Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial.

Q fever in the Netherlands is becoming more common. A Q fever infection is a
serious threat to certain risk groups, including pregnant women. Pregnant women
are more often than the general population asymptomatic. Studies from France
show that an infection with Coxiella burnetii may cause obstetric complications
including spontaneous abortion, intrauterine fetal death, intrauterine growth
retardation and oligohydramnios. The aim of this study is to assess the
effectiveness and cost effectiveness of a multidisciplinary screening program,
whereby pregnant women in first line healthcare in high-risk areas for Q-fever
are screened with a single bloodsample during pregnancy. If found positive for
Q fever, advise for antibiotic treatment will follow as part of regular
healthcare. Threatment is therefor not part of the studyprotocol. The results
of this study will give more insights in the risks of asymptomatic Q fever in
pregnancy and the benefits and harms of a screening strategy during pregnancy.
This study will be used to give an evidence based advice to the Dutch minister
of health on screening for Q fever in pregnancy.

To assess the effects of a screening policy for Q fever in pregnant women from
areas with large numbers of Q fever cases on the pregnancy outcome and
cost-effectiveness from a societal and health care perspective.

We will conduct a clustered randomized controlled trial among pregnant women
within an area of high transmission. The study participants will be recruited
by the midwives in high risk areas, defined by postal code from the RIVM. To
inform the public in this area about the study we will publish an article in
local newspapers. The midwife centers will be randomized to recruit pregnant
women for either the control group or the intervention group. The pregnant
women will receive study information by mail using the midwives patients file.
It is estimated that approximately 10,000 eligible women live in the areas of
transmission. After written informed consent, they will start with the strategy
for which the midwife center is randomized.

Participants will be asked for a blood sample in their second trimester of
pregnancy, possibly combined with the routine structural ultrasound around 20
weeks of pregnancy to minimize hospital visit. If participants are enrolled in
their third trimester, they will have their blood sampling as soon as possible
after inclusion.

When taking part in the intervention group the sample will be tested
immediately for Q fever. If found positive for acute or chronic Q fever,
patients have to be referred, according to local protocol, to a hospital for
further pregnancy monitoring and long-term bacteriostatic treatment. Follow-up
blood samples are required at 14 days, 3, 6 and 12 months after the first blood
sampling as part of the standardized control of Q fever disease to diagnose
possible chronicity of infection. Furthermore, current routine for pregnant
women being treated with antibiotics against Q fever is to perform monthly
blood analyses to monitore treatment, and if the serological parameters
descend, these controls are brought back to once every two months. According to
local protocol patients with Q fever have to deliver in hospital. After
pregnancy serology should be continued with check-ups at 3, 6 and 12 months
following the current protocol. Furthermore, after delivery a bacteriocide
treatment with doxycycline or an alternative will be started by the specialist
as part of regular health care.

In the control arm the blood samples will be stored, and analyzed for Q fever
after delivery. If tested positive for Q fever after pregnancy antibiotics
could be started if needed as part of regular health care.

At baseline, a questionnaire will be administered to all participants asking
about the current pregnancy , pregnancy outcome of any previous pregnancies and
demographics. Further risk factors for pregnancy outcome will also be obtained
such as smoking and drinking behavior, risk-elevating comorbities and
medication use.
After delivery all relevant outcome data will be collected by questionnaires
filled out by the midwife, GP or specialist after delivery, notably the
presence of obstetric complications. One month after delivery or end of
pregnancy, a last questionnaire will be administered to the participant to
verify potential long-term consequences of Q fever, potential loss of income,
health-related quality-of-life, fatigue and depressive symptoms. Furthermore
questions will be asked about the condition of the newborn and risk-accessing
questions for Q fever infection will be asked.

In the context of the secondary research questions an extra blood sample will
be required, and placentas as well as amniotic fluid will be collected after
delivery from both the intervention and the control group. The latter will only
take place in a limited number of women and only if they gave birth in a
hospital.

All participants will receive usual care and will be asked to visit the general
practitioner if symptoms of Q fever occur. He/she will start diagnostic
research and treatment or will refer the patient to the hospital. Furthermore,
both arms have access to an expert team for support.

The intervention is screening for Q fever with a single bloodsample during
pregnancy. Treatment of Q fever positive patients is part of standard care of
the specialist, so is not part of the intervention in this study.

There is no risk associated with blood drawing other than the occasional
standard discomfort associated with venapuncture, i.e. hematoma, redness,
swelling, pain or fainting and thus the burden is minimal.
Information of risks and adverse effects of antibiotic treatment will be given
to the pregnant womem by the prescribing physician, since this treatment is
part of standard health care. Antibiotic treatment is not part of this
studyprotocol.

The advantage might be that pregnant women in this area, if recruited by a
midwife center which is randomised for the intervention group, have the
possibility to be screened for Q fever, and if found positive that they can be
treated for it. However, this study will show us if this is a true advantage or
not, especially for asymptomatic women. Also, an expert team will be available
for possible questions for both groups.

The participants need to consent that any information that is observed which
may have clinical relevance will be given to the researcher. This study will
give better insights into the effects of a screening strategy for Q fever on
pregnancy outcome and cost-effectiveness.

The study will primarily provide insights into the balance of risks of
undetected and detected q-fever during pregnancy.