Lyme disease in pregnancy

The implications of LD in pregnancy are poorly understood. Pregnancy can increase vulnerability to vector-based infections due to a weakened immune system [25, 26], and infection in pregnancy can pose risks to the fetus [27, 28]. LD is a spirochetal infection, and other spirochetal infections, including syphilis and leptospirosis, are transmitted in utero and can have serious consequences for the fetus and newborn [29, 30]. Data on infection rates among pregnant people are sparse [1] and challenges with diagnosis coupled with poor understanding of LD in pregnancy may limit the detection of LD in people who are pregnant. There is limited evidence regarding vertical transmission of LD and the health outcomes of people with LD in pregnancy and their offspring [1, 31–33], and there are significant knowledge gaps relating to fetal infection and adverse birth outcomes [1]; however, the potential risk of maternal-fetal transmission of LD is publicly acknowledged by the US Centres for Disease Control (CDC), Health Canada, and the National Institutes of Health (NIH) [34–36]. A recent review of 31 studies investigating maternal-fetal transmission of LD found statistically probable transmission in 13 (42%) and possible transmission in 2 (6%) of the studies [37]. Adverse outcomes, including deaths, heart anomalies, and preterm birth, were lower when mothers had been treated with antimicrobials (74% with no antimicrobial treatment, 29% with oral antimicrobials, and 12% with intravenous antimicrobials) [37].

In humans, vertical transmission of Lyme disease to the fetus, neonate and/or placenta has been described in published papers, conference abstracts and medical textbooks. These include 19 cases of congenital infection in which Borrelia burgdorferi (Bb) or Borrelia species was identified in fetal or infant tissue upon autopsy (following miscarriage, stillbirth or neonatal death) utilizing various direct detection methods such as culture, PCR, microscopy and LD specific histological techniques [38–45]. An additional 15 cases of suspected or probable congenital Lyme infection and adverse outcomes have been reported [43, 46–55], including 2 cases in which Bb specific antibody was detected in the cerebral spinal fluid of symptomatic infants [48, 49]. Furthermore, 2 cases of live-birth in which Bb was identified by PCR in cord blood of infants whose mothers were treated [56], and 1 case of live-birth (twins) where one twin had IgG and IgM antibodies to Lyme disease in cord blood have been reported [57]. Bb has also been identified in placentas from both treated [43, 45, 50, 56–61] treatment not specified [62, 63], and untreated pregnancies [43]. One study identified Bb in placentas of 3 asymptomatic pregnancies whose Lyme two-tier serology was borderline (1) or negative (2), highlighting an important question of the possibility of silent maternal-fetal transmission of the spirochete [62].

Transmission via breastfeeding has not been documented [33, 64] However, Bb DNA has been identified by PCR in breastmilk from two lactating mothers who were untreated for Lyme disease in pregnancy [65]. Although transmission via breast milk has not been reported, it cannot be ruled out [66, 67]. There is currently minimal documentation of sexual transmission of LD [68] however data from animal models and human studies suggests that it may be possible, and further research is needed [69, 70].

Reported adverse pregnancy outcomes associated with gestational LD include placental infection, miscarriage, stillbirth, neonatal death, and intrauterine growth restriction. A heterogeneous range of newborn outcomes includes prematurity, respiratory distress, hyperbilirubinemia, hypotonia, sepsis and orthopedic, dermatologic, urologic, cardiac and ophthalmologic anomalies [31, 32, 39–55, 71, 72]. Treatment of LD in pregnancy was shown in one study to reduce the chances of adverse effects to 11% compared to >50% without treatment [1], suggesting that diagnosis and treatment of LD during pregnancy is important. Researchers have emphasized that patients with unrecognized or undiagnosed Lyme disease in pregnancy who are therefore not treated for LD should be those of greatest concern for clinicians [31].

Knowledge gaps regarding LD in pregnancy are due to the lack of robust epidemiological studies and longitudinal follow-up [1, 25]. To prepare for further research on perinatal transmission of LD, and in keeping with the importance of patient engagement in research priority setting acknowledged by national research funding bodies [73–75] we sought to understand the research priorities of people who have experienced LD in pregnancy. Our primary research question was: What are the research priorities of people who have had LD during pregnancy regarding LD in pregnancy? We were also interested in soliciting feedback to help us determine the feasibility of recruiting people with LD in pregnancy to examine the perinatal transmission of LD. Our secondary research question was: What would be the barriers and facilitators to recruiting people with LD in pregnancy to prospective research investigating the perinatal transmission of LD?

Study participants

Inclusion criteria for focus group participants were a) a diagnosis or suspected diagnosis of LD and b) having been pregnant at least once, regardless of pregnancy outcome. We chose to include participants with suspected diagnoses given the documented challenges related to appropriate diagnosis of LD [77, 78].; however, only 9% of survey respondents with LD had a suspected diagnoses versus confirmed diagnosis (91%). There was no geographic restriction on participants’ place of residence. Individuals who participated in the online survey between September 25, 2020 and November 28, 2020 were recruited to participate in the focus groups.

Data collection

Survey participants who met the eligibility criteria and indicated an interest in participating were emailed further study information and a consent form to be completed online prior to participation. Focus groups were scheduled when a minimum of 3 participants could attend, with a target size of 6–8 participants per group. Scheduling continued until all respondents had been scheduled or had been provided three reminders to participate. Focus groups were hosted online via Zoom between October 26, 2020 and December 16, 2020 and were digitally recorded.

The focus groups were facilitated by two trained and experienced researchers (AO, OM) using a semi-structured interview guide. The semi-structured interview guide had two primary questions: 1) What topics or areas of research do you consider priorities regarding LD in pregnancy? and 2) If you were pregnant, would you be willing to participate in a study involving collecting placental tissue, cord blood, or breast milk, and why or why not? Additional sub-questions were used to prompt elaboration on the enabling factors or barriers to facilitate future research. Demographic information was collected from focus group participants through an online survey administered using a secure web-based research platform, REDCap.

Data analysis

The audio recordings of the focus groups were transcribed using Otter.ai, a web-based artificial intelligence transcription application. The transcripts were anonymous but potentially identifying information was not removed. We used interpretive content analysis [79, 80], using the conventional approach to analyze the transcripts of the focus groups [81]. We used an inductive approach to categorize the patterns and themes that we identified in the participants’ responses to the interview questions. This approach produces data-driven themes rather than fitting the data into researchers’ pre-conceptualized categories or theoretical analysis [80–82]. An experienced researcher (OM) analyzed the data, and the themes were then reviewed and refined by the principal investigator (EKD). An additional team member (LG), experienced in qualitative research, analyzed the transcripts, and independently identified themes to ensure rigor. The entire research team reviewed both sets of analyses and came to a consensus on the final themes and findings.

Research priorities

The research priorities shared by participants fell into five broad themes: Transmission, Testing, Treatment, Disease presentation, and Education. These are described below and summarized in Table 2.

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Table 2. Research priorities of people who have experienced Lyme disease and pregnancy.

https://doi.org/10.1371/journal.pone.0294265.t002

Barriers & enablers to research participation

Discussion of barriers and enablers to research participation led to input from participants regarding general interest levels in research on LD in pregnancy and suggestions for recruitment strategies in addition to the identification of barriers and enablers of participation. These four topics are discussed below. The barriers and enablers are also presented in Table 3.

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Table 3. Barriers and enablers to research participation for people with Lyme disease in pregnancy.

https://doi.org/10.1371/journal.pone.0294265.t003

All study participants indicated that if they were eligible, they would participate in future research studies recruiting pregnant individuals with LD. This included the willingness to participate in the collection of biological samples, including the placenta/placental tissue, cord blood, and breast milk. Participants cited two main motivations: altruism and the potential to gain information about their child. Participants’ desire to participate in future research arose from believing that it would be helpful to all to learn more about the disease, particularly because the research would have the potential to help people diagnosed with LD in future. As one participant explained, “I think a lot of us are wanting to not only help ourselves but help others because we live in these shoes every day.” (FG 2) Many participants had suffered or watched loved ones suffer from LD and wanted to help others in similar situations. Secondly, participation in research was seen as a potential opportunity for parents to gain information about their child’s LD status or diagnosis earlier.

Participants identified five factors that would impede their participation in future LD research (see Table 3). Participants were wary about how their data and information would be used and would not participate if their data were to be shared with any third parties. Accessibility and capacity to participate in the study program was another potential barrier, as long distances, lack of transportation, and the fatigue often experienced by those with LD and pregnancy could pose challenges to those wanting to participate. Institutional factors, like the cooperation of healthcare providers, hospitals, and clinics to support the research, could potentially hinder participation. Unsupportive healthcare providers and the stigma that can be associated with LD in the medical community could be an impediment, particularly if the support of medical professionals was required to collect the biological samples. Some participants had previously attempted to collect their placenta and other samples for a different research study and were unable to receive the biological materials. Finally, participants expressed reticence to collect samples during pregnancy if this collection would potentially increase the risk of complications such as miscarriage.

Participants also identified several factors that would facilitate their participation in future LD studies: institutional buy-in, anonymity, study methods, and incentives and costs (Table 3). Having institutional buy in from hospitals, clinics, and medical professionals, as well as from designated labs and locations for any other study procedures would make participants feel more comfortable and less concerned about potential stigmatization. Additionally, participants would appreciate the ability to participate anonymously and not have to share any diagnoses with health professionals outside the study. The study methods could make a great difference in enabling people to participate in research. Keeping the requirements of participants simple, realistic, and not onerous will enable participation. Additionally, participants were critical of certain laboratory tests used to detect for LD, so they would recommend not using an ELISA test. Participants wanted to know that the research would contribute meaningfully to the understanding, diagnosis, and treatment of LD, and be widely disseminated to help others. Finally, financial incentives and/or reducing participation costs would be another factor to facilitate greater participant recruitment. A suggested non-financial incentive would be for there to be long-term medical follow-up for participants (including babies born to participants with LD), so that if a positive diagnosis is discovered during the study, participants have an easy route to access medical care.

Finally, participants recommended several recruitment strategies for future LD research from their perspective as research participants in our current study. Using targeted advertising and social media sites like Facebook were highly endorsed and perceived as having wide reach. Participants suggested that contact with LD patients could be facilitated through consent to contact lists maintained by hospitals and other healthcare institutions. Lyme literate medical doctors (LLMDs), fertility specialists, naturopaths treating and caring for Lyme patients, and midwifery practice groups were also identified as reliable routes for recruitment, since they can directly recommend and advertise the study to patients/clients. Organizations supporting LD patients and LD research would also be potential routes for recruitment through email lists or advertisements posted on websites or social media.

Strengths & limitations

A strength of our study was the open, worldwide recruitment. However, the findings may be more representative of American and Canadian priorities due to the majority of participants being from these countries. Our findings may be less applicable to other jurisdictions, as peoples’ experiences and perceptions are shaped by the health system where they live and seek care. Most of our participants had been diagnosed with LD more than ten years ago and we did not collect data in this phase of the study to describe the timing of LD diagnosis in relationship to the timing of pregnancy or LD diagnosis in children. The demographics of our participants suggest that they likely were not representative of all people who have LD during pregnancy. Our participants may have experienced greater morbidity from LD and higher rates of LD in their offspring than average, which likely influenced our findings. However, the perspectives of people with chronic LD are particularly valuable in identifying the limits of current medical understanding about this disease. The online focus group format may have prohibited the participation of rural dwellers and people with low socioeconomic status. Our findings are also potentially limited by selection bias, as those who had negative experiences may have been more likely to participate as a way to share their experience. Previous research has shown that people with LD often describe being treated in ways that were condescending, dismissive, or patronizing [96]. A strength of our study was that participants expressed appreciation of the opportunity to share their concerns and priorities, which enabled us to give voice to a group that has often not been listened to. However, it is possible we didn’t hear from individuals who have lost trust in healthcare and research due to their negative experiences with the healthcare system. We chose to take an inclusive approach to eligibility to participation so enrollment in this study didn’t require proof of diagnosis. Given the challenges of LD diagnosis, this may be considered a strength, but the research priorities identified may have differed if we had implemented more rigid eligibility criteria.

Implications for research

The priorities identified by participants in our study should provide direction for future LD research. To enhance the recruitment of people with LD in pregnancy in research, researchers can attend to the barriers and enablers identified (Table 3). Researchers should design their studies to reduce barriers to participation, for example, by maximizing institutional support, ensuring methods that are not onerous for participants, providing incentives and limiting costs to participate, safeguarding patient data and anonymity, and minimizing health risks during pregnancy. It appears that conducting prospective research with those with LD in pregnancy is feasible based on their willingness to participate in future research.

Research focusing on improving both treatment within the medical system and collaboration with alternative practitioners may be another potential area of research. Echoing our participants’ experiences, the literature demonstrates that physicians are not well educated about LD. Prior research found that clinicians demonstrated basic knowledge of LD, had suboptimal practices, misinterpreted Western blot tests [97, 98], and struggled with diagnosing or conceptualising chronic LD [99]. Furthermore, our participants desired clinicians to be more collaborative with alternative healthcare providers. Many participants were seeking care primarily from naturopaths, as their needs were not getting met in the dominant medical system. Research shows that LD patients sought alternative methods when diagnostic procedures and treatments didn’t resolve their symptoms [100]. Their escalating health issues, and the stigma they faced led to feelings of desperation and abandonment, ultimately leading them to seek alternative practitioners outside the medical system [100]. There is potential for furthering knowledge if researchers and research funders ensure that approaches to care that are being used by complimentary and alternative medicine have the same opportunities for research evaluation as allopathic treatments.

Conclusion

People who experience LD in pregnancy identify a broad range of research gaps that they believe are important to address. Priority topics span Transmission, Testing, Treatment, Disease presentation, and Education. Our findings indicate that some of these priorities would be well addressed through prospective research studies and that this patient population would be willing to participate in such research.