The number of pregnancies in women with pre-existing medical conditions has increased over the last decades (1–3). A Danish registry study of more than 1.3 million births found an increase in the prevalence of maternal chronic conditions over a period of 25 years from 3.7% in 1989 to 15.7% in 2013 (1).

Three main factors contributing to this ongoing trend can be identified. First, the shift to delay childbearing resulting in advanced maternal age is associated with a higher prevalence of chronic conditions, such as cardiovascular diseases, obesity, or diabetes (4, 5). Second, advances in the treatment of severe childhood conditions result in higher life expectancy of affected women, who enter adulthood and may consider pursuing pregnancy. Improved survival rates of childhood, adolescent, and young adult’s cancers (6) or of newborns with congenital heart disease (7–9) may serve as examples. Lastly, progress in assisted reproductive technologies allows pregnancies in women with reduced fertility due to their advanced maternal age or pre-existing condition (10).

Pregnancies in women with pre-existing conditions represent high-risk pregnancies and bear the risk of high-risk deliveries (11, 12). Maternal complications during pregnancy and childbirth, whether they occur because of the underlying chronic condition, obstetric risk factors, or both, may result in severe maternal morbidity (SMM) (12, 13). SMM is defined as a spectrum of complications during pregnancy, childbirth, and postpartum, which results in significant short-or long-term health issues for women including maternal death (14–16). The reasons for higher rates of adverse pregnancy outcomes in women with pre-existing conditions arise from the interactions of chronic disease and pregnancy itself. These may vary upon the underlying condition: While cardiac or renal conditions tend to deteriorate during pregnancy (17, 18), women affected by rheumatic disease or multiple sclerosis often enjoy a relapse-free time during pregnancy but are at risk of suffering from flares in the postpartum period (19–21). However, SMM not only affects maternal health but may also lead to perinatal morbidity and mortality. The spectrum of perinatal consequences includes prematurity, neonatal intensive care unit (NICU) admission, low birthweight, low APGAR-score, or perinatal death (11, 22, 23). Additionally, women with chronic health conditions may require long-term medication, but inadvertent intake of teratogenic or fetotoxic substances may negatively impact the intrauterine development. However, continuation of disease-specific medication is often indispensable for the women’s health (24).

For the above-mentioned reasons pregnancies and deliveries in women with pre-existing conditions are known to entail higher health care expenditures. Risk-adapted antenatal care may cause additional costs on the one hand, but expenses may be saved because of averted complications of childbirth (25). In Germany, reimbursement of antenatal care performed by hospital outpatient departments is regulated by the German Federal Joint Committee (26). However, costs for the time-and intervention-intensified risk-adapted maternity care in women with pre-existing conditions are likely to exceed this reimbursed sum.

A further aspect related to this topic involves the experience of becoming a mother in the presence of a pre-existing condition. The perception of pursuing pregnancy and becoming a mother has been investigated for specific conditions and in small sample sizes (27–30).

The management of pregnant women with pre-existing conditions requires knowledge of the interactions between chronic condition and pregnancy. The German maternity guidelines provide detailed instructions on the obstetric and fetal surveillance but lack specific instructions for counseling and treatment of women with pre-existing conditions (31). Furthermore, the understanding and management of chronic conditions during pregnancy, childbirth and postpartum period is being taught in the growing field of Obstetric Medicine as a subspeciality of internal medicine in only few countries, such as Canada, Australia and the United States of America (32). In Germany, only few university hospitals hold outpatient consultations for specific diseases in pregnancy but specialized sections covering all medical conditions are not yet established. At the Department of Obstetrics and Prenatal Medicine, University Hospital Bonn, Germany, women with pre-existing conditions are cared for within the frame of a specialized consultation. This includes preconception counseling and care during pregnancy, childbirth, and the puerperium within an interdisciplinary framework.

This study is designed to describe risk-adapted maternity care for women with pre-existing conditions on a medical, economic, and psychological level. By assessing rate of SMM among this special population data will be generated which may serve as a basis for recommendations of the care of women with pre-existing conditions during reproductive choice, pregnancy and postpartum period. Consequently, establishing a framework for the care of affected women is aim of this study. Furthermore, by capturing and analyzing costs and reimbursement of specialized care, data will be generated which may serve as basis for discussion with the relevant bodies. Lastly, the special perceptions and needs of affected women will be elucidated to provide care givers with evidence and to increase awareness for this steadily increasing group of patients.

The objectives of this three-dimensional study include the assessment of:

This study is designed as an observational, prospective, longitudinal single-center cohort study. Recruiting and data collection started in November 2022 and is scheduled to last until January 2024. Observation of participants covers the period from preconception counseling or initial consultation in pregnancy to hospital discharge after birth. Assignment to study and comparative groups is applied during recruiting.

This protocol is structured in accordance with the guidelines of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-Patient-Reported Outcomes (PRO)-Extension (33–35), although it is not considered an interventional trial. This extended version addresses the importance of patient-centered care by implementing recommendations to correctly document PRO in clinical trial protocols. In addition to this specific protocol writing guideline, we also applied aspects of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines as this study is designed as an observational cohort study (36, 37).

Note on language usage: in this work we use the terms “woman/women” to refer to individuals with a uterus and the biological capacity to become pregnant.

Study center is the Department of Obstetrics and Prenatal Medicine, University Hospital Bonn, Germany, which serves as a regional referral center and has a unique standing in Obstetric Medicine. The specialized outpatient department “Obstetric Medicine” cares for an increasing number of women with pre-existing medical conditions, which shapes the obstetric patient population and medical education at the department. It routinely interacts with related medical subspecialities and closely cooperates with the Center for Rare Diseases of the University Hospital Bonn.

All women presenting at the study center receive the same risk-adapted obstetric care during pregnancy and childbirth, irrespective of their participation in the study. While women with pre-existing conditions may require more frequent follow-up, interdisciplinary management, case conferences, and additional diagnostic investigations compared to healthy women with obstetric complications, healthy, “low-risk” women register for birth via a midwife appointment. This type of risk-adapted care is the standard of care at the study center and therefore is not considered a classical study intervention.

Women in all stages of pregnancy and women seeking preconception counseling who present at the study center can be included in this study if they meet the inclusion criteria and provide informed written consent. All participating women must be capable to fully understand the study requirements and intentions. The study group (S) is compared to two additional groups (K1 and K2). The inclusion criteria vary as follows.

Recruitment started on November 1, 2022 and is scheduled for a period of 15 months. All women presenting at the study center as outpatients or are admitted or referred for inpatient care are screened for eligibility by trained members of the study team. For S and K1 cases, a specialist in obstetrics with expertise in Obstetric Medicine confirms diagnosis and obstetric findings before recruitment. For K2, a midwife performs recruitment after assessment during booking. Additionally, all inpatient admissions are screened on an everyday basis for eligibility. S and K1 also include pregnant women who are admitted to the inpatient department or transferred from other hospitals due to maternal or obstetric complications, and who have not previously presented to the study center for co-care. In selected cases where maternal complications of the pre-existing condition require immediate delivery, postpartum recruitment is possible (e.g., admission with status epilepticus and suspected placental abruption). If a woman is eligible for enrollment, she is provided a printed study information, personal explanation of the study content by a member of the study team and gives informed written consent.

Assignment to the groups and stratification is applied during recruitment by the enrolling investigator in a ratio of 2:2:1 (S:K1:K2). This ratio arises from the expected homogeneity of K2, a resource-efficient project planning and the already well-investigated population represented by K2 in existing literature. If uncertainties regarding assignment to the correct group arise, consensus meetings are held to resolve the issue. In Figure 1, we provide an overview of the recruitment and assignment process.

Additionally, we stratified the recruited women as follows:

The rationale for stratification is the difference in the risk profiles of nulliparous vs. parous women and singleton vs. twin pregnancies. The same applies for women requiring inpatient care vs. outpatient consultation.

For every pregnant woman recruited in S, the subsequent pregnant woman who presents at the study center and meets the inclusion criteria for K1 and K2 is invited to participate. To ensure a complete and continuous stratification process analogous lists are compiled, which are only accessible to the members of the research team and are carefully handled in accordance with data protection regulations.

An overview of the participant timeline is visualized in Figure 2. Observation in S can start with preconception counseling or at any stage of pregnancy. Observation in K1 normally starts with the registration for birth but may also occur at an earlier stage of pregnancy due to obstetric complications. Observation in K2 starts with recruitment at booking. For all study participants, observation ends with discharge after delivery. Women recruited at preconception counseling who do not become pregnant during the recruitment period are excluded from analysis and studied separately.

The three-dimensional design of the ForMaT-Trial indicates three different outcome measures as follows:

Further items were established in a multistep process. An initial collection of main topics was developed via literature research, discussed in a consensus meeting with the team of the Center for Rare Diseases of the University Hospital Bonn, and transferred into a catalog of questions by the interprofessional study team. As an important next PRO-measure step, the catalog of questions was sent to 15 national umbrella organizations of patient advocacy groups, such as adults with congenital heart disease, inflammatory bowel disease, or familial adenomatous polyposis. The feedback and comments of affected persons were included in the catalog and an expert in statistics ultimately proofread the questionnaires. Thereafter, a pre-test was performed by at least two affected women, midwifes, medical students, and physicians.

Sample size estimation was based on the primary medical outcome SMM. For the estimation, both additional groups (K1, K2) were pooled which results in a matching ratio of 2 women (S) vs. 3 women (K1 + K2). Following the multiply matched study design, a score test established on a conditional logistic regression model was used (41). The test assesses the effect of a binary variable (= with/without pre-existing medical condition) on the outcome with a variable number of cases and controls in a matched set. Assuming a SMM rate of 50 per 1,000 women in S and a SMM rate of 23/1000 in K1 + K2 257 matched sets of size 5 (2:3) are required to provide 90% power at a significance level of 5%. Considering a drop-out rate of about 15%, 1,500 women in 300 matched sets of size 5 have to be recruited.

Trial data consist of three categories: medical outcome data, economic data, and questionnaires. Medical outcome is collected via database query of the hospital information system ORBIS (Dedalus Healthcare, Bonn, Germany), the ultrasound software ViewPoint™ (Version 6, GE HealthCare, Solingen, Germany), and the pediatric software Neodat (Version 5, Paedsoft, Tuebingen, Germany). Economic data are collected via database query of the information system SAP (SAP R/3 ECC 6.0, IS-H Release 617 Package, Walldorf, Germany). All questionnaires are completed online with the assistance of a study team member. Data management and monitoring is performed by the Clinical Support Study Center of the University Hospital Bonn, Bonn, Germany. All relevant trial data are entered in a specifically build REDCap© database (Version 12.0.27, Nashville, Tennessee, United States).

All medical parameters will be summarized using descriptive statistics. The primary medical outcome will be analyzed with a conditional logistic regression model to assess the effects of pre-existing medical conditions on the SMM rate. Odds ratios obtained from this model with corresponding 95% confidence intervals will be reported. Further secondary medical maternal and perinatal parameters will be compared between the study and additional groups. Additional analyses of medical parameters will be considered in subgroups given by different pre-existing conditions in the study group and are exploratory in nature. The main analysis will be performed on complete cases and the significance level will be set to 0.05. A sensitivity analysis will include the use of multiple imputation strategies to address possible missing observations.

For analysis of costs, a health economic evaluation to determine the costs associated with the interventions and services in the different groups will be conducted. This includes, for example, consultation time, laboratory tests, medical procedures, hospitalization, or medication. The resource use of implemented care of all the three groups will be captured, both for inpatient and outpatient setting. Thereafter, this resource use will be multiplied times unit prices to derive respective costs from a provider (in-and outpatient healthcare provider) and healthcare system perspective (statutory health insurance).

The items of the questionnaires will be summarized descriptively at each time point. Health-related quality of life will be analyzed as pre-specified in the manual of the EQ-5D-5L™ tariff and compared over time (42). The birth experience assessed by the German version of the BSS-R will be reported via the total score and the three subscales (stress during labor, personal attributes, and quality of care provision) (39).