancy.

Immediate steps. Give oxygen if saturation is under 94%. Place the woman in the left lateral position after 20 weeks, establish intravenous access, and start continuous monitoring.

For suspected sepsis, complete within 1 hour:

• Blood cultures and lactate.
• Broad spectrum intravenous antibiotics.
• Crystalloid 500 mL boluses (up to 30 mL/kg for hypotension or lactate of 4 mmol/L or more). Reassess after each bolus for pulmonary oedema, which occurs readily in pregnancy.

Start noradrenaline through a large vein when systolic pressure stays under 90 mmHg after fluids. Call the senior obstetrician, anaesthetist, microbiologist and neonatal team.

Antipyretic and supportive care. Paracetamol 1 g orally or intravenously every 4 to 6 hours (maximum 4 g daily; 3 g daily with alcohol use, malnutrition or liver impairment). Give fluids and light clothing. Tepid sponging has limited value.

Avoid NSAIDs and aspirin for fever in pregnancy. Avoid them from 20 weeks because of foetal renal effects and ductus arteriosus constriction, and avoid them in dengue. Offer folic acid 5 mg daily if fever occurred before 12 weeks and she is not already taking it.

Empirical antibiotics for sepsis of unknown source

• Piperacillin with tazobactam 4.5 g intravenously every 6 hours (every 8 hours in less severe illness).
• Or ceftriaxone 2 g intravenously once daily with metronidazole 500 mg intravenously every 8 hours.
• Add gentamicin 5 mg/kg intravenously once daily (adjusted to renal function) for severe sepsis.
• Meropenem 1 g intravenously every 8 hours when extended spectrum beta lactamase producing organisms are likely or the woman has been in hospital.
• Add clindamycin 900 mg intravenously every 8 hours when toxic shock or group A streptococcal infection is suspected (suppresses toxin production).
• Add vancomycin 25 mg/kg loading dose, then 15 mg/kg every 12 hours, adjusted to trough levels, for suspected methicillin resistant Staphylococcus aureus.
• Narrow antibiotics after culture results and reassess at 48 hours. Avoid tetracyclines and fluoroquinolones in pregnancy unless no alternative exists.

Intra amniotic infection.

• Ampicillin 2 g intravenously every 6 hours with gentamicin 5 mg/kg intravenously once daily.
• After caesarean birth, add metronidazole 500 mg intravenously every 8 hours (or clindamycin 900 mg every 8 hours).
• Give paracetamol and cooling.
• Deliver irrespective of gestation. Continue antibiotics until afebrile for 24 hours.

Septic abortion and retained products.

• Antibiotics: ampicillin 2 g every 6 hours, gentamicin 5 mg/kg once daily, and metronidazole 500 mg every 8 hours intravenously.
• Evacuate the uterus within 6 hours of starting antibiotics.
• Give anti D immunoglobulin for rhesus negative women (250 IU before 20 weeks).
• Screen for tetanus and clostridial infection when severe.

Pyelonephritis.

• Admit. Give ceftriaxone 1 to 2 g intravenously once daily (or cefuroxime 1.5 g intravenously every 8 hours). Add gentamicin 5 mg/kg once daily for sepsis.
• Change to oral cefalexin 500 mg every 6 hours (or by sensitivity) after 24 to 48 hours afebrile, to complete 10 to 14 days.
• Then give nightly suppression to 2 weeks after birth: cefalexin 250 to 500 mg at night, or nitrofurantoin 50 to 100 mg at night, avoided close to term.

Pneumonia. Amoxicillin 1 g orally three times daily for 5 days with azithromycin 500 mg orally daily for 3 days. For severe disease, give ceftriaxone 2 g intravenously once daily with azithromycin 500 mg intravenously once daily. Give oxygen to keep saturation at 95% or more.

Influenza. Oseltamivir 75 mg orally twice daily for 5 days (10 days in severe disease). Start within 48 hours and do not delay for test results. Pregnancy and the postpartum period up to 2 weeks are risk factors for severe illness. Add antibiotics for suspected secondary bacterial pneumonia. Vaccinate with inactivated vaccine in any trimester.

COVID-19. Give supportive care and oxygen. Give dexamethasone 6 mg daily for up to 10 days when oxygen is needed, and prophylactic enoxaparin 40 mg subcutaneously once daily (weight adjusted). Seek specialist advice on antivirals.

Malaria

• Uncomplicated falciparum malaria: artemether with lumefantrine (tablets of 20 mg artemether and 120 mg lumefantrine), 4 tablets orally at 0, 8, 24, 36, 48 and 60 hours with fatty food. This is acceptable in all trimesters.
• Alternative in the first trimester when it is unavailable: quinine 600 mg orally every 8 hours with clindamycin 450 mg orally every 8 hours for 7 days.
• Severe malaria (any trimester): artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours, then once daily until oral treatment is tolerated (minimum 3 doses), then a full oral course of artemether with lumefantrine.
• In severe malaria, check glucose every 4 hours (hypoglycaemia is common), treat anaemia, restrict fluids (pulmonary oedema), and give antibiotics for possible bacteraemia.
• Vivax malaria: chloroquine 10 mg base/kg, then 10 mg/kg at 24 hours and 5 mg/kg at 48 hours. Avoid primaquine in pregnancy. Give weekly chloroquine 5 mg base/kg until after birth and breastfeeding, then radical cure.
• Prevention: insecticide treated nets, and intermittent preventive treatment with sulfadoxine 500 mg with pyrimethamine 25 mg (3 tablets) as a single dose at each scheduled visit from 13 weeks, at least 1 month apart. Women taking cotrimoxazole for HIV do not receive it.

Listeriosis. Ampicillin 2 g intravenously every 4 hours for 14 days (21 days with meningitis), with gentamicin 5 mg/kg once daily for the first 7 days. Use trimethoprim with sulfamethoxazole for penicillin allergy. Assess the foetus and alert the neonatal team. Counsel on food safety.

Typhoid fever. Ceftriaxone 2 g intravenously once daily for 10 to 14 days, or azithromycin 1 g orally on the first day then 500 mg once daily for 6 days. Avoid fluoroquinolones.

Dengue. Give supportive care with paracetamol, oral fluids, daily haematocrit and platelet count, and intravenous crystalloid for plasma leak. Avoid NSAIDs and aspirin. Admit when warning signs occur: abdominal pain, persistent vomiting, bleeding, rising haematocrit, falling platelets under 100 x 10^9/L. Manage the critical phase (days 3 to 7) in a unit that can monitor fluid balance.

Varicella. Aciclovir 800 mg orally five times daily for 7 days if the rash is within 24 hours and gestation is over 20 weeks. For pneumonitis or severe disease, give intravenous aciclovir 10 mg/kg every 8 hours (adjusted to renal function). Give varicella zoster immunoglobulin within 10 days of exposure for non immune women.

Tuberculosis. Isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg and ethambutol 15 mg/kg once daily for 2 months, then isoniazid and rifampicin for 4 months, with pyridoxine 25 mg daily. Provide specialist care and HIV testing.

Meningitis. Ceftriaxone 2 g intravenously every 12 hours with amoxicillin 2 g intravenously every 4 hours (listeria cover) and dexamethasone 10 mg intravenously every 6 hours for 4 days. Add aciclovir 10 mg/kg intravenously every 8 hours when encephalitis is possible.

Appendicitis and other surgical sepsis. Arrange early surgical review, imaging with ultrasound or MRI, and surgery. Do not delay surgery for pregnancy. Antibiotics: ceftriaxone 2 g once daily with metronidazole 500 mg every 8 hours.

Foetal care. Use continuous cardiotocography in unwell women from viability. Treat maternal fever promptly because foetal tachycardia often settles.

• Betamethasone 12 mg intramuscularly twice, 24 hours apart, between 24 and 34 weeks and 6 days when birth is likely within 7 days, with monitoring of blood glucose.
• Magnesium sulphate 4 g intravenously over 15 to 30 minutes then 1 g/h for neuroprotection when birth is imminent before 30 weeks.
• Deliver for severe maternal sepsis not responding to treatment, intra amniotic infection, or foetal compromise.

Special groups.

• HIV: continue antiretroviral therapy and check interactions. Rifampicin lowers dolutegravir levels; double the dolutegravir dose to 50 mg twice daily.
• Sickle cell disease: add early broad spectrum cover and oxygen.
• Renal impairment: adjust gentamicin and avoid nephrotoxic drugs.
• Region specific: treat malaria in febrile pregnant women on a positive test even in areas of high transmission. Give antibiotics at the first level facility before referral.

Monitoring. Check temperature, pulse, blood pressure, respiratory rate, saturation, mental state and urine output every 15 minutes to 1 hour in sepsis, then every 4 hours. Repeat lactate within 2 hours if above 2 mmol/L. Take daily bloods (full blood count, creatinine, liver tests, C reactive protein). Monitor foetal heart rate by cardiotocography or auscultation as gestation allows. Review cultures at 24 and 48 hours.

Referral and escalation. Refer to critical care for septic shock, lactate over 4 mmol/L, respiratory failure or organ dysfunction. Involve microbiology and infectious diseases for unusual or resistant organisms, malaria and HIV. Refer to the obstetric team for any fever with obstetric signs, and to surgery for abdominal causes. Notify public health for notifiable infections.

Admission criteria. Admit for temperature of 38.0°C or more with any red flag, suspected intra amniotic infection, pyelonephritis, malaria, listeriosis, pneumonia needing oxygen, dehydration, inability to take oral treatment, immunosuppression, or no safe route to follow up. Women with a self limiting viral illness, a normal examination, normal observations and reliable follow up may be managed at home with review within 24 to 48 hours.

Discharge and follow up. Discharge when afebrile for 24 to 48 hours, observations are stable, oral treatment is possible and the foetal state is reassuring. Complete the antibiotic course. Arrange antenatal review within 1 week. Arrange growth scans 2 to 4 weeks after significant infection (malaria, cytomegalovirus, toxoplasma, listeria, varicella).

Safety netting. Return at once for temperature of 38.0°C or more that returns, shivering, confusion, fast breathing, severe headache or neck stiffness, rash, reduced foetal movements, contractions, leaking fluid, bleeding, severe abdominal or loin pain, or inability to keep fluids down.