Q fever in pregnancy

INTRODUCTION — 

Q fever during pregnancy presents serious risks to the pregnant patient and developing fetus, beyond the risks of infection in nonpregnant individuals. Treatment is also different in both antibiotic selection and duration.

This topic discusses the clinical manifestations (including fetal complications), diagnosis, treatment, and prevention of Q fever infection in pregnant patients.

Acute Q fever and chronic Q fever in nonpregnant patients are discussed separately, as is the epidemiology of Q fever. (See "Acute Q fever in nonpregnant patients" and "Chronic Q fever, including endocarditis" and "Q fever: Epidemiology, microbiology, and diagnostic tests".)

EPIDEMIOLOGY — 

It is difficult to estimate the incidence of Q fever during pregnancy because 90 percent of infections during pregnancy are thought to be asymptomatic [1,2].

The reported incidence of acute Q fever (symptomatic or asymptomatic) in most cohort studies of pregnant patients in endemic or epidemic settings ranges from 1 to 12 percent [1,3-5]. These studies were performed during outbreaks in three different European countries (France, the Netherlands, and Germany).

Seroprevalence surveys documenting past exposure have been performed in multiple regions, either in endemic regions or in relation to outbreaks. A wide range of prevalence rates has been reported, from as low as 0.15 percent to as high as 30 percent [2]. Overall, prevalence of infection appears to be in accordance with prevalence in nonpregnant individuals [6]. Drawing conclusions about the incidence of Q fever from seroprevalence data is complex, mainly due to different seasonal and annual patterns in epidemic and endemic settings.

Based on a review of epidemiologic studies, it has been suggested that a seroprevalence rate greater than 13 percent is an indicator for a high incidence setting for Q fever during pregnancy [2].

RISK FACTORS — 

Risk factors for acquisition of Q fever during pregnancy are the same as those for patients who are not pregnant. (See "Q fever: Epidemiology, microbiology, and diagnostic tests", section on 'Risk factors'.)

There is no evidence that pregnancy increases the risk of acquiring infection; however, pregnancy is associated with higher risk of adverse outcomes from infection, including pregnancy-related complications. (See 'Pregnancy complications' below.)

CLINICAL MANIFESTATIONS — 

Clinical manifestations of Q fever infection during pregnancy are similar to those of Q fever in nonpregnant patients, except pregnant patients are more likely to be asymptomatic and may also present with adverse pregnancy outcomes.

Clinical syndromes — Observational studies suggest that most pregnant patients who acquire infection during pregnancy have no symptoms [1,2].

Among patients with symptoms, a febrile flu-like illness is the most common presentation, but pregnant patients can also develop other clinical syndromes that occur in nonpregnant patients with acute Q fever (eg, pneumonia, hepatitis). (See "Acute Q fever in nonpregnant patients", section on 'Clinical syndromes'.)

Chronic Q fever is rare in pregnant patients [1,7].

Some patients may present for the first time with a serious pregnancy complication, as described below. (See 'Pregnancy complications' below.)

Pregnancy complications

Adverse fetal outcomes — Acute Q fever (symptomatic or asymptomatic) can cause adverse fetal outcomes, including abortion, intrauterine fetal demise, intrauterine growth restriction, premature birth, and low birth weight [2,8-11].

In endemic areas, acute Q fever has been found to be a significant cause of these adverse outcomes. For example, a study from the endemic country of Israel found evidence of acute Q fever in 12 of 386 pregnant patients (3 percent) with preterm delivery [8]. In a study of 179 pregnant patients in endemic Reunion Island, 10 of 179 patients (6 percent) with stillbirth or miscarriage had evidence of acute Q fever [9].

The risk of adverse outcome is the highest when acute Q fever is acquired during the first trimester and when untreated or inappropriate treatment is given [11]. In the largest cohort study of pregnant patients with Q fever (n = 53), obstetric complications occurred in 30 of 37 patients (81 percent) who received no treatment or inappropriate treatment; 15 (40 percent) had fetal death [11].

Congenital malformation in association with Q fever has been described in a few case reports, but the causality is not entirely clear. In a meta-analysis of 136 cases of Q fever in pregnancy derived from case reports and case series, congenital malformations were reported in seven cases (5 percent) [12]. These malformations included hypospadias, Potter syndrome with bilateral renal agenesis, congenital hydronephrosis, syndactyly, omphalocele, and adrenal hypoplasia. According to this meta-analysis, the cumulative incidence ratio of fetal malformations in patients with Q fever compared with the general population was 16.1 (95% CI 6.1-42.7). Selection and publication biases may have influenced these rates, and microbiologic evidence of fetal infection with Q fever was presented in only one case.

The risk for parent-to-child transmission of the infection to live neonates is questionable but theoretically possible, particularly if the pregnant patient acquires the infection near delivery and does not receive treatment. Neonatal Q fever has been mentioned in abstracts of non-English publications [13,14].

The pathogenesis of adverse fetal outcomes appears to be due to transmission of the bacterium to the placenta and deceased fetuses, including dissemination to multiple fetal organs [7,11,12,15]. Placentitis and placental insufficiency has also been documented. The ability of Coxiella burnetii to hide within phagolysosomes inside trophoblasts appears to provide a protected niche for bacterial replication, as was demonstrated in an ex vivo model [16]. Different C. burnetii strains may exhibit varying interactions with trophoblasts, and the host immune response appears to play a crucial role in the final outcome [17].

Adverse parental outcomes — Two types of adverse parental outcomes have been observed: an increased risk for the pregnant parent of progression to chronic Q fever and a possible risk of reactivation of infection during subsequent pregnancies [2,10].

●Risk of progression to chronic Q fever – Pregnancy has been found to be a risk factor for progression from acute to chronic Q fever in case-control studies [18,19].

In a French cohort study of 53 pregnant patients with Q fever, 28 (53 percent) developed a chronic Q fever serologic profile, three of whom developed endocarditis [11]. More recent studies have observed serologic profiles consistent with chronic infection (phase I immunoglobulin G >800), but the patients did not develop other nonserologic manifestations of chronic Q fever and so did not meet the definition of chronic Q fever [20-22]. (See "Chronic Q fever, including endocarditis", section on 'Diagnostic criteria for chronic Q fever'.)

An accurate estimation of the overall risk of progression necessitates larger scale studies.

●Risk of reactivation during subsequent pregnancies – Data regarding the risk of reactivation in future pregnancies are scarce. There is uncertainty whether and how frequently reactivation truly occurs.

In one French series, 6 of 19 patients (32 percent) with a prior pregnancy complicated by Q fever required treatment during a subsequent pregnancy, presumably due to increased serologic titers; all had favorable pregnancy outcomes [11]. In another cohort from France, none of eight patients who had subsequent pregnancies (and were treated for infection in the former pregnancy) experienced Q fever reactivation [20].

DIAGNOSIS

When to suspect Q fever — As with nonpregnant patients, Q fever should be suspected in patients with compatible clinical findings and a potential exposure. Exposures may include proximity to livestock or to an endemic region or local outbreak. (See "Acute Q fever in nonpregnant patients", section on 'When to suspect acute Q fever' and "Q fever: Epidemiology, microbiology, and diagnostic tests", section on 'Risk factors'.)

Having a high index of suspicion for Q fever is important for pregnant patients, especially in endemic or outbreak settings, given the impact of the diagnosis on parent and fetus.

In hyperendemic or epidemic settings, some clinicians recommend screening asymptomatic pregnant individuals for evidence of active infection, as discussed below. (See 'Role of serologic screening' below.)

Confirming the diagnosis — Similar to other cases of acute Q fever, the diagnosis in pregnancy is primarily based on serology and, when available, C. burnetii polymerase chain reaction (PCR) in serum.

Confirming the diagnosis is especially important in pregnant patients because of the implications of this diagnosis on the parent and fetus. The two most reliable methods to differentiate between recent or acute Q fever and past infection are either a PCR test or acute and convalescent titers to demonstrate seroconversion. PCR has a narrower window of detection but is especially useful early in illness, prior to the development of positive antibodies [23].

A diagnosis of probable acute Q fever can be made based on a single serology test, especially if the result can be compared with titers drawn in the past. However, if no prior tests are available, convalescent titers can confirm the diagnosis.

More detailed discussions of the diagnosis of acute Q fever are found separately. (See "Acute Q fever in nonpregnant patients", section on 'Diagnosis' and "Q fever: Epidemiology, microbiology, and diagnostic tests", section on 'Diagnostic tests'.)

Chronic Q fever is rare during pregnancy, and diagnosis is discussed separately. (See "Chronic Q fever, including endocarditis", section on 'Diagnosis'.)

Screening echocardiography — We perform a screening echocardiogram in every pregnant patient with Q fever. Underlying valvular disease is another risk factor for progression to chronic Q fever, and a baseline echocardiogram allows comparison should future echocardiography be indicated. (See "Acute Q fever in nonpregnant patients", section on 'Role of pretreatment echocardiography'.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of acute Q fever is similar in pregnant and nonpregnant patients. (See "Acute Q fever in nonpregnant patients", section on 'Differential diagnosis'.)

In pregnant patients, specific complications of pregnancy should also be considered based on the clinical syndrome. (See "Approach to the pregnant patient with a respiratory infection" and "Approach to evaluating pregnant patients with elevated liver biochemical and function tests" and "Urinary tract infections and asymptomatic bacteriuria in pregnancy" and "Clinical chorioamnionitis".)

TREATMENT

Acute Q fever — Once acute Q fever is strongly suspected during pregnancy, treatment should be immediately initiated while awaiting laboratory results.

Antibiotic regimens — Treatment of Q fever in pregnant patients differs from nonpregnant patients by both agent and duration of therapy.

Preferred regimen — Our preferred regimen is trimethoprim-sulfamethoxazole (one double-strength tablet twice daily) for the first 32 weeks of pregnancy, followed by azithromycin (500 mg orally once daily) for the final eight weeks of pregnancy. Treatment is for the entire duration of pregnancy, if possible. (See 'Duration of therapy' below.)

During the first trimester, we administer high-dose folic acid supplementation (1 mg orally once daily); during the final two trimesters, standard folic acid supplementation (at least 0.4 mg orally once daily) is appropriate.

Folic acid supplement is added to trimethoprim-sulfamethoxazole to reduce the risk of neural tube defects and other congenital malformations, which occur during the first trimester. The increased risk of such defects seems to be very low and is based on low-quality evidence [24]. It is recommended to avoid trimethoprim-sulfamethoxazole in the last month of pregnancy due to concerns about fetal kernicterus, so we switch to azithromycin during this period. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Pregnancy and breastfeeding' and "Azithromycin and clarithromycin", section on 'Pregnancy'.)

Alternative regimen — Azithromycin (500 mg orally once daily) for the entire duration of pregnancy is an alternative for patients unable to take trimethoprim-sulfamethoxazole.

Azithromycin may have higher minimum inhibitory concentrations against C. burnetii than other antibiotics, so its efficacy has been questioned [25]. Additional concerns have been raised about its safety during the first trimester, but at least one study found that macrolides, including azithromycin, were not associated with an increased risk of congenital anomalies [26].

Doxycycline, the drug of choice for nonpregnant patients, is avoided during pregnancy (if other options are available) due to concerns about its ability to accumulate in developing teeth and bones and to cause liver toxicity. Permanent discoloration of teeth has been documented with tetracyclines, especially with prolonged therapy, but data specific to doxycycline are scarce [10,27,28].

Duration of therapy — The optimal duration of therapy during pregnancy is not well defined, and experts recommend treatment for the entire duration of pregnancy [10,11]. In patients who cannot take therapy for the entire pregnancy, a minimum treatment duration of at least five weeks should be encouraged. It is crucial to discuss the risks and benefits of treatment with pregnant patients to allow informed decision making.

The evidence for the protective effect of treatment for Q fever in pregnancy is primarily based on the experience of a single referral center [11,20,29]. The largest study evaluated 53 patients who had Q fever during pregnancy [11]. Seven of 16 patients (44 percent) who received appropriate treatment, defined as at least five weeks of trimethoprim-sulfamethoxazole, had obstetric complications compared with 30 of 37 (81 percent) of inappropriately treated patients. Treatment was associated with a lower rate of patient progression to serologically diagnosed chronic Q fever; a patient serologic profile of chronic Q fever was observed in 25 untreated patients (68 percent) compared with 3 treated patients (19 percent).

It is important to note that the rates of complications without treatment may have been overestimated in these studies. For example, in 16 of the 37 untreated patients (43 percent), the diagnosis of Q fever was made after the occurrence of obstetric complication. Despite the inherent biases in such observational studies, valuable insights can be gleaned about the interactions between Q fever, pregnancy, and treatment.

Chronic Q fever — Data regarding treatment of chronic Q fever during pregnancy are scarce due to the rarity of this condition. Suggested regimens are discussed separately. (See "Chronic Q fever, including endocarditis", section on 'Children and pregnant patients'.)

The challenge of treating chronic Q fever during pregnancy is heightened due to the limited options of effective drugs that can be safely given during pregnancy [30]. Additionally, the frequent need for surgical interventions in cases of Q fever endocarditis or vascular infection further complicates the management of these patients.

Pregnant patients with chronic Q fever should be referred to experts experienced in its management, preferably as part of a multidisciplinary team that includes an infectious diseases specialist, gynecologist, clinical pharmacologist, and other specialists as needed based on the site of infection (eg, cardiologist, heart surgeon, and vascular surgeon).

Monitoring and follow-up — The increased risk of progression to chronic Q fever necessitates close follow-up for any patient diagnosed with acute Q fever during pregnancy.

We clinically evaluate and perform follow-up serology every one to three months during pregnancy; then three months, six months, and nine months after pregnancy; and then every 6 to 12 months until five years from the initial diagnosis have passed. We follow this same protocol for patients with a history of acute Q fever who become pregnant in the future.

Although the risk for neonatal infection is questionable, neonates born to parents who had Q fever during pregnancy should be thoroughly evaluated for abnormal heart sounds, hepatosplenomegaly, and abnormal cell counts or liver enzymes. If any clinical suspicion of transmission exists, serologic testing and serum PCR should be performed on the infant. Consultation with a pediatric expert is suggested. (See 'Adverse fetal outcomes' above.)

PREVENTION

Environmental exposures — Raising awareness and educating pregnant patients about exposure to livestock and the related risks is important. Visiting farms, particularly in areas known to be affected by Q fever, should be avoided during pregnancy [31].

Appropriate precaution measures should be implemented for any planned at-risk exposure. Special attention should be given for educating individuals at risk of occupational exposure, such as veterinarians and farmers [32].

If a known high-risk exposure occurs (for example, if a pregnant person has close contact during livestock parturition), we suggest clinical and serologic screening as soon as possible and at least four weeks later to exclude acquisition of infection.

Role of serologic screening — The frequent absence of symptoms in acute Q fever during pregnancy, combined with the potential for fetal complications, has led to the consideration of a screening approach in high-risk settings. Such an approach would allow for early detection and treatment to reduce adverse outcomes.

Active surveillance of asymptomatic pregnant patients in an outbreak setting has been suggested in guidelines. The European Centre for Disease Prevention and Control (ECDC) recommends serology testing twice during pregnancy for patients living within a 5 km radius of an outbreak source [31].

A cluster randomized trial was performed during the Dutch outbreak to assess the value of serologic screening [5]. In the trial, 1229 pregnant patients from 55 midwife centers were randomized to have Q fever serologic testing between 20 and 32 weeks of gestation. Five hundred and thirty-six patients were randomized to having the samples analyzed immediately and receiving treatment if serology was consistent with infection; the remaining 693 patients' serologic tests were frozen and analyzed after delivery. No difference in the rate of obstetric complications was detected (odds ratio 1.54, 95% CI 0.60-3.96); the rate of seropositivity was 15 percent in each group. One limitation of this study was that it targeted patients in the late stages of pregnancy, potentially missing diagnoses of Q fever before week 20, which is the period with the highest risk for adverse pregnancy outcome.

Cost-effectiveness studies for screening are lacking. One uncontrolled study suggested the number needed to screen for discovery of one case of Q fever during pregnancy in an outbreak region was 31 [1].

Currently, experts debate the value of screening for pregnant patients [33]. While awaiting more controlled studies, we encourage a screening approach in particularly high-risk settings.

Future pregnancies — Patients who are diagnosed with Q fever during pregnancy should be advised to notify their clinician if they become pregnant in the future. Close monitoring for reactivation of infection is often advised, as described above. (See 'Monitoring and follow-up' above.)

There is no defined time interval to wait for becoming pregnant after acute Q fever. The United States Centers for Disease Control and Prevention (CDC) recommends a one-month interval after recovery from acute Q fever before attempting to conceive [10].

Vaccination — Q fever vaccine is primarily available in Australia, where it is used for the immunization of individuals with high-risk occupational exposure. Its safety during pregnancy has not been studied, and it is not routinely recommended for pregnant patients [34]. (See "Acute Q fever in nonpregnant patients", section on 'Prevention'.)

Infection control measures — Transmission of C. burnetii during delivery is very rare. The CDC recommends additional precautions beyond standard precautions for aerosol-generating procedures. Since the course of delivery is not always predictable and may involve splashing of infected materials, we suggest face mask and eye protection or face shield during delivery [10]. Appropriate handling of soiled laundry should be practiced [10].

Occupational Q fever infection in an obstetrician has been reported [15], and a seroprevalence study performed in obstetric workers in 1977 found increased risk [35]. However, in a 2020 study in Thuringia, Germany (an endemic region), obstetricians were found to have no increased risk [36].

Vaginal bleeding in a pregnant patient with Q fever has been reported as a source of nosocomial infection in a case report [37]. Pregnant patients with Q fever who experience vaginal bleeding should be hospitalized in a single room if possible or use a separate toilet.

For workers with known or potential exposures, the CDC recommends against routine post-exposure prophylaxis; instead, any acute febrile illness occurring within six weeks of exposure warrants medical evaluation and immediate treatment [10].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Q fever".)

SUMMARY AND RECOMMENDATIONS

●Risk factors – Risk factors for the acquisition of Q fever during pregnancy are the same as those for patients who are not pregnant. (See 'Risk factors' above.)

●Clinical syndromes – Among patients with symptoms, a febrile flu-like illness is the most common presentation, but pregnant patients can also develop other clinical syndromes that occur in nonpregnant patients with acute Q fever (eg, pneumonia, hepatitis) (see "Acute Q fever in nonpregnant patients", section on 'Clinical syndromes'). Chronic Q fever is rare during pregnancy.

●Pregnancy complications – Some patients may present during pregnancy with only a serious pregnancy complication. (See 'Pregnancy complications' above.)

•Adverse fetal outcomes – Acute Q fever (symptomatic or asymptomatic) can cause adverse fetal outcomes, including abortion, intrauterine fetal demise, intrauterine growth restriction, premature birth, and low birth weight.

The risk is highest if acute Q fever is acquired during the first trimester and if untreated or inappropriate treatment is given. (See 'Adverse fetal outcomes' above.)

•Adverse parental outcomes – Two types of adverse parental outcomes have been observed: an increased risk for the pregnant parent of progression to chronic Q fever and a possible risk of reactivation of infection during subsequent pregnancies. (See 'Adverse parental outcomes' above.)

●Diagnosis – Because of the impact of infection on the patient and fetus, having a high index of suspicion for Q fever is important, especially in endemic or outbreak settings. (See 'When to suspect Q fever' above.)

Like acute Q fever in nonpregnant patients, the diagnosis in pregnancy is primarily based on serology and, when available, C. burnetii polymerase chain reaction (PCR). (See 'Confirming the diagnosis' above.)

●Treatment – Once acute Q fever is strongly suspected during pregnancy, treatment should be immediately initiated while awaiting laboratory results. Treatment of Q fever in pregnant patients differs from nonpregnant patients. (See 'Treatment' above.)

•Acute Q fever

-Preferred regimen – We suggest trimethoprim-sulfamethoxazole (one double-strength tablet twice daily) for the first 32 weeks of pregnancy, followed by azithromycin (500 mg orally once daily) for the final eight weeks of pregnancy (Grade 2C). Treatment is for the entire duration of pregnancy. (See 'Duration of therapy' above.)

During the first trimester, we administer high-dose folic acid supplementation (1 mg orally once daily); during the final two trimesters, standard folic acid supplementation (at least 0.4 mg orally once daily) is appropriate. (See 'Preferred regimen' above.)

-Alternative regimen – Azithromycin (500 mg orally once daily) for the entire duration of pregnancy is an alternative for patients unable to take trimethoprim-sulfamethoxazole.

Doxycycline (the drug of choice for nonpregnant patients) is avoided during pregnancy due to concerns about its accumulation in developing teeth and bones and liver toxicity in pregnant patients. (See 'Alternative regimen' above.)

-Duration of therapy – The optimal duration of therapy during pregnancy is not well defined, and experts recommend treatment for the entire duration of pregnancy. In patients who cannot take therapy for the entire pregnancy, a minimum treatment duration of at least five weeks is encouraged. (See 'Duration of therapy' above.)

•Chronic Q fever – Data regarding treatment of chronic Q fever during pregnancy are scarce due to the rarity of this condition. Pregnant patients with chronic Q fever should be referred to experts experienced in its management. Suggested regimens are discussed separately. (See "Chronic Q fever, including endocarditis", section on 'Children and pregnant patients'.)

●Monitoring and follow-up – We clinically evaluate and perform follow-up serology every one to three months during pregnancy; then three months, six months, and nine months after pregnancy; and then every 6 to 12 months until five years from the initial diagnosis have passed. We follow this same protocol for patients with a history of acute Q fever who becomes pregnant in the future. (See 'Monitoring and follow-up' above.)

●Prevention

•Environmental exposures – Raising awareness and educating pregnant patients about exposure to livestock and the related risks is important. (See 'Environmental exposures' above.)

•Role of serologic screening – The frequent absence of symptoms in acute Q fever during pregnancy, combined with the potential for fetal complications, has led some experts to screen pregnant patients in high-risk settings to allow early detection and treatment. European guidelines recommend testing twice during pregnancy for patients living within a 5 km radius of an outbreak source. (See 'Role of serologic screening' above.)

•Future pregnancies – Patients who are diagnosed with Q fever during pregnancy should be advised to notify their clinician if they become pregnant in the future. Close monitoring for reactivation of infection is often advised. (See 'Future pregnancies' above and 'Monitoring and follow-up' above.)

•Infection control – We suggest face masks and eye protection or face shields, in addition to usual precautions, for obstetric staff during delivery. Transmission of C. burnetii during delivery is very rare but has been reported.

Pregnant patients with Q fever who experience vaginal bleeding should be hospitalized in a single room if possible or use a separate toilet. (See 'Infection control measures' above.)