Symptoms of postural orthostatic tachycardia syndrome in pregnancy: a cross-sectional, community-based survey

Abstract

Objective:

To evaluate the relationship between postural orthostatic tachycardia syndrome (POTS) and pregnancy.

Design:

Cross-sectional survey

Setting:

International

Population or Sample:

A total of 8,941 female patients with a diagnosis of POTS.

Methods:

Data from the survey were analyzed using descriptive measures and stratified for comparisons.

Main Outcome Measures:

Symptom course of POTS during pregnancy. Secondary outcomes included pregnancy losses, POTS onset during pregnancy, and the impacts of comorbid diagnosis of Ehlers-Danlos syndrome or an autoimmune disorder on symptoms during pregnancy.

Results:

Overall, 40.8% (n=3,652) of participants reported ≥1 pregnancy. Most participants experienced worsening symptoms in the first (62.6%) and third (58.9%) trimesters, 3 months after pregnancy (58.7%), and 81.1% at any point in their pregnancy. Most participants with worsening symptoms in the first trimester also experienced worsening symptoms in the second (61.6%) and third (68.1%) trimesters, but if they improved in the first trimester, then this improvement persisted in the second and third trimesters. Of participants who reported that POTS was triggered by a specific event (41.3%), 8.1% reported pregnancy as the trigger for onset.

Conclusions:

POTS symptoms in the first trimester of pregnancy may help predict symptom course throughout the duration of pregnancy. Some individuals may experience an initial onset of POTS during pregnancy. This novel information may guide clinicians in counseling patients with POTS who are planning pregnancy.

‘Tweetable’ Abstract:

Large study finds that most patients with #POTS (Postural Orthostatic Tachycardia Syndrome) experience a worsening of POTS symptoms during pregnancy.

Introduction:

Postural orthostatic tachycardia syndrome (POTS) is a syndrome of heterogenous etiology leading to chronic orthostatic intolerance¹. Individuals with POTS experience an increase in heart rate of ≥30 bpm (or ≥40 bpm if 12–19 years of age) within ten minutes of standing, in association with chronic orthostatic symptoms lasting at least three months or longer, and in the absence of orthostatic hypotension (≥20/10 mmHg decrease in blood pressure within three minutes of upright posture)^{2, 3}. POTS primarily affects females of reproductive age, and although the true prevalence is unknown, it is estimated to affect up to 1% of the North American population⁴.

Despite a primarily female demographic, there are minimal data evaluating the impact of POTS on pregnancy, or the impact of pregnancy on POTS. Literature regarding POTS and pregnancy is limited, in part, by small sample sizes^{5, 6}. Some studies report an overall improvement of POTS symptoms throughout the course of pregnancy^{7, 8}, but with variable symptom response. These studies were of small sample size, making it difficult to generalize findings and translate them to clinical care. Further, a significant minority of POTS patients are also diagnosed with a range of autoimmune disorders⁹, as well as Ehlers-Danlos Syndrome (EDS), a systemic connective tissue disorder (though the underlying mechanism of these relationships has not yet been identified identified^9–11), which both may impact pregnancy.

Using a cross-sectional, POTS-patient community-based online survey, this study aimed to evaluate the impact of pregnancy on POTS; specifically, POTS symptom course as well as the impacts of either autoimmune disorders or EDS on the symptom course of POTS in pregnancy. In addition, differences between patients who identified pregnancy as the event leading to initial onset of POTS and those who did not were also evaluated. Together, these findings may aid clinicians in the management of POTS patients who are pregnant or who are considering pregnancy.

Methods:

Survey Design and Delivery:

A comprehensive questionnaire was developed in partnership between Vanderbilt University Medical Center (Tennessee, USA), and Dysautonomia International (New York, USA), a patient advocacy group. Members of Dysautonomia International’s Patient Advisory Board were engaged to help develop and test the questionnaire in an iterative process⁹. All questions about the impact of POTS on pregnancy were included (Table S1), as there are not core outcome sets for research on POTS in pregnancy. The survey was written in English and delivered in an online format. Participants reported the time taken to complete the survey was between 45 – 90 minutes, and they had the option to save the survey and return later. Questionnaire results were stored in a secure Research Data Capture (REDCap) electronic database at Vanderbilt University¹². This is a retrospective study. This study received ethics approval from both the Vanderbilt University Institutional Review Board (IRB#140303) and the University of Calgary Conjoint Health Research Ethics Board (REB15–2922).

Study Participants:

The inclusion criteria were a self-reported physician diagnosis of POTS and ability to complete an English language survey on an electronic device using an internet connection. POTS patients were recruited primarily through the Dysautonomia International organization’s website and social media channels. POTS patients provided electronic informed consent (or parent/guardian consent in addition to participant assent if the patients were <18 years of age) to complete the survey.

Analysis:

Survey data collected between July 2015-June 2022 were included in this analysis. Data were exported from REDCap¹² and imported into IBM SPSS Statistics 28 (IBM, Armonk, NY) for analysis. POTS patients were included in this analysis if they indicated their biological sex at birth as female, were post-menarche, and disclosed their pregnancy history. Participants were excluded from the ‘comorbidity analysis’ if they did not respond to the co-morbidities section of the survey. POTS patients were excluded from the total number of respondents to each question if they did not answer a question or answered “prefer not to say”. Participants who answered ‘not applicable (N/A)’ or ‘not sure’ regarding pregnancy symptoms questions were excluded in those analyses. Participants who indicated a diagnosis of one of more autoimmune disorders (listed in Table S2), were grouped into a composite autoimmune variable (POTS+AI). Participants who did not report a diagnosis of an autoimmune disorder were grouped as POTSnoAI. Participants with diagnoses of both EDS (POTS+EDS), and POTS+AI were grouped together in a composite POTS+EDS+AI variable and compared to paticipants without EDS and AI (POTSnoEDSnoAI). Symptom comparisons between participants who reported a diagnosis of POTS+EDS and participants who did not report a diagnosis of EDS (POTSnoEDS), with POTS+AI and POTSnoAI, as well as participants with and without POTS onset during/after pregnancy, excluded “N/A” and “not sure” responses. Specific numbers of patients who responded to the individual questions are reported. Continuous data are presented as mean ± standard error of the mean. Categorical data are presented as percentage and number of participants who answered each question, or percentage only, if the number of participants is included in a table or figure.

Statistical Analyses:

Descriptive analyses including total number and percentage of participants for categorical variables and measures of central tendency for continuous variables were performed. Wilcoxon Rank Sum tests were conducted to evaluate differences between group of POTS patients (i.e. POTS+ EDS and POTSnoEDS, POTS+AI and POTSnoAI, POTS+EDS+AI and POTSnoEDSnoAI, and those with and without initial POTS onset during pregnancy), for non-parametric continuous variables. Pearson’s Chi-Square tests were conducted to evaluate differences between these groups for categorical variables. Symptom responses with categories of “better”, “same”, or “worse” were grouped into 2 categories: “better/same” or “worse”, for statistical comparisons. A p-value <0.05 was considered statistically significant.

Patient and Public Involvement:

The study questionnaire was developed by Vanderbilt University in partnership with Dysautonomia International. Members of Dysautonomia International’s Patient Advisory Board participated in the development of the questionnaire to ensure that questions were relevant to patients and reflected patient priorities. Dysautonomia International reviewed the study results and helped to identify key results to highlight in this manuscript, as well as relevant points to include in the manuscript discussion. Dysautonomia International will also aid in knowledge translation, through sharing the study results to the patient community and members of the public.

Funding:

This work was supported in part by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number P01 HL056693, by the National Center for Advancing Translational Sciences Award UL1 TR000445.

Results:

Participants:

A total of 14,455 participants consented to complete the survey (Figure 1). Participants who did not report a physician diagnosis of POTS and those who reported their biological sex as male were excluded. Participants were also excluded if they were pre-menarche or did not disclose their menstrual status, or did not disclose their pregnancy history. A total of 8,941 female, post-menarche POTS patients with known pregnancy history were included in this analysis.

Figure 1.

Participant Flow Diagram. A total of 8,941 females with a physician-made diagnosis of postural orthostatic tachycardia syndrome (POTS) participated in this analysis.

Patient Demographics and Comorbidities:

The majority of participants were white (93.3%), non-Hispanic (95.2%) and 18 years of age or older (90.7%, Table S3). The mean age of POTS symptom onset was 20.8±0.1 years. POTS+EDS was reported in 25.4% of participants. POTS+AI was reported by 17.1% of participants. POTS+EDS+AI was reported by 5.6% of participants.

Symptoms:

Commonly reported symptoms in this study cohort (at the time of survey completion) included lightheadedness (99.0%), tachycardia/palpitation (97.4%), headache (95.2%), difficulty concentrating (94.6%), and pre-syncope (94.0%; Table S3). A more in-depth analysis of symptom profiles in individuals with physician-confirmed POTS who responded to this survey was recently published by Shaw et al⁹.

Pregnancies:

In total, 3,652 patients (40.8%) reported ≥1 pregnancy. Amongst POTS patients who had been pregnant at least once, the mean number of pregnancies was 2.73±0.03. Overall, 89.3% of participants reported ≥l live births (mean 1.91±0.02/patient) and 44.2% of participants reported ≥ 1 pregnancy loss (mean 0.78±0.02/patient).

Fewer POTS patients with POTS+EDS (36.9%) had been pregnant compared to POTSnoEDS (42.0%, p<0.001; Table S4). Patients with POTS+EDS had fewer live births and more pregnancy losses than patients with POTSnoEDS. Mean number of pregnancies was similar (Table 1). More patients with POTS+AI (52.4%) had been pregnant compared to POTSnoAI (38.3%, p<0.001). Patients with POTS+AI had more pregnancies and more pregnancy losses than POTSnoAI. Live births were similar between POTS+AI and POTSnoAI (Table 1). Patients with POTS+EDS+AI had more pregnancy losses than patients who had POTSnoEDSnoAI (Table 1). Pregnancies and live births were not different between these groups.

Table 1.

Mean Number of Pregnancies, Live Births and Pregnancy Losses in POTS+EDS, POTS+Autoimmune and POTS+EDS+Autoimmune.

Group	Comparison	Pregnancies		Live Births		Pregnancy Losses
		Mean	p-value	Mean	p-value	Mean	p-value
POTS+EDS	POTS+EDS	2.80±0.07	0.9	1.80±0.04	0.003	0.93±0.06	0.001
	POTSnoEDS	2.72±0.03		1.95±0.02		0.74±0.03
POTS+Autoimmune	POTS+AI	2.95±0.07	0.005	2.00±0.05	0.08	0.93±0.07	<0.001
	POTSnoAI	2.69±0.03		1.9±0.02		0.75±0.03
POTS+EDS+Autoimmune	POTS+EDS+AI	2.91±0.14	0.3	1.78±0.08	0.1	1.11±0.1	<0.001
	POTSnoEDSNoAI	2.66±0.04		1.91±0.03		0.71±0.03

POTS symptom course during pregnancy:

A summary of the question structure is provided in Table S1. Overall, a significant proportion of participants reported N/A for their POTS symptoms during pregnancy: first trimester: 39.9% (1,446 of 3,620), second trimester: 45.2% (1,631 of 3,612), third trimester: 45.5% (1,641 of 3,603), post-pregnancy: 43.4% (1,565 of 3,608), with subsequent pregnancies: 54.7% (1,963 of 3,586).

Excluding participants who reported N/A during pregnancy, the majority of POTS patients experienced a worsening of POTS symptoms in the first trimester (62.6%) and third trimester (58.9%), when compared to their typical POTS symptoms (Table 2). In the second trimester, just under half of patients experienced a worsening of symptoms (48.2%) compared to typical POTS symptoms. In contrast, a significant minority of participants experienced improvement in their POTS symptoms during the first (20.0%), second (34.8%) and third (26.4%) trimesters.

Table 2.

Postural Orthostatic Tachycardia Syndrome (POTS) Symptoms during and after pregnancy, and with subsequent pregnancies, compared to POTS symptoms pre-pregnancy.

Time Frame	Improved POTS Symptoms (%)	Same POTS Symptoms (%)	Worse POTS Symptoms (%)
First Trimester (T1) (total n=1,606)	20.0	17.3	62.6
Second Trimester (T2) (total n = 1,511)	34.8	17.0	48.2
Third Trimester (T3) (total n = 1,518)	26.4	14.7	58.9
Post-Pregnancy (total n = 1,636)	24.8	16.5	58.7
Subsequent Pregnancies (total n = 1,065)	12.0	35.4	52.6

Most participants who experienced improved POTS symptoms during the first trimester (n=271) also experienced improved POTS symptoms in the second (77.1%; Figure 2A) and third trimesters (62.7% Figure 2B). Conversely, most participants who experienced a worsening of POTS symptoms in the first trimester (n=683) experienced a continued worsening of POTS symptoms in the second (61.6%; Figure 2C), and third (68.1%; Figure 2D) trimesters relative to their baseline pre-pregnancy POTS symptoms.

Figure 2.

A-B: Postural orthostatic tachycardia syndrome (POTS) symptoms in the second trimester (T2) and third trimester (T3) for participants who had better POTS symptoms in the first trimester (T1), compared to pre-pregnancy. C-D: Symptoms in T2 and T3 for participants who had worse POTS symptoms in T1 compared to pre-pregnancy.

Of participants who experienced no change in POTS symptoms during the first trimester (n=250), 46.4% continued to have no change during the second trimester, while 37.2% experienced a worsening of symptoms. In the third trimester, 52.8% of participants with no change in POTS symptoms during the first trimester experienced a worsening of symptoms. Overall, 81.1% of participants (n=1,138) experienced a worsening of their POTS symptoms at some point during pregnancy.

A majority of patients also reported a worsening of their POTS symptoms during the three months after delivery, when compared to their typical pre-pregnancy POTS symptoms (58.7%; Table 2). Furthermore, a majority of POTS patients with multiple pregnancies reported that their symptoms worsened during subsequent pregnancies, when compared to symptoms during their earlier pregnancies (52.6%).

There was no statistically significant difference in the worsening of symptoms between POTS+EDS patients and POTSnoEDS patients at any point in pregnancy, or with subsequent pregnancies (Table S5). A larger proportion of POTS+EDS patients (63.4%) had worse POTS symptoms during the postpartum period, than POTSnoEDS (56.6%; p=0.02). There were no statistically significant differences in worsening of symptoms between POTS+AI and POTSnoAI at any point in pregnancy, during the postpartum period, or with subsequent pregnancies (Table S6).

Initial POTS onset during pregnancy:

Overall, 41.3% of POTS patients reported POTS symptoms started within three months of a ‘specific event’ (Table S7). Of those patients, 8.1% reported that their initial POTS onset was during or within three months of (during/after) pregnancy. A similar proportion of POTS+EDS and POTSnoEDS (8.0%) patients reported the initial POTS onset was during/after pregnancy (p=0.8). This is equivalent to 3.1% of all participants with POTS+EDS, and 3.4% of all participants with POTSnoEDS. A similar proportion of POTS+AI (7.0%) and POTSnoAI (8.3%) patients reported an initial POTS onset was during/after pregnancy (p=0.3). This is equivalent to 3.1% of all participants with POTS+AI and 3.4% of all participants with POTSnoAI.

The mean number of pregnancies (2.70± 0.09 per patient vs. 2.74± 0.03 per patient, p=1.0) were not different between patients who reported pregnancy as a trigger for their initial POTS onset and those who did not. However, live births were higher (2.06± 0.06 per patient vs. 1.89±0.02 per patient, p=0.02) and pregnancy losses were lower in POTS patients who reported POTS onset during/after pregnancy (0.66±0.08 per patient vs. 0.79±0.02 per patient, p=0.009).

Participants who reported the initiation of POTS symptoms during/after pregnancy were more likely to have worsening symptoms in the second (62.5%vs. 46.7%, p<0.001) and third (68.0% vs. 58.2%, p=0.01) trimesters of pregnancy compared to participants with POTS not triggered during/after pregnancy. Worsening first (66.7% vs. 62.2%, p=0.3) trimester symptoms were not different between the two groups. Post-pregnancy symptoms were also more likely to be worse in the POTS onset during/after pregnancy group (67.8% vs. 56.7%, p=0.002), as well as with subsequent pregnancies (69.2% vs. 50.2%, p<0.001) compared to those without a POTS onset during/after pregnancy. A summary of symptom responses in participants who reported POTS onset during/after pregnancy is shown in Table S8.

Discussion:

Main Findings:

This is the largest evaluation of pregnancy symptoms in females with POTS, with 3,652 females reporting ≥1 pregnancy. Most participants reported that their POTS symptoms worsened in the first and third pregnancy trimesters, with just under half worsening the second trimester compared to baseline. Among those who experienced improved POTS symptoms in the first trimester, most continued to have improved POTS symptoms throughout the pregnancy. Conversely, most participants with worsening POTS symptoms in the first trimester had ongoing worsened symptoms in the second and third trimesters. The trajectory of POTS symptoms in the first trimester may inform prognosis regarding POTS symptoms throughout the remainder of pregnancy. Most participants also reported a worsening of POTS symptoms in the postpartum period and during subsequent pregnancies. Some individuals experienced a new onset of POTS during or shortly after pregnancy.

Strengths and Limitations:

This international evaluation of POTS in pregnancy is ~50 times larger than prior studies,^{5–8, 13–15} aprovides a more comprehensive assessment of the patient experience of POTS and pregnancy than past studies. The results of this large survey may aid clinicians in the counselling of patients with POTS who are pregnant or are considering pregnancy.

As these survey data were self-reported, both a misclassification bias and a selection bias are possible. POTS patients self-reported a physician diagnosis of POTS. Therefore, it is possible that the specific diagnostic criteria may not have been met for each participant. POTS patients could have also reported inaccurate information, although there would be little motivation for intentional misrepresentation. The time between pregnancy and the time of survey completion was also variable and could have led to a recall bias. Many participants are likely to have been pregnant before they developed POTS. A not applicable (“N/A”) option was included in the symptom questions, allowing each participant to indicate that POTS symptoms were not applicable to their pregnancy.

Participants were primarily recruited through online social media. While use of social media is very common, not everyone will have been aware of the survey. Participants in the survey had to be able to read English or had resources for translation. These two factors may have reduced the representativeness of the study population, and the generalizability of the results.

Interpretation:

Symptom Course:

Common POTS symptoms are detailed in the first manuscript on this survey.⁹ A systematic review of POTS and pregnancy found that POTS symptoms worsened during the first trimester and improved during the second trimester, with variable symptom course in the third trimester⁵, which are consistent with our findings. Kimpinski et al. found worse symptoms of orthostatic intolerance in the first trimester, with improvement in the second and third trimesters, in a group of 51 POTS patients⁸. Kanjwal et al studied 22 POTS patients, reporting that 55% had improved POTS symptoms, 13% had no change in symptoms, and 31% had worsening POTS symptoms throughout their pregnancies⁷. Another small study of 10 POTS patients found 40% with worse POTS symptoms, 20% with unchanged symptoms, and 40% with improved symptoms throughout the overall pregnancy¹³. We are able to provide a broader assessment of symptom course throughout pregnancy due to our much larger study sample.

Initial POTS onset during pregnancy:

Pregnancy losses were lower in participants who reported the initial POTS onset was during or within three months after pregnancy. The reason for this is unknown. It is possible that patients who developed POTS during or shortly after pregnancy could have avoided future pregnancies. Alternatively, they could have managed their future pregnancies more closely, reducing the risk of pregnancy loss. Participants whose POTS onset was during/after pregnancy were more likely to have worsening symptoms in their second and third trimesters as well as worsening symptoms with subsequent pregnancies, compared to patients without POTS onset during pregnancy. The onset of POTS during/after pregnancy may lead to more significant POTS symptoms throughout the entire pregnancy and during the post-partum period.

Pregnancies:

One or more pregnancies were reported by 41% of participants. At least one pregnancy loss was reported by 44.2% of participants who had been pregnant, with a mean of 0.78±0.02 pregnancy losses per patient. A similar proportion of pregnancy losses (43%) were reported in a large study in Israel.¹⁶ A study of 51 POTS patients found a much lower pregnancy loss rate of 7% (8 out of 116 total pregnancies)⁸ amongst 10% of all participants (5 of 51), much lower than the 44% of participants in this current survey. Our large sample size may more accurately reflect the actual pregnancy loss rate in POTS of 0.78±0.02 per patient.

Comorbid EDS:

EDS was present in 25% of females with POTS, similar to prior studies.¹¹ Hypermobile EDS is most commonly associated with POTS¹⁰. Symptoms during pregnancy were similar among POTS patients whether or not they had EDS. A larger proportion of POTS+EDS reported worse POTS symptoms in the post-partum period. Patients with POTS & EDS had higher rates of pregnancy losses prior to 24 weeks than participants without EDS. Previously, small studies have provided conflicting results regarding pregnancy loss and EDS^{17, 18}.

Comorbid Autoimmune Disorders:

One or more comorbid autoimmune disorders were reported by 17.1% of participants. POTS symptom course during pregnancy was not different between POTS patients with or without an autoimmune disorder. However, POTS patients with autoimmune disorders had both higher rates of pregnancies and pregnancy losses. Increased risk of pregnancy loss has been documented in several autoimmune diseases^{19, 20}.

Implications for Clinical Care:

Clinicians should screen POTS patients for Ehlers-Danlos Syndrome and autoimmune conditions commonly seen in POTS (including Hashimoto’s thyroiditis, Sjogren’s Syndrome, celiac disease, rheumatoid arthritis and lupus), and these conditions should be optimally treated before or early in pregnancy in an effort to reduce the risk of pregnancy loss. Patients with POTS contemplating pregnancy should be advised that their POTS symptoms will likely worsen during pregnancy. Clinicians should work with patients to optimize treatment and reduce symptoms as much as possible both prior to and during pregnancy, including medications that are not contraindicated during pregnancy, and non-pharmacological treatments to decrease the symptom burden.^{2, 21} Prevention of syncope is especially important²².

Conclusion:

This study, which would not have happened without the partnership with Dysautonomia International, reports on a large sample of patients with POTS, characterizing their symptom course during pregnancy. Most patients with POTS experience a worsening of POTS symptoms during pregnancy. POTS symptoms in the first trimester of pregnancy may help predict symptom course throughout the duration of pregnancy. Some individuals may experience an initial onset of POTS during pregnancy. Co-morbid Ehlers-Danlos syndrome or autoimmune disorders may put patients with POTS at increased risk of pregnancy loss. Additional research is needed to understand the reasons for the worsening POTS symptoms during pregnancy, and to develop the evidence-base to improve clinical care for patients with POTS during pregnancy.