The ChroPreg trial is a two-arm parallel-group investigator-initiated RCT. Participants will be randomized to either a midwife-coordinated, individualized, and specialized maternity care intervention (ChroPreg) as an add-on intervention to standard care or standard care alone with a 1:1 allocation. The trial is designed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines for RCTs (32), extended in the Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide (33), and in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines for reporting trial protocols (34).
The study will take place at the Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. The department is highly specialized and in addition to serving as a birth facility for women living in the local area of the hospital in Copenhagen, it is a tertiary referral center for a large geographical area. In 2017, 5471 women gave birth at the hospital and 700 of these women had one or more chronic diseases. Participants will be recruited among the women attending antenatal care at Rigshospitalet. In Denmark, all women with normal pregnancies receive antenatal care primarily from midwives, whereas pregnant women with chronic disease and complicated pregnancies receive obstetrician-led antenatal care including consultations with midwives.
Inclusion and exclusion criteria
The Danish Health Authorities define chronic disease as a prolonged disease or a disease that continuously recurs (35). Eligible participants will be: pregnant women with one or more chronic diseases diagnosed before pregnancy and for which the pregnant woman is followed by an obstetrician during pregnancy, ≥18 years, able to understand spoken and written Danish, give informed consent, pregnant with a single live fetus, and be between week 12 and 19 of pregnancy at time of inclusion. Potential participants will be excluded from the study for the following reasons: multiple pregnancy, substance abuse, psychiatric disease as the only chronic disease, and pregnant women with diabetes and heart disease (these women already receive specialized care programs at Rigshospitalet).
As a part of the standard antenatal care, women who fulfill the study criteria will be invited to participate in the study by a midwife responsible for the coordination of specialized antenatal care. Eligible participants who verbally consent to receiving more information about the study will be given written information, and subsequently be contacted by telephone by one of the investigators. If the woman is still interested in receiving information about the study, preliminary questions will be answered. Thereafter, the woman is given the choice between a face-to-face meeting at the hospital or receiving additional information by telephone. At the face-to-face meeting or during the telephone conversation, more detailed verbal information about the study will be provided and the potential study candidate will have the opportunity to ask further questions about the study. If the woman decides to participate, informed consent will be obtained, and the baseline questionnaire will be completed. The randomization and allocation to one of the two RCT arms will be carried out by one of the investigators. The choice between mode of receiving information either by telephone or face-to-face is provided to accommodate women who do not live near the hospital or have other reasons to prefer receiving information by telephone. A Danish RCT study tested the effect of face-to-face versus telephone information when including study participants and found no differences in level of comprehension between the two groups (36).
Randomization and blinding
After verbal and written informed consent is obtained the participants are randomized by one of the investigators to either the ChroPreg intervention plus standard care or standard care alone in a ratio of 1:1. The allocation sequence is computer-generated with a varying block size concealed to the researchers. The allocation will be centrally conducted using the online clinical trial management and randomization system EasyTrial (easytrial.net, Aalborg, Denmark). After allocation the participants will be informed about the allocation and further plan of the trial.
The specialized midwives who will deliver the intervention will not be blinded to the allocation and neither will the participants. However, the research staff who will collect data from medical records and questionnaires will be blinded to treatment allocation, as will the chief investigator (HKH) and the trial statistician (SR).
Sample size calculation
A total of 274 women will be enrolled in the study. The sample size was determined using unpublished data on 426 pregnant women with chronic diseases hospitalized at Rigshospitalet during pregnancy and in the post-partum period in 2017. The average length of hospital stay (LOS) during pregnancy was 3.9 days; however, due to a right-skewed distribution, log-transformed LOS was used as the outcome for the sample size calculation. Therefore, the effect of the intervention is expressed as a ratio. We expect a reduction of 25% in LOS in the intervention group compared to the control group, corresponding to an improvement of log (1–0.25) = -0.29 on log scale. The SD of number of days in hospital on log scale was 0.80. With a difference of 0.29, SD = 0.80, a power of 0.8 and a significance level of 0.05, an analysis by the two-sample t-test requires 123 women in each group. We expect 10% to be lost to follow-up, leading to a total of 137 women needing to be enrolled in each group.
Standard care alone
Participants allocated to the control group will receive standard care alone. Pregnant women with chronic disease are considered to have high-risk pregnancies and are referred to the appropriate level of specialized maternity care. All pregnant women with chronic disease will be followed by an obstetrician and an individual care plan is designed considering the character and severity of the disease and the pregnancy associated risks. Routinely in Denmark, all pregnant women including pregnant women with chronic diseases are also followed by midwives during pregnancy. The standard care appointments for midwife consultation are timed approximately around weeks:14–18, 28, 35, 38, and 40 and include physical examinations, discussion about lifestyle, symptoms of normal and complicated pregnancy, breastfeeding and preparation for delivery. At Rigshospitalet, all pregnant women are offered two auditorium prenatal classes delivered by a midwife. After childbirth, women can contact the department and request a conversation about the delivery with a midwife, and women who have experienced severe or unexpected complications may be offered a postnatal consultation with an obstetrician.
The ChropPreg intervention plus standard care
The ChroPreg intervention is designed based on a review of the literature on complex interventions in maternity care (18-20) and aimed to fit the needs of women with chronic disease. Complex interventions (37) consist of a number of components that may work independently and interdependently, and it can be difficult to identify the “active ingredient” of the intervention, rendering it even more important to describe the different components, the hypothesized mechanism behind each component, and the interaction between the components (37). The three main components of the ChroPreg intervention are described in more detail below.
The ChroPreg intervention is provided by specialized midwives (SM). In addition to the standard care outlined above, women in the intervention group will receive additional antenatal consultations, postpartum follow-up and care coordination. Both standard care midwife consultations and the extra consultations will be provided by the same SM (content described below and Table 1).
1. Midwife-coordinated and individualized care
The participant will be seen by the same SM throughout pregnancy, and in the postpartum period. During the study period, the SM will identify the special needs and wishes of each woman and will discuss the optimal care of the woman with the obstetrician responsible for her medical care. The SM will be assisting the participants in coordinating antenatal visits to fit their everyday life and to avoid unnecessary hospital visits and in communicating with other care providers, who are part of the standard Danish healthcare system (e.g. general practitioner and health visitor) as well as other health care professionals from other departments at the hospital. The participants can contact the SM by e-mail and during weekly phone hours. If the participant is hospitalized during pregnancy the SM will contact the woman by phone and arrange an appointment. Assisting the participants when in labor is not a part of the intervention.
2. Additional ante and postpartum consultations
In addition to the standard care, two additional antenatal consultations will be scheduled with the SM at 20–24 and 30–33 weeks of pregnancy to discuss psychological well-being in pregnancy, breastfeeding and individualized preparation for childbirth, and postpartum care. The purpose is to support the woman’s own capacity to handle her pregnancy, childbirth and everyday life as a new mother with a chronic disease. If the need arises, the SM can refer the woman to a psychologist at the hospital for additional consultation. After birth, the SM follows up on the psychological well-being during the planned telephone support postpartum, and 4–6 weeks after birth, a consultation is planned with the SM to discuss the woman’s overall experience and issues important to the woman regarding her pregnancy and delivery.
3. Specialized midwives (SM)
The SMs have attended a 3-day training in chronic disease and pregnancy. The training includes basic medical knowledge on lupus erythematosus, rheumatoid arthritis, lung disease, kidney disease, hypertension, multiple sclerosis, epilepsy and other neurological diseases, inflammatory bowel disease, hematological diseases, and thyroid disease. Additional topics in the training program are: pre-pregnancy counseling, pathophysiology, pregnancy complications, obstetric treatment, medication, lactation, and interdisciplinary collaboration. The training also includes psychological aspects of pregnancy complicated by chronic disease. Topics covered in the program are: psychological development during pregnancy, signs and symptoms of depression and anxiety during pregnancy and postpartum, prenatal attachment, and facilitating conversations about the woman’s experience of childbirth. Furthermore, the SMs will receive training in how to best support pregnant women in coping with the everyday challenges of pregnancy and their new role as a mother when living with a chronic disease. A manual for all activities in the intervention will be developed and used as a tool by the SMs.
Table 1. Description of planned midwife-activities in the ChroPreg intervention group and standard
Table 1. should be placed here (located at the end of this document)
Data will be collected from medical records and using electronic self-administered questionnaires. Data will be obtained at baseline (t1) and three times during the study period: at 33–37 weeks of gestation (t3), at two weeks after delivery (t4), and at two months after delivery (t5). The participants will complete the first electronic questionnaire after signing the informed consent to participate and before randomization. The subsequent questionnaires will be sent as a link in an e-mail.
The primary outcome is Length of Hospital Stay (LOS) measured as the number of days (mean and standard deviation (SD)) spent in hospital during pregnancy and until two weeks after delivery. Data will be collected from patient records two weeks after delivery.
- Psychological well-being
a. WHO (Five) Well-Being Index (WHO-5) (38) measures current (e.g. preceding two weeks) psychological well-being and consists of 5 positively phrased items, each scored on a Likert scale (0 = none of the time, 5 = all the time). The raw score ranges from 0, indicating the lowest possible well-being, to 25, indicating the highest possible well-being. This score is multiplied by a factor of 4, creating a score ranging from 0–100 with 100 being the highest possible well-being. WHO-5 has high psychometric validity and it can be used as an outcome measure in clinical trials (38).
b. Edinburgh Postnatal Depression Scale (EPDS) (39) is a self-reported scale consisting of 10 items scored on a 4-point Likert scale (0–3) concerning intensity of depressive mood and symptoms during the last seven days ( 0 indicates absence of depressive mood and/or symptoms and 3 indicates the worst mood and/or symptoms on a given item). The lowest overall score is 0 and the highest overall score is 30. Cut-off scores for likelihood of clinical depression have been suggested to be at ≥10 and ≥13 (39, 40) and therefore we include both cut-offs scores in our statistical analysis to avoid the risk of failed detection of cases. The EPDS has been validated for use as a detection tool for antenatal and postnatal depression (40, 41) and it has been translated and used in Danish research (42)
c. Cambridge Worry Scale (CWS) (43) measures pregnant women’s degree of worry during pregnancy. The questionnaire consists of 16 items concerning different areas of possible worry on a 6-point Likert scale (0 = no worry, 5 = highest degree of worry). The scale ranges from 0 to 60 with 60 indicating the highest possible level of worry. CWS has a high internal validity and reliability and has been utilized in clinical studies including populations of women with high-risk pregnancies (44, 45) .
- Health-Related Quality of life (HRQoL) and self-rated health
SF-12 (46) is an abridged version of the 36-Item Short Form Survey questionnaire developed to measure health-related quality of life and thereby self-rated health in a single item. The instrument is well-validated and reliable and widely used including during pregnancy and in the postpartum period (46, 47) . The SF-12 questionnaire consists of 12 items that measure physical and mental health, divided into eight subscales: physical and social functioning, role limitation due to physical and mental health, bodily pain, general health perceptions (self-rated health), vitality, and mental health. The scores from the subscales can be calculated in two overall scores: Physical Component Summary (PCS) and Mental Component Summary (MCS) with higher scores indicating better health-related quality of life (46).
3. Patient satisfaction
The Pregnancy and Childbirth Questionnaire (PCQ) (48) contains two subscales: 1) pregnancy-related items (18 items) covering two domains, personal treatment and patient education/information, and 2) birth-related items (7 items). The PCQ consists of 25 items rated on a 5-point Likert scale (1 = totally agree, 5 = totally disagree). Higher scores indicate higher patient satisfaction with quality of care. The questionnaire has been rated to have good internal consistency and reliability (49).
4. Health-economic outcomes
a. Antenatal contacts (measured as number of scheduled and unscheduled visits with obstetric doctors and midwives and telephone consultations).
1. Pregnancy and delivery outcomes
Pregnancy and delivery outcomes will be tracked for the purposes of this study. Exploratory outcomes are considered to be hypothesis generating.
Pregnancy complications (gestational diabetes, pregnancy-induced hypertension, preeclampsia) (yes/no); labor onset (spontaneous or induced); preterm delivery (yes/no); mode of delivery (percentage of participants with spontaneous vaginal delivery, or caesarean section (planned or emergency)); use of labor analgesia ( no analgesia/any analgesia, epidural analgesia (yes/no)); outpatient telemonitoring for pregnancy complications (yes/no and duration (days)); newborn’s well-being at time of delivery (Apgar score ≤7 at 5 minutes postpartum (yes/no)) ; newborn’s birth weight (measured in kilograms); breastfeeding (intention to breastfeed (yes/no); breastfeeding two months after delivery (yes/no); and intended duration (months) of breastfeeding).
Analyses are to be performed based on the intention-to-treat principle. Unadjusted and adjusted comparisons of log-transformed number of days in hospital in the two groups will be performed using the general linear model; however, optionally, a generalized linear model (e.g. Poisson or negative binomial) will be used if we find such a model to fit better to the distribution of the number of days in hospital. Furthermore, the two groups will be compared with respect to the proportion of women with three or fewer days in hospital. Comparison of secondary and exploratory outcomes will similarly be performed using the general or generalized linear models as appropriate. In case of an uneven allocation of pregnancies with congenital malformations or chromosomal abnormalities to the two groups, analyses will be performed in the sub group of women without pregnancies with congenital malformations or chromosomal abnormalities. Missing data techniques (e.g. multiple imputation) will be employed if a substantial amount of the data is missing.