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Postural Orthostatic Tachycardia Syndrome during pregnancy: A systematic review of the literature

      Abstract

      Purpose

      Postural Orthostatic Tachycardia Syndrome is most commonly seen in women of child bearing age, however little is known about its effects in pregnancy.

      Method

      A systematic review was conducted in March 2015 and updated in February 2018. Medline, Embase, PsychInfo, CINHAL, and the Cochrane Library were searched from database inception. The ClinicalTrials.gov site and bibliographies were searched. MeSH and Emtree headings and keywords included; Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia Syndrome, and were combined with pregnancy and pregnancy related subject headings and keywords. Searches were limited to English. Eligible articles contained key words within the title and or abstract. Articles were excluded if Postural Orthostatic Tachycardia Syndrome was not pre-existing.

      Results

      Eleven articles were identified as eligible for inclusion. Studies were appraised using the PRISMA 2009 guidelines. The overall quality of evidence was poor using the NHMRC Evidence Grading Matrix, which was attributed to small sample sizes and mostly observational studies, emphasizing the need for future high quality research. Findings in this review must be used with caution due to the poor quality of the literature available.

      Conclusions

      Postural Orthostatic Tachycardia Syndrome should not be a contraindication to pregnancy. Symptom course is variable during pregnancy and the post-partum period. Continuing pre-conception medication may help symptoms, with no significant risks reported. Obstetric complications, not Postural Orthostatic Tachycardia Syndrome, should dictate mode of delivery. Postural Orthostatic Tachycardia Syndrome did not appear to affect the rate of adverse events. These results are important in determining appropriate management and care in this population.

      Abbreviations:

      POTS (Postural Orthostatic Tachycardia Syndrome), CS (caesarean section)

      Keywords

      1. Introduction

      Postural Orthostatic Tachycardia Syndrome (POTS) is a condition of the autonomic nervous system that is five times more likely to affect women, and occurs most often in child bearing age (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Glatter K.A.
      • Tuteja D.
      • Chiamvimonvat N.
      • Hamdan M.
      • Park J.K.
      Pregnancy in postural orthostatic tachycardia syndrome.
      ;
      • Raj S.R.
      The postural tachycardia syndrome (POTS): pathophysiology, diagnosis & management.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Benrud-Larson L.M.
      • Dewar M.S.
      • Sandroni P.
      • Rummans T.A.
      • Haythornthwaite J.A.
      • Low P.A.
      Quality of life in patients with postural tachycardia syndrome.
      ;
      • Low P.A.
      • Sandroni P.
      • Joyner M.
      • Shen W.-K.
      Postural tachycardia syndrome (POTS).
      ). The prevalence of POTS is unknown due to difficulty with diagnosis, however it is estimated that between 500,000 and 3,000,000 Americans are affected (
      • Mar P.L.
      • Raj S.R.
      Neuronal and hormonal perturbations in postural tachycardia syndrome.
      ;
      • Robertson D.
      The epidemic of orthostatic tachycardia and orthostatic intolerance.
      ;
      • Mustafa H.I.
      • Raj S.R.
      • Diedrich A.
      • Black B.K.
      • Paranjape S.Y.
      • Dupont W.D.
      • Williams G.H.
      • Biaggioni I.
      • Robertson D.
      Altered systemic hemodynamic & baroreflex response to angiotensin II in postural tachycardia syndrome.
      ;
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ). It is characterized by symptoms of orthostatic tachycardia including tachycardia, palpitations, syncope or pre-syncope, light headedness, cognitive dysfunction, nausea, exercise or heat intolerances, and fatigue (
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ;
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ). It is heterogeneous in nature with patients often displaying multiple, nonspecific symptoms with varying degrees of functional impairment (
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ;
      • Kavi L.
      • Gammage M.D.
      • Grubb B.P.
      • Karabin B.L.
      Postural tachycardia syndrome: multiple symptoms, but easily missed.
      ). In severe cases, morbidity and functional disability may be similar to that of chronic obstructive pulmonary disease or heart failure (
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). Misdiagnosis is common due to inconsistency in clinical presentation, difficulty with diagnosis, and lack of awareness or acceptance of the reality of the condition (
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ).
      In adults, the current criteria for a POTS diagnoses is: the presence of excessive tachycardia and symptoms of orthostatic intolerance for more than six months, an increase of 30 beats per minute or heart rate >120 beats per minute on Head Up Tilt test within 10 min of standing, an absence of orthostatic hypotension, and improvements of symptoms upon recumbence (
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ;
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ;
      • Busmer L.
      Diagnosis and management of postural tachycardia syndrome.
      ;
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo Clinic experience.
      ). An extensive history is essential so that physiological conditions such as pheochromocytoma, or psychological conditions such as conversion disorder can be excluded before a diagnosis of POTS can be made (
      • Busmer L.
      Diagnosis and management of postural tachycardia syndrome.
      ;
      • Benrud-Larson L.M.
      • Dewar M.S.
      • Sandroni P.
      • Rummans T.A.
      • Haythornthwaite J.A.
      • Low P.A.
      Quality of life in patients with postural tachycardia syndrome.
      ;
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo Clinic experience.
      ).
      Similar conditions to POTS have been described since 1871 when Jacob Mendes Da Costa observed orthostatic symptoms in soldiers which he diagnosed as Irritable Heart Syndrome (
      • Da Costa J.M.M.D.
      Art. I.-on irritable heart; a clinical study of a form of functional cardiac disorder and its consequences.
      ). Similar symptoms were later described by Sir Thomas Lewis, Robert D. Rudolf, and Paul Wood (
      • Mathias C.J.
      • Low D.A.
      • Iodice V.
      • Owens A.P.
      • Kirbis M.
      • Grahame R.
      Postural tachycardia syndrome—current experience and concepts.
      ;
      • Rudolf R.D.
      The irritable heart of soldiers (Soldier's heart).
      ;
      • Lewis T.
      The Tolerance of Physical Exertion, as Shown by Soldiers Suffering From So-called "Irritable Heart".
      ). Other diagnoses for these symptoms include Da Costa Syndrome, Soldier's Heart, neurasthenia, anxiety neurosis, effort intolerance, neurocirculartory asthenia (
      • Mathias C.J.
      • Low D.A.
      • Iodice V.
      • Owens A.P.
      • Kirbis M.
      • Grahame R.
      Postural tachycardia syndrome—current experience and concepts.
      ;
      • Low P.A.
      • Sandroni P.
      • Joyner M.
      • Shen W.-K.
      Postural tachycardia syndrome (POTS).
      ;
      • Wood P.
      Da Costa's Syndrome (or Effort Syndrome). Lecture I.
      ). POTS was finally defined by Ronald Schondorf and Phillip Low at the Mayo Clinic in 1993 (
      • Schondorf R.
      • Low P.A.
      Idiopathic postural orthostatic tachycardia syndrome - an attenuated form of acute pandysautonomia.
      ).
      Current research is predominantly focused on the general diagnosis and management of this complex condition. This includes an exploration of pharmacological management (
      • Busmer L.
      Diagnosis and management of postural tachycardia syndrome.
      ;
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ), which has been noted to be of particular concern to patients. Common medications may include fludrocortisone, β-blockers such as propranolol, midodrine (
      • Busmer L.
      Diagnosis and management of postural tachycardia syndrome.
      ;
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ;
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ;
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ), ivabradine (
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ;
      • Busmer L.
      Diagnosis and management of postural tachycardia syndrome.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ;
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ), selective serotonin reuptake inhibitors (
      • Busmer L.
      Diagnosis and management of postural tachycardia syndrome.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ), clonidine (
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ;
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ), desmopressin (DDAVP) (
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ), methyldopa, modafinil (
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ), and pyridostigmine (
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ;
      • Pavlik D.
      • Agnew D.
      • Stiles L.
      • Ditoro R.
      Recognizing postural orthostatic tachycardia syndrome.
      ;
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ). The medications prescribed for the management of POTS vary in their safety profiles and, whilst the potential harm from medications during pregnancy may be alleviated with appropriate choice of medication and monitoring, the lack of guidelines for pharmacological management in POTS and pregnancy may pose a risk to both mother and baby (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ).
      A small number of previous studies have shown links between POTS and gynecological disorders. A study by Peggs et al. (2012) assessed the gynecological history and menstrual cycle lightheadedness of POTS patients compared to healthy controls. This study found significantly higher rates of amenorrhea, lightheadedness in all phases of the menstrual cycle and particularly in the follicular phase, dysfunctional uterine bleeding, endometriosis, galactorrhea, uterine fibroids, and ovarian cysts (
      • Peggs K.J.
      • Nguyen H.
      • Enayat D.
      • Keller N.R.
      • Al-Hendy A.
      • Raj S.R.
      Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome.
      ).
      In 2015, the Heart Rhythm Society released an international consensus statement to provide guidance to clinicians in the diagnosis and management of POTS (
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ). However, there are no clinical guidelines found in the available literature for the management and treatment of POTS during pregnancy, leaving patients and clinicians uncertain of the appropriate management. Patients may turn to the academic literature or the internet causing confusion. This may increase the potential risk to the mother and or fetus, and may adversely affect the patient-clinician relationship. As POTS is more common in women of child-bearing age, there is an urgent need to more closely examine the physical and psychological management of POTS during pregnancy.
      The aims of this paper are to: evaluate the quality of the evidence available surrounding pre-existing POTS in pregnancy, determine what is currently known about pre-existing POTS and pregnancy, and specify areas where further research is needed.

      2. Sources

      A search of the available evidence was conducted in March 2015 and updated in February 2018. The electronic databases Medline, Embase, PsychInfo, CINHAL, and the Cochrane Library were searched from database inception. These databases index a wide range of qualitative and quantitative journals across a number of different health disciplines. The search strategy was constructed using both subject and keyword word searching and translated for each specific database. Subject headings, keywords and phrases included; ‘Postural* Tachycardia Syndrome’, ‘Postural Tachycardi* Syndrome’, as well as ‘Orthostatic Intolerance’. These were combined using the Boolean operator ‘AND’ with ‘pregnancy’ related subject headings and keywords. Details of the complete search strategies can be found in Appendix A. The search was limited to English language citations. Librarians from the University of Newcastle and Hunter New England Health Libraries, John Hunter Hospital were consulted to ensure satisfactory search techniques. The ClinicalTrials.gov site was searched to identify any relevant unpublished studies. A search of the literature available on the Dysautonomia International (www.dysautonomiainternational.org) and PoTS UK (www.potsuk.org) websites was also conducted, as well as contacting the board of directors and chairperson from each website to assist in identifying other relevant studies. Manual searching of relevant bibliographies was completed to ensure all articles were captured. Where only abstracts were available, attempts to contact the authors were made to ensure the full body of knowledge was identified.

      2.1 Inclusion criteria

      Searches were limited to original research articles published in the English language. The terms ‘pregnancy’ and ‘postural tachycardia syndrome’ or ‘postural orthostatic tachycardia syndrome’ were required to appear in any part of the title or abstract

      2.2 Exclusion criteria

      Studies were excluded if the full text was not available, and if POTS was diagnosed during pregnancy or post-partum due to differences in clinical management.

      3. Study selection

      Ninety-eight articles were identified in the literature search. Eleven studies met the inclusion criteria. Of these, eight were case reports that included one to seven patients. Three of the studies, including one case report, employed retrospective chart reviews. One study used self-administered questionnaires that asked about symptoms and medication use during the pre-conception, pregnancy and post-partum periods, and mode of delivery. Two of the case reports included a brief review of the literature, one focusing on previous cases reported in the literature, and the other on medications reported in the previous literature. Seven studies were conducted in the United States, three in the United Kingdom and one in India. Sample sizes ranged between one and 51 participants.
      The one case report that was excluded was due to the diagnosis of POTS being made during the post-partum period. Five conference abstracts were excluded as no full text was available. This decision was made by one of the authors (KM) and confirmed by another of the authors (CC). Fig. A summarizes the retrieval process and study selection.
      Fig. A
      Fig. APRISMA flowchart (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ) showing the retrieval process of articles included in the systematic review.

      3.1 Quality appraisal

      The McMasters Critical Review Form for Quantitative Studies was selected to appraise the methodological quality of the 11 selected studies (
      • Law M.
      • Stewart D.
      • Pollock N.
      • Letts L.
      • Bosch J.
      • Westmorland M.
      ). This critical appraisal tool was chosen as it provides a consistent checklist for the different methodological designs presented across the articles included in this review. The studies scored between six and eight out of ten, with the majority of points lost in the following sections: detailed sample description, informed consent, and reliable and valid outcome measures. Appendix B summarizes the scores.
      The strength of evidence was determined using the National Health and Medical Research Council (NHMRC) Evidence Grading Matrix, which provides a rating between A (excellent) and D (poor). These are based on the volume of evidence, consistency, clinical impact, generalizability, and applicability to the Australian healthcare context (
      • NHMRC
      NHMRC additional levels of evidence and grades for recommendations for developers of guidelines: stage 2 consultation.
      ). The overall rating of the evidence reviewed was Grade D (poor) as outlined in Appendix C. This was due to the evidence predominantly being level III (case-control and retrospective cohort studies) or IV (case studies) according to the NHMRC Evidence Hierarchy (
      • NHMRC
      NHMRC additional levels of evidence and grades for recommendations for developers of guidelines: stage 2 consultation.
      ). Despite this, all 11 articles were included due to the small number of articles to draw from.
      The PRISMA 2009 checklist for systematic reviews was utilized in the writing of this review to ensure quality and transparency in reporting (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ).

      4. Results

      Each article was independently reviewed by two of the authors (KM, CC). Any discrepancies in the findings were discussed and resolved by returning to and reassessing the articles in question. The general quality of the reviewed articles was poor. The sample sizes were very small; five studies reported on single cases, two studies reported on two cases, and the remaining four studies contained seven, ten, 22 and 51 participants. Table A provides an overview of the included studies. The majority of the studies were observational. There were no longitudinal analyses, so temporality and casualty cannot be inferred. Furthermore, potential confounders were not taken into account in the majority of the studies. The results below are presented in this context, as descriptive examples of the potential course, treatments and experiences of POTS during pregnancy.
      Table AOverview of included studies.
      ReferenceStudy design/number of casesMedications use during pregnancySymptoms course of POTS in pregnancyAntenatal complicationsMode of deliveryLabour analgesia/anesthesiaNeonatal outcomesPostnatal POTS symptoms
      Kimpinski et al., 2010 (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      )
      retrospective chart review/51 women - 116 pregnancies, parous Vs nulliparousvariablemiscarriage, placenta previa, placental abruption and malpresentation resulting in peripartum hysterectomylive birth, no complications to babyimproved
      Lide & Haeri, 2015 (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      )
      case report/2propranolol commenced at 15 weeks1 exacerbation at 15 weeksspontaneous vaginalepidural without complicationlive birth, no complications to babystable
      propranolol commenced at 10 weeks1 exacerbation at 10 weekshyperemesis garvidarumspontaneous vaginalepidural without complicationlive birth, no complications to babystable
      Blitshteyn et al., 2012 (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      )
      self-reported questionnaires with longitudinal follow up/10 women - 42 pregnancies, 25 miscarriages, 17 live birthsfludrocortisone, β-blockers, midodrinevariable - unchanged 20%, improved 40%, worsened 40%hyperemesis garvidarum, tachycardia, hypotension, fatigue, presyncope, anaemia, pre-eclampsiavaginal, emergency cesarean section, forceps deliveryepidural, general, unknownprematurity (<32 weeks), fetal distress syndromeunchanged 20–40%, improved 10–30%, worsened 50%
      Kanjwal et al., 2009 (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      )
      retrospective chart review/22β-blockers, midodrine, selective serotonin reuptake inhibitors, fludrocortisonevariable - unchanged 13%, improved 55%, worsened 31%hyperemesis gravidarum, complete heart blockvaginal, cesarean sectionDown's Syndrome, asymptomatic ostium secundum atrial septal defect, ventricular septal defectunchanged 69%, worsened 27%, depression
      Glatter et al., 2005 (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      )
      case report/2midodrinevariable - decompensation at 6 months, placed on bedrest at 7 monthshyperemesis gravidarum, severe dyspnoea, tachycardia, syncopeelective cesarean section at 37 weeks due to maternal clinical decompenssationepidural without complicationlive birth, no complications to babyimproved
      variable - decompensation at 6 months, bedrest at 30 weekshyperemesis gravidarum, syncope, tachycardia, premature labour at 30 weekselective cesarean section at 37 weeks due to maternal clinical decompenssationlive birth, no complications to babyimproved
      Powless et al., 2010 (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      )
      retrospective chart review/7 women, 9 pregnanciesβ-blockers, midodrine, fludrocortisone, pyridostigminevariablegestational hypertension, preterm premature rupture of membranes with premature onset of labour, oligohydramnios, chronic placental abruption, breech presentation, premature rupture of membranesspontaneous vaginal, induced vaginal, elective cesarean sectionepidurallive births
      Pramya et al., 2012 (
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      )
      case report/1metoprololstablespontaneous vaginalepidural without complicationlive birth, no complications to babystable
      McEvoy et al., 2007 (
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      )
      case report/1fludrocortisone, propranololstablepregnancy induced hypertensionassisted forcepsepidurallive birth, no complications to baby
      Corbett et al., 2006 (
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      )
      case report/1metoprololworsenedemergency cesarean section for active phase arrestepidural, proceeding to general analgesia post delivery for haemodynamic instabilitylive birth, no complications to babyimproved
      Kodakkattil & Das, 2009 (
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      )
      case report/1unchangedthreatened preterm labour, syncope with seizureinduced vaginalepidural without complicationlive birth, no complications to babystable
      Jones & Ng, 2008 (
      • Jones T.L.
      • Ng C.
      Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome.
      )
      case report/1worsenedelective cesarean section at 38 weeksepidural without complicationlive birth, no complications to baby
      Five main areas were covered by the articles and these are outlined below.

      4.1 Symptom course during pregnancy

      Eight of the 11 studies addressed symptom course during pregnancy. These studies showed the course of POTS symptoms during pregnancy and the post-partum period to be variable. It is difficult to predict the course for an individual patient. There seemed to be a general trend towards an exacerbation of symptoms in the first trimester, an improvement of symptoms in the second trimester, and a variable course in the third trimester and the post-partum period (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ). This pattern or trend of the variable symptoms course appeared in multiple studies: ten patients by Blitshteyn et al. (2012), 51 patients by Kimpinski et al. (2010) and 22 patients by Kanjwal et al. (2009). Both Blitshteyn and Kanjwal reported 60% to 68% of their patients respectively remained either stable or experienced improved symptoms during pregnancy, with only 40% and 31% of patients respectively experiencing a worsening of symptoms (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). Three studies suggested that improvements in POTS symptoms may be naturally occurring due to the increase in fluid, blood and plasma levels in pregnancy, as well as subsequent increases in cardiac output and blood pressure. This was particularly seen in the later trimesters (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Glatter K.A.
      • Tuteja D.
      • Chiamvimonvat N.
      • Hamdan M.
      • Park J.K.
      Pregnancy in postural orthostatic tachycardia syndrome.
      ).
      By six months post-partum, 50–69% of patients in the studies by Blitshteyn et al. (2012) and Kanjwal et al. (2009) reported their symptoms remained stable or improved, whilst 27–50% reported worsening of symptoms (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). Glatter et al. (2005) reported that one patient felt better at six months post-partum than before pregnancy, possibly due to the increase in upper body resistance training with caring for a newborn (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). This improvement was also reported in the case study by Pramya et al. (2012).
      At one year post-partum, 40% of patients felt their symptoms were unchanged, 10% reported an improvement in experienced symptoms, and 50% described worsening symptoms (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). At 22 months post-partum, one patient reported a significant reduction in syncope but remained disabled by other POTS symptoms (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ).

      4.2 Medication use

      The limited evidence suggests that medication use in pregnancy appeared to be safe under close observation of the physician, where it was decided that the benefit outweighed the risk. Medications utilized for the treatment of POTS during pregnancy reported in the literature included beta blockers (propranolol, metoprolol) (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ;
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ), fludrocortisone (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ), midodrine (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Glatter K.A.
      • Tuteja D.
      • Chiamvimonvat N.
      • Hamdan M.
      • Park J.K.
      Pregnancy in postural orthostatic tachycardia syndrome.
      ), pyridostigmine (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ), and selective serotonin reuptake inhibitors (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). Ondansetron was used to successfully treat hyperemesis gravidarum (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). Phenylephrine was recommended during labour for hemodynamic stability (
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ;
      • Jones T.L.
      • Ng C.
      Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome.
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ).
      Across the ten studies that addressed medication use in pregnancy and delivery, no reported adverse events or complications related to medication use were identified. Blitshteyn et al. (2015) reported that birth weight was slightly below the population average. Although not statistically significant, this was thought to be related to the use of beta blockers (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). Patients who did not require medication for treatment of POTS prior to pregnancy were less likely to report exacerbation of symptoms during pregnancy and were less likely to require treatment (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ). Patients who continued using medications during pregnancy were less likely to experience exacerbations and were more likely to remain stable or report improved POTS symptoms (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ).
      Lide and Haeri (2015), in their medication review, highlighted that there are currently no clinical guidelines for the use of medication to treat POTS in pregnancy and that treatment is individualized to the patient and their symptomology (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ). The authors suggested that propranolol should be considered as the first line treatment in POTS and pregnancy due to its safe pregnancy and lactation profile (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ). Other medications may be used but require close monitoring of mother and baby (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ).

      4.3 Anesthesia and analgesia during delivery

      Seven of the 11 case studies, involving between one and seven patients, addressed anesthesia and analgesia during delivery. Three case studies focused specifically on the anesthetic management of patients with POTS. These case studies reported that anesthesia and analgesia, along with the increased stress of labour on the autonomic nervous system, can prove particularly challenging to the POTS patient. Four of the case studies reported physiological changes including hemodynamic instability and tachycardia throughout labour. These case studies also consistently reported that early analgesia with close monitoring of hemodynamic status may reduce tachycardia and associated complications (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ;
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ). Early consultation with an anesthetist or anesthesiologist was recommended (
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ;
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ;
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ).
      Epidural (bolus and or infusion) with phenylephrine during delivery was described in four studies and was used to prevent reactive tachycardia in the presence of peripheral vasodilation causing hypotension (
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ;
      • Jones T.L.
      • Ng C.
      Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome.
      ;
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ;
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ). McEvoy et al. (2007) recommend phenylephrine as the first line treatment in this setting, over labetalol which must be titrated in smaller doses and its effects in the pregnant POTS patients may be unpredictable (
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ). Corbett et al. (2006) cautioned against the use of epinephrine due to an increased risk of causing tachycardia, especially in patients with hyperadrenergic POTS (
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ). This author also suggested that epidural appears to be safer than spinal anesthesia which may cause sudden changes in systemic vascular resistance and subsequent hemodynamic instability (
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ). Fluid loading may also be useful in maintaining hemodynamic stability (
      • Jones T.L.
      • Ng C.
      Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome.
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ;
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ).
      Powless et al. (2010) described two of their seven patients giving birth without anesthesia and analgesia and without complications (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ). These findings highlight the need for each individual patient to be assessed during pregnancy, and the importance of close monitoring during labour to avoid unnecessary intervention or a delay in appropriate management of pain and associated hemodynamic changes.

      4.4 Mode of delivery

      There remain no clear recommendations regarding the mode of delivery for women experiencing POTS. Glatter et al. (2005) was the first to report on two cases of severe POTS in pregnancy and recommended that patients undergo a caesarean section (CS) to reduce the extreme physical stressed placed on the mother during labour (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). However subsequent case studies have shown that vaginal delivery can be achieved without major complications with appropriate planning, monitoring and pain management (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ). Only one patient elected to have a CS and this was reported to be based on the previously published recommendations by Glatter et al. (2005) (
      • Glatter K.A.
      • Tuteja D.
      • Chiamvimonvat N.
      • Hamdan M.
      • Park J.K.
      Pregnancy in postural orthostatic tachycardia syndrome.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ). Twelve patients across six studies were reported to have delivered by CS, nine of whom were recommended to undergo CS for obstetric complications unrelated to POTS including breech position and an active phase arrest (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Corbett W.L.
      • Reiter C.M.
      • Schultz J.R.
      • Kanter R.J.
      • Habib A.S.
      Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report.
      ), and three due to the obstetricians recommendations based on an increase in POTS symptoms (
      • Glatter K.A.
      • Tuteja D.
      • Chiamvimonvat N.
      • Hamdan M.
      • Park J.K.
      Pregnancy in postural orthostatic tachycardia syndrome.
      ;
      • Jones T.L.
      • Ng C.
      Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome.
      ). Only one patient had an instrument assisted delivery using forceps which was recommended to reduce hemodynamic fluctuations in the second stage of labour caused by the Valsalva maneuver (
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ). Labour was induced in one patient due to maternal syncope, and the patient delivered vaginally with no complications (
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ). All other reported patients delivered vaginally with no complications (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ;
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ).

      4.5 Complications and adverse events

      Complications and adverse events rates amongst women with POTS were generally found to be similar to that of the general population (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ) at around 8% (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ), although sample sizes in these studies were small. No clinically important differences were found in the study by Kimpinski et al. (2010) between 61 nulliparous and 51 parous women with pre-existing POTS (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ). No complications or adverse events were reported to be POTS related, including during pregnancy (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ), during vaginal or CS delivery (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ), or to mother or baby (
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ;
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). Three studies concluded that POTS should not be considered a contraindication to pregnancy with pregnancy itself appearing to be relatively safe (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). Kanjwal et al. (2009) reported that risk factors for the mother should be assessed as per normal obstetric practices (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ).
      The retrospective study by Blitshteyn et al. (2012) reported higher rates of miscarriage (59.9%) compared to the general population (31%) (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). Even after excluding one woman with a history of 13 miscarriages at less than ten weeks gestation and no history of clotting, autoimmune or genetic disorders, the rate remained high (41%) (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ). This finding was not supported in other studies and requires further consideration before an association can be made between POTS and miscarriage in pregnancy (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ).
      Blitshteyn et al. (2012) also noted higher rate of hyperemesis gravidarum or severe vomiting (59%) when compared to the general population (0.5–2%) possibly due to co-morbid migraine which was also common amongst their participants (30%) (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ).
      General complications and adverse events to the mother and/or baby reported across seven case studies in the literature included hyperemesis gravidarum (
      • Glatter K.A.
      • Tuteja D.
      • Chiamvimonvat N.
      • Hamdan M.
      • Park J.K.
      Pregnancy in postural orthostatic tachycardia syndrome.
      ;
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ;
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ), gestational hypertension (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ;
      • McEvoy M.D.
      • Low P.A.
      • Hebbar L.
      Postural orthostatic tachycardia syndrome: anesthetic implications in the obstetric patient.
      ), threatened preterm labour (
      • Kodakkattil S.
      • Das S.
      Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS).
      ), complete heart block requiring insertion of a permanent pacemaker (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ), oligohydramnios at term (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ), preterm rupture of the membranes (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ), chronic placental abruption (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ), breech presentation (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ), miscarriage (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ), placenta previa resulting in miscarriage (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ), placental abruption with malpresentation resulting in a peripartum hysterectomy (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ), fetal distress syndrome (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ), Down Syndrome (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ), asymptomatic ostium secundum atrial septal defect (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ), and a small ventricular septal defect with spontaneous closure (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). None of these complications reported were considered to be related to POTS. The mother's preconception health was not always disclosed which may cause a potential bias towards POTS as a risk factor. In the case of Down Syndrome, the mother was of advanced age (37 years old) which is a well-known risk factor for Down Syndrome (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). The authors noted that the etiology of the complete heart block was unclear, and may not be POTS related (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). Despite the limitations of the studies, POTS is not considered to increase the risk of complications and adverse events (
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ;
      • Pramya N.
      • Puliyathinkal S.
      • Sagili H.
      • Jayalaksmi D.
      • Reddi Rani P.
      Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature.
      ).

      5. Discussion

      The findings presented in this review were not unexpected due to the heterogeneous nature of POTS. Since symptoms and management of POTS varies from patient to patient, it is reasonable to expect that the experience of pregnancy and labour would also be quite variable in its course. However it was surprising to find an absence of research into, or acknowledgement of, the patient perspective with POTS and pregnancy. Of the 11 studies reviewed, only Glatter et al. (2005) appeared to mention from observation the women's improvement in physical and mental wellbeing after the birth of their child, speculating this may have occurred with the change in focus from their health to baby's wellbeing and increase upper body training with caring for a child (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). This is important to note as evidence suggests that maternal chronic illness is related to poorer perinatal health outcomes (
      • Tyer-Viola L.A.
      • Lopez R.P.
      Pregnancy with chronic illness.
      ).
      It is imperative that future research explores the patient experience to be able to better understand the patients' needs, as currently no studies on pregnancy and POTS address this issue. Understanding the patient experience will help shape and inform future quantitative research, identify patient-centered priorities of antenatal and postnatal care, and illuminate the issues that are most important to patients. From this, clinical guidelines can be created for POTS and pregnancy, reducing uncertainly for both patient and clinician.
      Due to the small number of studies available over the past ten years, patients and clinicians are often left to approach the management of the pregnancy by trial and error based on cases of patients who may not share the same POTS symptomology or cause, and on recommendations that may now be out of date. This was demonstrated in the study by Powless et al. (2010) where a patient elected to have a CS despite its risks and without obstetric indications (
      • Powless C.A.
      • Harms R.W.
      • Watson W.J.
      Postural tachycardia syndrome complicating pregnancy.
      ) based on an earlier outdated study of only two cases of severe POTS (
      • Kanjwal K.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome.
      ). Patients and clinicians may be left uncertain of the appropriate course of action for the individual, or with contradictory information that can be confusing and affect the patient – clinician relationship. This is particularly important when considering medications in the pregnant POTS patient. Whilst the relative safety of the medications reported in the literature is recognized, safety profiles are still viewed with a certain amount of subjectivity depending on the individual physician's experience, knowledge and specialty. Patients are often managed by multiple specialists with varying opinions on the relative safety of the medications in pre-conception, pregnancy, labour and breastfeeding which may lead to increased ambiguity regarding safety, particularly from the patient's point of view. Furthermore many medications used in the treatment of POTS, such as ivabradine, modafinil or pyridostigmine, have not been sufficiently and rigorously explored for safety in pregnant or lactating women and caution must be used. The cause and course of POTS may differ significantly between each patient and therefore treatment and management of both POTS and pregnancy is highly individual (
      • Lide B.
      • Haeri S.
      A case report and review of postural orthostatic tachycardia syndrome in pregnancy.
      ;
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • Low P.A.
      Effect of pregnancy on postural tachycardia syndrome.
      ). Blitshteyn et al. (2012) noted patients and clinicians need to be aware of the existing data to aid in the development of a management plan for pre-conception, pregnancy and labour, which may help reduce anxieties and help patients prepare for the possibilities of symptom exacerbation (
      • Blitshteyn S.
      • Poya H.
      • Bett G.C.
      Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes.
      ).
      The long list of serious general complications reported in the literature is of concern given the small sample sizes. Without the patients preconception health status and medications disclosed, it is difficult to be able to confidently conclude that these complications were not attributed to POTS. Given the complexities of POTS, the various medications utilized during pregnancy, and the variable course of pregnancy in general, it may be possible that there are unknown risks associated with POTS in pregnancy. Further research into complications in pregnancy with POTS is warranted.
      Although during quality appraisal the majority of the studies received a favorable score with the McMasters checklist, the NHMRC score indicates that the overall quality of the evidence is poor. This is primarily due to the majority of studies being case reports with very limited patient numbers. These provide interesting insights but are unable to be used to produce generalizable evidence based guidelines with translatable clinical practice recommendations for patients with a diagnosis of POTS who wish to become, or who are pregnant.
      This systematic review highlights the need for more rigorous high quality research into POTS during pregnancy. Future research in this area is vital to improve the care and consistency of patients with POTS considering pregnancy or who are pregnant. Whilst this review may be used to inform clinical care, large prospective studies with longitudinal follow-up are needed to objectively and comprehensively address the questions faced by this population. These question include, but are not limited to: short and long term effects of pregnancy on POTS, POTS symptom course during pregnancy, duration of symptom exacerbation, rates of pregnancy induced hypertensive disorders, risk of antenatal and postnatal mental health disorders in the POTS population, appropriate medication to treat POTS during pregnancy, the possible short and long term effects of medication on the fetus, the potential for the requirement of an obstetrician who specializes in high risk pregnancies, and the exploration of lived experience of pregnancy and POTS symptoms as perceived by the women themselves. Addressing pregnancy in women diagnosed with POTS is vital in ensuring patients and their families are adequately prepared during the preconception stage and throughout pregnancy and labour, as well as ensuring patients feel confident in the management of the POTS and pregnancy. However, without further research, this goal is unlikely to be met.
      Clinical guidelines for POTS and pregnancy need to be developed to provide expert consensus for clinicians. A consumer's guide to the clinical guidelines would also be recommended given the concerns of this group of patients and the confusion that may be encountered particularly concerning medication and mode of delivery. It is acknowledged however that producing these kinds of studies may be extremely difficult given the prevalence of POTS.

      5.1 Conclusion

      The findings of this systematic review must be used with caution due to the overall small number and poor quality of articles discussing pre-existing POTS in pregnancy. However, based on the evidence available, the symptom course of POTS appears to be variable during pregnancy and the post-partum period. Patients who required medication pre-conception may benefit from continuing medication in pregnancy to help stabilize or improve symptoms. It is consistently recommended that patients receive an early review with an obstetrician and an anesthetist. Early initiation of pain relief may reduce the risk of hemodynamic instability during labour. Mode of delivery should be based on obstetric complications rather than on a diagnosis of POTS. Vaginal delivery appears to be safe in the absence of obstetric complications and with close monitoring. Adverse events do not appear to be higher than the general public. Current knowledge suggests patients and clinicians should be reassured that POTS does not appear to be a contraindication to pregnancy. Further high quality research is crucial in improving knowledge and quality of care of patients with pre-existing POTS who are, or wish to become pregnant.

      Financial disclosure

      No funding was received for this review

      Conflict of interest

      Kate Morgan declares that she has no conflict of interest. Dr. Catherine Chojenta declares that she has no conflict of interest. Dr. Meredith Tavener declares that she has no conflict of interest. Ms. Angela Smith declares that she has no conflict of interest. Professor Deb Loxton declares that she has no conflict of interest. The authors alone are solely responsible for the content and writing of this paper.

      Ethical approval

      This article does not contain any studies with human participants performed by any of the authors.

      Informed consent

      For this type of study formal consent is not required.

      Author contributions

      K. Morgan: Project development, Data collection, Data analysis, Manuscript writing/editing.
      C. Chojenta: Project development, Data analysis, Manuscript writing/editing.
      M. Tavener: Project development, Manuscript writing/editing.
      A. Smith: Search design, Manuscript writing/editing.
      D. Loxton: Project development, Manuscript writing/editing.

      Acknowledgements

      The authors would like to thank Lauren E. Stiles, J.D. (Dysautonomia International), Debbie Booth (faculty librarian, The University of Newcastle), and Dr. Gary Crowfoot (The University of Newcastle) for their help with the literature search. No compensation was provided or received.

      Condensation

      Although evidence regarding Postural Orthostatic Tachycardia Syndrome in pregnancy is scarce and of poor quality, it suggests the condition may be safe with close monitoring.

      Source of the work

      This work was completed at The University of Newcastle, Newcastle, New South Wales, Australia.

      Appendix A. Search strategy

      Tabled 1
      LineSearch termResults
      1Postural Orthostatic Tachycardia Syndrome328
      2(“postural orthostatic tachycardia syndrome” or “postural tachycardia syndrome”).ti,ab,kw.648
      3(orthostatic adj (tachycardia or intolerance)).ti,ab,kw.1327
      4exp Posture/68,505
      5exp Tachycardia/44,937
      64 and 5335
      71 or 2 or 3 or 61739
      8exp Pregnancy/826,342
      9exp Pregnancy complications391,368
      10Pregnancy Outcome/44,347
      11pregnan*.ti,ab,kw.463,795
      12(labo?r or antenatal or ante-natal or neonat* or postnatal* or post-natal* or primigravid* or post-partum or postpartum or obstetric* or childbearing or child-bearing or nulliparous or parous or gyn?ecolog*).ti,ab.591,015
      138 or 9 or 10 or 11 or 121,304,499
      147 and 1335
      15limit 14 to english language33
      Tabled 1
      LineSearch termResults
      1postural orthostatic tachycardia syndrome1204
      2(“postural orthostatic tachycardia syndrome” or “postural tachycardia syndrome”).ti,ab.1107
      3(orthostatic adj (tachycardia or intolerance)).ti,ab.2024
      4Postural tachycardia syndrome963
      51 or 2 or 3 or 42593
      6exp pregnancy/733,507
      7exp pregnancy complication/128,970
      8pregnancy outcome/46,963
      9pregnan*.ti,ab.615,926
      10(labo?r or antenatal or ante-natal or neonat* or postnatal* or post-natal* or primigravid* or post-partum or postpartum or obstetric* or childbearing or child-bearing or nulliparous or parous or gyn?ecolog*).ti,ab.801,834
      116 or 7 or 8 or 9 or 101,510,353
      125 and 1152
      13Limit 12 to English language51
      Tabled 1
      LineSearch termResults
      1(“postural orthostatic tachycardia syndrome” or “postural tachycardia syndrome”).ti,ab.59
      2(orthostatic adj (tachycardia or intolerance)).ti,ab.96
      3tachycardia/245
      4syndromes/13,333
      5autonomic nervous system disorders97
      64 or 513,611
      73 and 630
      81 or 2 or 7116
      9exp pregnancy/22,824
      10obstetrical complications/or pregnancy outcomes/2167
      11pregnan*.ti,ab.41,297
      12(labo?r or ante-natal or neonat* or postnatal* or post-natal* or primigravid* or post-partum or postpartum or obstetric* or childbearing or child-bearing or nulliparous or parous or gyn?ecolog*).ti,ab.81,829
      139 or 10 or 11 or 12111,329
      148 and 130
      Tabled 1
      LineQueryResults
      S1(MH “Postural Orthostatic Tachycardia Syndrome”)149
      S2TI (“postural orthostatic tachycardia syndrome” or “postural tachycardia syndrome”) OR AB (“postural orthostatic tachycardia syndrome” or “postural tachycardia syndrome”)243
      S3TI (“orthostatic tachycardia” or “orthostatic intolerance”) OR AB (“orthostatic tachycardia” or “orthostatic intolerance”)300
      S4S1 OR S2 OR S3397
      S5(MH “Pregnancy+”)166,264
      S6(MH “Pregnancy Complications”)14,344
      S7(MH “Pregnancy Outcomes”)18,027
      S8TI pregnan* OR AB pregnan*95,702
      S9TI (labour or labor or antenatal or ante-natal or neonat* or postnatal* or post-natal* or primigravid* or post-partum or postpartum or obstetric* or childbearing or child-bearing or nulliparous or parous or gynecolog* or gynaecolog*) OR AB (labour or labor or antenatal or ante-natal or neonat* or postnatal* or post-natal* or primigravid* or post-partum or postpartum or obstetric* or childbearing or child-bearing or nulliparous or parous or gynecolog* or gynaecolog*)128,070
      S10S5 OR S6 OR S7 OR S8 OR S9266,912
      S11S4 AND S1011
      S12S4 AND S10 Narrow by Language: - English11
      Tabled 1
      LineSearch termResults
      1MeSH descriptor: [Postural Orthostatic Tachycardia Syndrome] this term only19
      2“postural orthostatic tachycardia syndrome” or “postural tachycardia syndrome”68
      3“orthostatic tachycardia” or “orthostatic intolerance”162
      4MeSH descriptor: [Posture] explode all trees3934
      5MeSH descriptor: [Tachycardia] explode all trees1621
      6#4 and #524
      7#1 or #2 or #3 or #6179
      8MeSH descriptor: [Pregnancy] explode all trees5948
      9MeSH descriptor: [Pregnancy Complications] explode all trees9556
      10MeSH descriptor: [Pregnancy outcome] this term only3080
      11Pregnan*:ti,ab25,551
      12Labor or labour or antenatal or ante-natal or neonat* or postnatal* or post-natal* or primigravid* or post-partum or postpartum or obstetric* or childbearing or child-bearing or nulliparous or parous or gynecolog* or gynaecology*71,991
      13#8 or #9 or #10 or #11 or #1283,703
      14#7 and #133

      Appendix B. McMaster Critical Review Form for quantitative studies scores (
      • Law M.
      • Stewart D.
      • Pollock N.
      • Letts L.
      • Bosch J.
      • Westmorland M.
      )

      Tabled 1
      NoReferenceMcMaster quantitative critical appraisal scoring items
      12345678910Score
      1Kimpinski et. Al. 2010YYCase-controlYYN/AYYYY8/10
      2Glatter et. Al. 2005YYCase studyYN/AN/AYYYY7/10
      4Kanjwal et. Al. 2009YYSingle case designYN/ACTYYYY7/10
      5Blitshteyn et. Al. 2012YYSingle case designYN/AN/AYYYY7/10
      8Pramya et. Al. 2012YYCase studyYN/AN/AYYYY7/10
      12Lide and Haeri 2015YYCase studyYN/AN/AYYYY7/10
      13Powless et. Al. 2010YYSingle case designYN/AN/ACTYYY6/10
      14McEvoy et. Al. 2007YYCase studyYN/AN/AYYYY7/10
      15Corbett et. Al. 2006YYCase studyYN/AYYYYY8/10
      16Kodakkattil and Das 2009YYCase studyYN/ACTYN/AYY6/10
      17Jones and Ng 2008YYCase studyYN/AYYYYY8/10
      Y = Yes, N = No, CT = Cannot tell, N/A = not applicable.
      Item 1: Was the purpose stated clearly?
      Item 2: Was the relevant background literature reviewed?
      Item 3: Describe the study design.
      Item 4: Was the design appropriate for the study?
      Item 5: Was the sample described in detail? Was informed consent obtained?
      Item 6: Were outcome measures reliable and valid?
      Item 7: Was the intervention described in detail?
      Item 8: If appropriate, were results reported in terms of statistical significance? Were analysis methods appropriate?
      Item 9: Were all participants accounted for? If any participants dropped out from the study, were they accounted for?
      Item 10: Were study conclusions appropriate given the study methods and results?

      Appendix C. NHMRC Evidence Grading Matrix with overall scores from the review (
      • NHMRC
      NHMRC additional levels of evidence and grades for recommendations for developers of guidelines: stage 2 consultation.
      )

      Tabled 1
      ComponentABCDOverall score
      ExcellentGoodSatisfactoryPoor
      Volume of evidenceSeveral level I or II studies with low risk of biasOne or two level II studies with low risk of bias or a SR/multiple level III studies with low risk of biasLevel III studies with low risk of bias, or level I or II studies with moderate risk of biasLevel IV studies, or level I to III studies with high risk of biasD
      ConsistanceAll studies consistantMost studies consistant and inconsistence may be explainedSome inconsistency reflecting genuine uncertainty around clinical questionEvidence is inconsistantD
      Clinical impactVery largeSubstantialModerateSlight or restrictedD
      Able to generalisePopulation/s studied in body of evidence are the same as the target population for the guidelinePopulation/s studied in the body of evidence are similar to the target population for the guidelinePopulation/s studied in body of evidence different to target population for guideline but it is clinically sensible to apply this evidence to target populationPopulation/s studied in body of evidence different to target population and hard to judge whether it is sensible to generalise to target populationB
      ApplicabilityDirectly applicable to Australian healthcare contextApplicable to Australian healthcare context with few caveatsProbably applicable to Australian healthcare context with some caveatsNot applicable to Australian healthcare contextC

      Appendix D. PRISMA 2009 Checklist (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      )

      Tabled 1
      Section/topic#Checklist itemReported on page #
      Title
      Title1Identify the report as a systematic review, meta-analysis, or both.1
      Abstract
      Structured summary2Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.3–4
      Introduction
      Rationale3Describe the rationale for the review in the context of what is already known.5–7
      Objectives4Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).7
      Methods
      Protocol and registration5Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.N/A
      Eligibility criteria6Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.8
      Information sources7Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.8
      Search8Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.8
      Study selection9State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).9
      Data collection process10Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators11–12
      Data items11List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made9
      Risk of bias in individual studies12Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.9–12
      Summary measures13State the principal summary measures (e.g., risk ratio, difference in means).N/A
      Synthesis of results14Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.N/A
      Risk of bias across studies15Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).9–12
      Additional analyses16Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.N/A
      Results
      Study selection17Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.9
      Study characteristics18For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.9
      Risk of bias within studies19Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).9–12
      Results of individual studies20For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.N/A
      Synthesis of results21Present results of the review or each meta-analysis done, including confidence intervals and measures of consistency.9–12
      Risk of bias across studies22Present results of any assessment of risk of bias across studies (see Item 15).11–12
      Additional analysis23Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).N/A
      Discussion
      Summary of evidence24Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).23–26
      Limitations25Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).23–26
      Conclusions26Provide a general interpretation of the results in the context of other evidence, and implications for future research.26–27
      Funding
      Funding27Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.N/A

      Appendix E. List of included studies

      • 1.
        Blitshteyn S, Poya H, Bett GC. Pregnancy in postural tachycardia syndrome: clinical course and maternal and fetal outcomes. J Matern Fetal Neonatal Med. 2012;25(9):1631–1634.
      • 2.
        Corbett WL, Reiter CM, Schultz JR, Kanter RJ, Habib AS. Anaesthetic management of a parturient with the postural orthostatic tachycardia syndrome: a case report. BJA: The British Journal of Anaesthesia. 2006;97(2):196–199.
      • 3.
        Glatter KA, Tuteja D, Chiamvimonvat N, Hamdan M, Park JK. Pregnancy in postural orthostatic tachycardia syndrome. Pacing Clin Electrophysiol. 2005;28(6):591–593.
      • 4.
        Jones TL, Ng C. Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome. Int. 2008;17(4):365–369.
      • 5.
        Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Outcomes of pregnancy in patients with preexisting postural tachycardia syndrome. Pacing Clin Electrophysiol. 2009;32(8):1000–1003.
      • 6.
        Kimpinski K, Iodice V, Sandroni P, Low PA. Effect of pregnancy on postural tachycardia syndrome. Mayo Clinic Proceedings. 2010;85(7):639–644.
      • 7.
        Kodakkattil S, Das S. Pregnancy in woman with postural orthostatic tachycardia syndrome (POTS). J Obstet Gynaecol. 2009;29(8):764–765.
      • 8.
        Lide B, Haeri S. A Case Report and Review of Postural Orthostatic Tachycardia Syndrome in Pregnancy. American Journal of Perinatology Reports. 2015;5(1):e033.
      • 9.
        McEvoy MD, Low PA, Hebbar L. Postural orthostatic tachycardia syndrome: Anesthetic implications in the obstetric patient. Anesth Analg. 2007;104(1):166–167.
      • 10.
        Pramya N, Puliyathinkal S, Sagili H, Jayalaksmi D, Reddi Rani P. Postural orthostatic tachycardia syndrome complicating pregnancy: a case report with review of literature. Obstetric Medicine (1753-495X). 2012;5(2):83–85.
      • 11.
        Powless CA, Harms RW, Watson WJ. Postural tachycardia syndrome complicating pregnancy. J Matern Fetal Neonatal Med. 2010;23(8):850–853.

      Appendix F. Excluded studies and reason for exclusion

      • 1.
        Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Postpartum postural orthostatic tachycardia syndrome in a patient with the joint hypermobility syndrome. Cardiol Res Pract. 2009;2009:187543
      Exclusion reason: Patient developed POTS in the post-partum period.
      • 2.
        Kimpinski K, Iodice V, Low PA. Postural Tachycardia Syndrome associated with peripartum cardiomyopathy. Auton Neurosci. 2010;155(1–2):130–131
      Exclusion reason: Patient developed POTS in the post-partum period.
      • 3.
        Lide B, Haeri S. A Case Report and Review of Postural Orthostatic Tachycardia Syndrome in Pregnancy. AJP Reports. 2014;5(1):e33-e36
      Exclusion reason: Links to 2015 article of the same entitled (included article).
      • 4.
        Peggs KJ, Nguyen H, Enayat D, Keller NR, Al-Hendy A, Raj SR. Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome. International journal of gynaecology and obstetrics: The official organ of the International Federation of Gynaecology and Obstetrics. 2012;118(3):242–246
      Exclusion reason: Participants were required to have a diagnosis of POTS for at least six months prior to enrolling in the study, however pregnancy was assessed historically with no record of whether patients had a pre-existing diagnosis of POTS before pregnancy.

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