León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 https://doi.org/10.1186/s12884-022-05042-x RESEARCH Open Access Women’s values and preferences on low‑molecular‑weight heparin and pregnancy: a mixed‑methods systematic review Montserrat León‑García1,2,3*, Brittany Humphries4,5, Andrea Maraboto3, Montserrat Rabassa1, Kasey R. Boehmer3,6, Lilisbeth Perestelo‑Perez7,8,9, Feng Xie5,10, Irene Pelayo11,12, Mark Eckman13, Shannon Bates14, Anna Selva2,15 and Pablo Alonso‑Coello1,16 Abstract Background: Venous thromboembolism (VTE) in pregnancy is an important cause of maternal morbidity and mor‑ tality. Low-molecular-weight heparin (LMWH) is the cornerstone of prophylaxis and treatment of thrombotic events during pregnancy. LMWH has fewer adverse effects than other anticoagulants, does not cross the placenta, and is safe for the fetus. However, the use of LMWH during pregnancy is sensitive to womens’ underlying preferences. The objec‑ tive of this review is to systematically assess women’s values and preferences research evidence on this topic. Methods: We searched four electronic databases from inception to March 2022, and included studies examining values and preferences of using LMWH among pregnant women at risk of VTE. We followed a convergent integrated mixed-methods design to compare and contrast quantitative outcomes (utility and non-utility measures) and qualita‑ tive findings. We assessed the certainty of the values and preferences evidence with the GRADE approach for quanti‑ tative findings, and with GRADE-CERqual for qualitative evidence. Results were presented in a conjoint display. Results: We screened 3,393 references and identified seven eligible studies. The mixed methods analysis resulted in four themes. Datasets confirmed each other in that: 1) the majority of women consider that benefits of treatment outweigh the inconveniences of daily injections; and 2) main concerns around medication are safety and injections administration. Quantitative outcomes expanded on the qualitative findings in that: 3) participants who perceived a higher risk of VTE were more willing to take LMWH. Finally, we found a discrepancy between the datasets around: 4) the amount of information preferred to make the decision; however, qualitative data expanded to clarify that women prefer making informed decisions and receive support from their clinician in their decision-making process. Conclusions: We are moderately confident that in the context of pregnancy, using LMWH is preferred by women given its net beneficial balance. Integrating data from different sources of evidence, and representing them in a jointly manner helps to identify patient’s values and preferences. Our results may inform clinical practice guidelines and support shared decision-making process in the clinical encounter for the management of VTE in the context of pregnancy. *Correspondence: mleong@santpau.cat 1 Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 2 of 18 Keywords: Venous thromboembolism, Low-molecular-weight-heparin, Pregnancy, Values and preferences Background limitation, in which judgements about integration could Venous thromboembolism (VTE) in pregnancy is an rarely be made due to the lack of integration of data and important cause of maternal morbidity and mortality in findings [14]. Therefore, this review contributes to the developed countries [1], responsible for approximately field of mixed methods research by using an integrative- 1.5 to 2% of maternal deaths during pregnancy and the convergent design [15] that are optimal to conduct the postpartum period [2, 3]. The normal hypercoagulable study of this phenomena [16–18]. state during pregnancy increases the risk of develop- Our aim was to conduct a systematic review on values ing VTE by 5- to tenfold compared with non-pregnant and preferences for LMWH therapy during pregnancy women [2, 3]. Other medical conditions in pregnancy, using a mixed-methods integrative design. We conducted such as inherited or acquired risk factors for thrombo- this review as part of the DASH-TOP project [19] that sis (thrombophilia), can also increase risk of VTE and aims to improve the quality of thromboprophylaxis deci- poor pregnancy outcomes, including placental abrup- sions in this population. tion, preeclampsia, fetal growth restriction, stillbirth, and recurrent miscarriage [4]. Low-molecular-weight Methods heparin (LMWH) is the cornerstone of prophylaxis and We registered the protocol in PROSPERO treatment of thrombotic events during pregnancy and (CRD42020193925), and adhered to the PRISMA (Preferred the postpartum period [5]. LMWH has fewer adverse Reporting Items for Systematic reviews and Meta-Analyses) effects than other anticoagulants, does not cross the pla- 2020 statement [20]. centa, and is safe for the fetus [6, 7]. However, the use of LMWH during pregnancy is challenging, as it is expen- Design sive, uncomfortable to administer, may be associated We followed a mixed-methods approach [21–24] to syn- with an increased risk of major obstetrical bleeding, and thesize and integrate different types of evidence, either may jeopardize the use epidural analgesia [7–10]. quantitative and qualitative [25–27]. We followed a con- Like many other decisions in health care, the preven- vergent integrated design that comprises three-steps tion of VTE during pregnancy does not have a single (Fig. 1) i) Segregated data extraction and analyses of the best option. Many factors influence the decision-making evidence, maintaining a clear distinction between quan- process, and, therefore, it is considered a preference- titative and qualitative datasets with individual synthesis sensitive decision [11]. This is probably one of the rea- prior to the mixed-methods synthesis [24, 28]; ii) Integra- sons why in a recent critical appraisal of guidelines for tion of data following a QUANT + qual integration pro- the prevention and treatment of pregnancy-associated cedure [25]; and, iii) Mixed-methods synthesis. VTE, recommendations were inconsistent [5]. Similarly, one “strongly recommended for use in practice” guide- Data sources and searches line included in the critical appraisal, the American We used a validated search strategy to identify studies on Society of Hematology 2018, concluded that healthcare patients’ values and preferences [29]. The search strategy professionals should make decisions through a shared used terms related to LMWH and pregnancy. Searches decision-making (SDM) process, incorporating patients’ were conducted from inception to September 2020 in values and preferences [12]. the following databases: in MEDLINE (accessed via Pub- Two previous reviews have addressed the topic of val- Med), PsycINFO (accessed via EBSCO host), CINAHL ues and preferences in thrombosis [11, 13]. These reviews (accessed via EBSCO host), and The Cochrane Central show that patients’ values and preferences appear to Register of Controlled Trials (search strategies are avail- be highly variable. However, to date, there is not a spe- able in the Additional file 1. and preserve search strings cific review addressing women’s values and preferences on searchRxiv https://​searc​hrxiv.​org/). We conducted lit- for antithrombotic therapy during pregnancy. Further- erature surveillance via MEDLINE (accessed via PubMed more, one of these reviews [11] only included quantita- alerts) until the review was submitted for publication tive measures, while the other [13] collected information (July ­7th, 2022). We did not restrict our search by pub- from both quantitative and qualitative measures, but lication status, language, or date of publication. We also synthesized the information independently and did not reviewed reference lists of the included articles, and rel- integrate findings. Good Reporting of A Mixed Meth- evant systematic reviews. ods Study (GRAMMS) criteria have highlighted this León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 3 of 18 Fig. 1 Mixed-method analysis and synthesis Eligibility criteria Selection of studies and data extraction We included studies that enrolled pregnant women, or All steps were conducted independently by pairs of cali- women who were planning pregnancy, for whom antico- brated reviewers, using standardized and piloted forms. agulation with LMWH was considered and: Disagreements were resolved with the help of a third reviewer. • Examined women’s values and preferences for We extracted information on—study design; objectives; LMWH vs. watchful waiting or alternative antico- population characteristics (mean age, level of education agulant therapy. and income level); reasons for VTE risk in pregnancy • Examined choices patients make when presented (for example: history of VTE, thrombophilia, mechani- with management options regarding antithrombotic cal heart valves, antiphospholipid syndrome); if LMWH therapy. was used for prevention or treatment during antepartum, • Examined women’s experiences and beliefs of postpartum or both periods; and, a description of the LMWH therapy in pregnancy. methods used to obtain preferences (including instru- We considered studies to be eligible using preference- ments and techniques for preference elicitation). Out- elicitation methods detailed in (Fig. 2) Selva.et.al. 2017 comes included quantitative utility values and non-utility [13, 29]. measures (collected as means with standard deviations, interquartile ranges or percentages, as available), and We excluded studies that rated health states related qualitative preferences (collected as themes and illustra- to VTE in pregnancy, but did not involve the decision tive quotes). of whether to use LMWH. We also excluded studies addressing the use of other antithrombotic medicines Data synthesis and analysis such as aspirin. Finally, we excluded study protocols, con- We conducted a descriptive analysis for quantitative data ference abstracts, reviews, and non-peer reviewed publi- [30]. For utility outcomes, we reported the mean value cations such as letters or editorials. for the scores of the health state ‘Pregnancy with LMWH’ (participants rate how close the health state ‘pregnancy with LMWH’ is to good health on a 0–100 scale) [13, 31]. León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 4 of 18 Fig. 2 Preference-elicitation methods For non-utility outcomes, we reported overall means, fre- Appraisal of the evidence quencies or proportions. For quantitative studies, we applied the GRADE approach to For qualitative findings, we conducted open coding the- assess the risk of bias and certainty of evidence [34, 35]. For matic analyses to collect and analyze the data [28, 32, 33]. qualitative studies, we used the CASP Qualitative Check- We extracted interpretative findings reported by authors list tool [36, 37] to appraise the methodological quality, and and supporting quotes. We categorized these findings in the CERQual (Confidence in the Evidence from Reviews of themes using an iterative process that involved a careful Qualitative Research) approach to assess the certainty of and repetitive reading of all pieces of extracted text. evidence [38]. For the mixed-method synthesis we integrated the To assess the certainty of the evidence of the mixed- data following a QUANT + qual design [25]: themes methods findings, we selected the dataset with the high- from the quantitative data were prioritized and sup- est certainty of evidence [39]. plemented with qualitative findings (the rationale for having the quantitative dataset leading the integration Results is that there is a larger body of evidence [29]). We pre- Study and population characteristics sented this integration process using a conjoint display We identified 3,393 references, of which eight publica- [22, 26, 27]; specifically, we used a side-by-side com- tions [40–47] reporting on seven studies met our eligibil- parison [21, 22, 27] to assess whether datasets were in ity criteria (Fig. 3). discordance, confirmation, or expansion [27]. Discord- Included studies are summarized in Table 1. ance was defined as quantitative and qualitative results From the studies, we included information on 427 that were inconsistent or contradictory. Confirmation women, with a mean age of 33.8 years (SD = 5.53). Two occurred when findings from both types of data rein- studies were focused on the antepartum period [41, 43, forced each other. When findings from one type of data 47] in women where the risk of VTE was exclusively due expanded upon insights from the other type of data, this to history of VTE: one compared their choices regard- was classified as expansion. Findings were synthesized ing thromboprophylaxis [41, 47]; the other [43] stud- and reported narratively and tabulated. ied the use of unfractionated heparin (UFH) for both prevention and treatment purposes; although UFH León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 5 of 18 was not part of our inclusion criteria we included this Quantitative outcomes study as the authors reported on the preference regard- ing injectable administration of heparin, and in this Utility measures: Pregnancy with LMWH prophylaxis regard we found it relevant to inform the context of this decision-making process. Two studies [40, 42] focused In women with a previous VTE event, the utility value for on the postpartum period for women with multiple the health state ‘pregnancy with LMWH prophylaxis’ was risk factors for VTE. In both cases, authors explored measured using a feeling thermometer (a visual analogue women’s views, experiences and adherence to LMWH scale (VAS)) [41, 47]. The overall mean and standard for VTE prevention alone. The other three studies [44– deviation (SD) was 81 [15], meaning that women placed 46] assessed preferences, both during the antepartum receiving LMWH injections during pregnancy at around and postpartum periods: two [45, 46] included women 80 on a scale of 0 to 100, hence, taking LMWH during with antiphospholipid syndrome, which is associated pregnancy as something relatively close to good health. with recurrent pregnancy loss. The other study [44], included women with multiple risk factors such as his- Non‑Utility measures: Willingness to take LMWH tory of VTE, antiphospholipid syndrome, stillbirth in previous pregnancy and placental complications. They One study [41, 47] assessed the willingness for thrombo- collected views and beliefs about enoxaparin prescribed prophylaxis with LMWH in the antepartum population for both prevention and treatment. (in women with a previous VTE event) using two differ- ent instruments: Women’s values and preferences One of the included studies reported utility measures [41, 47], five reported non-utility measures [40–44, 47], and i) A direct choice exercise in which authors presented three studies informed qualitative findings [44–46]. women with a decision board that described differ- Women’s preferences reported from quantitative stud- ent risks of developing VTE during pregnancy based ies are outlined in Table S1, and from qualitative studies on characteristics of their prior VTE. The results in Table S2 (available in Additional file 2). showed that the majority of women were willing to take LMWH, regardless of their VTE risk, and that Fig. 3 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA. Statement 2020) flow chart) Table 1 Study and population characteristics Author, Year, Objective Population Methods GRADE (Risk Country of Bias) / [reference] CASP (unmet methodological quality criteria) Participants, n Mean age Education (%) Race (%) Pregnancy Indication Study Outcome (years) (SD / period, Reason for the use of design [Data presentation: range) for VTE risk in LMWH Collection Measurement pregnancy Methods] instrument Anderson, 1993 To determine 12 28.6 NR NR Period: Ante- Prevention/ Cross-sectional Non-utility: [43] the following: partum Treatment [Questionnaire] Researchers Moderate risk of Canada (1) whether Reason: Previ‑ self-developed bias women requir‑ ous VTE event questionnaire León‑García et al. BMC Pregnancy and Childbirth ing subcutane‑ ous heparin therapy during pregnancy pre‑ ferred admin‑ istering the (2022) 22:747 drug through an indwelling Teflon catheter as opposed to receiving twice daily subcutane‑ ous injections and (2) the efficacy and feasibility of administering heparin through an indwelling Teflon catheter Bates 2016 [41], To compare 123 33.94 (6.2) (1) Not NR Period: Ante- Prevention Cross-sectional Utility: Direct Eckman 2015 women’s complete high partum [Value elicita‑ techniques: VAS Moderate risk of [47], choices regard‑ school: 13.8% Reason: Previ‑ tion exercises Non-utility: bias Multicenter: ing thrombo‑ (2) Completed ous VTE event and Direct choice Canada, USA, prophylaxis dur‑ high school: Direct choice exercise Brazil, Finland, ing pregnancy 18.7% exercise] Norway and (3) Some post- Spain secondary or higher: 67.5% Page 6 of 18 Table 1 (continued) Author, Year, Objective Population Methods GRADE (Risk Country of Bias) / [reference] CASP (unmet methodological quality criteria) Participants, n Mean age Education (%) Race (%) Pregnancy Indication Study Outcome (years) (SD / period, Reason for the use of design [Data presentation: range) for VTE risk in LMWH Collection Measurement pregnancy Methods] instrument Guimicheva To explore 67 36.2 (4.4) NR Caucasian (73.1) Period: Post- Prevention Cross-sectional Non-utility: 2019 [40] women’s views, African-Carib‑ partum [Questionnaire] BMQ- question‑ Serious risk of UK experiences bean (23.9) Reason: Previ‑ naire bias León‑García et al. BMC Pregnancy and Childbirth and adherence Other (3.0) ous obstetric to postnatal complications thrombo‑ prophylaxis Hordern, 2015 To assess 111 NR NR NR Period: Post- Prevention Cross-sectional Non-utility: [42] reported patient partum [Structured Researchers Serious risk of (2022) 22:747 UK compliance Reason: Multi‑ interview] self-developed bias with a standard ple risk factors questionnaire course of post‑ for VTE: Previous natal throm‑ VTE event, boprophylaxis unprecedented in the form of thrombophilia low-molecular- thrombosis, and weight heparin previous obstet‑ (LMWH) ric complica‑ tions Martens, 2007 To explore 9 30 to 36 NR NR Period: Ante- Prevention Qualitative Qualitative: 4 and ­6a [45] the unique partum and [Semi-struc‑ Analytical Canada experiences, post-partum tured interview] themes challenges, and Reason: coping strate‑ Unprecedented gies of pregnant thrombophilia women thrombosis diagnosed with thrombophilia and who are on daily heparin injections Page 7 of 18 Table 1 (continued) Author, Year, Objective Population Methods GRADE (Risk Country of Bias) / [reference] CASP (unmet methodological quality criteria) Participants, n Mean age Education (%) Race (%) Pregnancy Indication Study Outcome (years) (SD / period, Reason for the use of design [Data presentation: range) for VTE risk in LMWH Collection Measurement pregnancy Methods] instrument León‑García et al. BMC Pregnancy and Childbirth Patel 2012 [44] To monitor 95 (quantitative) 33.03 years NR Caucasian (56.8) Period: Ante- Prevention/ Multiple meth‑ Non-utility: UK women’s adher‑ 30 (qualitative) (range 18–46) African-Carib‑ partum and Treatment odology BMQ- question‑ Moderate risk of ence to enoxa‑ bean (31.6) post-partum [questionnaire naire bias parin when pre‑ Asian (4.2) Reason: Multi‑ with open- Qualitative: scribed during Other (7.4) ple risk factors ended ques‑ Open-ended pregnancy and for VTE: Previous tions] questions the puerperium VTE event, (2022) 22:747 and to explore unprecedented women’s views thrombophilia and beliefs thrombosis, and about the previous obstet‑ enoxaparin ric complica‑ prescribed tions Skeith 2021 [46] To understand 10 NR NR NR Period: Ante- Prevention Qualitative Qualitative: 4 and ­6a Canada how patients partum and [Semi-struc‑ Analytical and physi‑ post-partum tured interview] themes cians navigate Reason: the decision- Unprecedented making process thrombophilia for use of LMWH thrombosis and and/or ASA in previous obstet‑ pregnancy ric complica‑ tions: at least 1 prior late pregnancy loss (> 10 weeks gestation) or 2 early preg‑ nancy losses (< 10 weeks gestation) a Criteria 4 and 6 correspond to CASP instrument criteria: selection bias and lack of consideration of the relationship between researchers and participants, respectively. NR: Not reported Page 8 of 18 León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 9 of 18 the higher their risk, the greater was their willingness One study [43] assessed the preferred mode of adminis- to take it. tration for UFH in women with a previous VTE event. ii) A probability trade-off exercise in which authors used The majority preferred injecting heparin through a Tef- this instrument to determine women’s thresholds lon catheter over standard subcutaneous injections. This for accepting LMWH prophylaxis [41]. The median was due mainly because it caused less pain and less bruis- threshold reduction in VTE risk at which women ing than injections. were willing to accept use of LMWH was 3%. Fur- thermore, women with less previous (under 2 weeks) Preferred amount of information regarding LMWH experience with LMWH during pregnancy compared to those with more experience, required a greater One study [42] assessed preferences regarding the VTE risk reduction; it also showed that there were no amount of the information given about the decision to significant differences between pregnant women and use LMWH during postpartum in women who had mul- women planning pregnancy. tiple risk factors for VTE in postpartum: the majority of women reported that they had received enough informa- Another study [42] assessed compliance with thrombo- tion about treatment, however 16.6% reported that they prophylaxis in women with thrombophilia, and reported would have liked more information or training on injec- that if thromboprophylaxis was indicated in a future tions before leaving the hospital. pregnancy, most women (94.5%) would accept it. Beliefs towards the harms, overuse, necessity, and Qualitative findings concerns of taking LMWH Qualitative findings included results mainly from women with unprecedented thrombophilia, but one of the stud- Two studies [40, 44] used the Beliefs about Medicines ies also included other risk factors for VTE [44]. We syn- Questionnaire (BMQ) [48] to assess the perception of thesized qualitative findings using five main themes. using LMWH in women in the postpartum period who have presented a previous obstetric complication [40] Attitude towards LMWH during pregnancy or had multiple risk factors for VTE [44]. The BMQ The majority of women were willing to receive LMWH questionnaire includes 18-items and four subscales injections [44–46]. They felt that responding to their assessing beliefs associated with the medication (in this situation by taking action with daily LMWH injections case use of enoxaparin). Subscales for general harm and comforted them and decreased anxiety. Women under- overuse (based on four items each) could have a mini- stood that the desired outcome of a successful pregnancy mum score of four and a maximum score of 20. Sub- could not be predicted and they accepted uncertainty scales for specific necessity and concerns (based on five and maintained the perspective that a positive outcome items each) have a minimum score of five and a maxi- far outweighed any temporary discomfort. Miscarriage mum score of 25. was considered a very traumatic situation and was per- ceived as leading to a high risk of complications during The Necessity-Concerns Differential (NCD) [48], is used pregnancy, thus they felt motivated to use LMWH; in the to report on the balance between necessity and concerns study [44] that included women at low risk for VTE, par- of medications. The Necessity-Concerns Differential ticipants still reported anxiety relief by using LMWH. (NCD) was found to be 1.18 [40] and 2.20 [44], both with a positive differential, suggesting that women felt that the Experience of using LMWH during pregnancy necessity of the enoxaparin was greater than any con- Three studies [44–46] reported challenges with injec- cerns they may have held regarding its use. tions, such as bruising, pain, and bleeding; one study [44] stated that easier routes of administration would be Reason for not being adherent when using LMWH desirable. However, complications of the medication did not influence the decision to take LMWH, and it became One study [42] conducted in women who had multiple part of their pregnancy experience. risk factors for VTE in postpartum, reported reasons for not completing treatment that included bruising or Concerns about medication wound complications; forgetting; fear or dislike of nee- The main concern surrounding LMWH was safety dles, and emotional reasons for stopping. [44–46]. The majority of women placed a higher prior- ity on their baby’s safety. However, in one study first-time Preference for route of administration mothers placed a higher priority on the baby’s safety, León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 10 of 18 while mothers with other children prioritized their own desired outcome of a successful pregnancy could not health. Other concerns included fear of forgetting a dose; be predicted, and uncertainty was well tolerated. The fear of needles; fear of bleeding during labor; and need- quantitative data expands on this by showing a direct ing a scheduled labor (off LMWH) to be able to get an relationship between high perceived risk and increased epidural. willingness to take the medication. Information needs to inform the decision Beliefs towards medication Two studies [44, 45] found that the majority of women This mixed-method theme was reported by six studies felt they had not received enough information to address [40, 42–46]. There was confirmation that women viewed their concerns. Most frequently, women felt uninformed LMWH more as a necessity than a concern; the main about how LMWH worked, injection technique and side consideration being safety, especially for their unborn effects. The information was not always prompted by the baby. Women preferred to use devices that facilitated physician and, in many cases, there were limited available the administration of the injections. Qualitative data resources for women. Information was gathered from dif- expanded upon quantitative data, by reporting other ferent sources including the internet, books on pregnancy, concerns associated with antepartum use of LMWH (for health professionals, or word of mouth. Sharing stories with example, withholding injections before a scheduled labor other women proved to have a compelling influence on and delivery). decision making, and was also reassuring and encouraging. Patient involvement in the decision-making Preferred amount of information regarding LMWH Seeking information proved a powerful means by which This mixed method theme was the least informed. Three women were able to take control and actively address studies reported discordances [42, 44, 45] and four their needs. In addition, patients described how physi- included expansion [42, 44–46]. Discrepancies occurred cians influenced their decision-making process, highlight- when women were asked about their preferences for ing the importance of the physician–patient relationship the amount of information they received. Quantitative [44–46]. Patients felt empowered by their healthcare pro- results reported that women felt well-informed, while the fessionals and did not feel pressured to take LMWH. Sev- opposite was the case in qualitative findings. eral women [45] expressed anxiety regarding the weight of In qualitative reports women understood that benefits responsibility involved in making medical decisions that outweighed risks, but they didn’t feel they had sufficient could affect the pregnancy outcome. information, especially about the effect of LMWH on their condition, injection techniques, side effects, or Mixed‑methods results what to do if a difficult situation arose. Qualitative data Three quantitative outcomes (Beliefs about harms, over- also expanded findings, showing that this decision needs use, necessity, and other concerns about taking LMWH; adequate support from the healthcare professional. reasons for reason for not being adherent when using LMWH; preference for route of administration) were Quality appraisal merged into a single outcome to inform the correspond- Assessments of the quality of the evidence are available ing mixed-methods theme (“Beliefs towards medica- Additional file 3. The certainty of the evidence for all the tion”). Four mixed-methods themes were identified. quantitative outcomes was rated as very low, mainly due to Results are detailed in Table 2. risk of bias (unclear sampling strategies [41, 43, 44, 47] and high attrition rates [40, 42]); indirectness (due to meth- Pregnancy with LMWH prophylaxis odological elements [40–44, 47]); and imprecision (small This theme was informed by four studies [41, 44–47]. sample sizes [40–44, 47]). Regarding qualitative research, Both datasets confirm findings on considering this health both studies [45, 46] presented methodological concerns state as close to ‘perfect health’ and having LMWH as an regarding selection bias, and lack of consideration of the option far outweighed any temporary discomfort caused relationship between researchers and women. The con- by the injections. Prior experience using LMWH was fidence for all qualitative findings was moderate (due to important and very informative on how women consid- concerns about rigor (unclear recruitment and sampling ered daily injections. strategy)) except for the finding Information needs to inform the decision [44, 45], which was rated as low, due Willingness to take heparin to concerns regarding adequacy and relevance of the data. Five studies informed this theme [41, 42, 44–47]. Both The certainty of the evidence for all the mixed-methods data sets confirmed that the majority of women would themes was rated as moderate, except for ‘Adequacy of the be willing to take LMWH; that they understood that the information regarding LMWH’ which was low. Table 2 Conjoint display Mixed-methods Quantitative outcomes Qualitative findings Mixed-methods findings Certainty of themes [ref] (Confirmation, Expansion, Discordance) the evidence Pregnancy with Utility Value: Mean Certainty of Theme(s) [ref ], representative quote Certainty of LMWH prophylaxis VAS scale (0–100) evidence evidence [Bates [ref ] 2016 [41], Eck‑ [Bates 2016 [41], Very Low Attitude towards the decision -making of Moderate Confirmation man2015 [47]; Eckman 2015 [47]] using LMWH Both datasets confirm the relief of having LMWH as an option far outweighed Moderate Skeith 2021 [46]; [Skeith 2021 [46]; Martens 2007 [45]; Patel any temporary discomfort caused by the injections, and reduced anxiety Martens 2007 [45]; 2012 [44]] towards the disease Patel 2012 [44]] LMWH injections with “minimal side effects, and that, compared to the emotional pain with loss, a little bit of physical pain from a needle is small potatoes] León‑García et al. BMC Pregnancy and Childbirth Experience of using LMWH during pregnancy Moderate [Skeith 2021 [46]; Martens 2007 [45]; Patel 2012 [44]] Although it wasn’t fun injecting myself it was part of the ritual. …It felt like I was doing something instead of just waiting there to (2022) 22:747 see if I would miscarry. …It felt like I at least had a very, very, very small hand in helping] Willingness to take Non-utility: Propor‑ Certainty of Theme(s) [ref ], representative quote CERQUAL assess‑ heparin tion (%) of women evidence ment [Bates 2016 [41], willing to take Eckman 2015 [47]; heparin (instru‑ Hordern 2015 [42]; ment [ref ]) Skeith 2021 [46]; -78.86 (direct Very Low Attitude towards the decision -making of Expansion Martens 2007 [45]; choice) Very Low using LMWH [Skeith 2021 [46]; Martens Moderate Women accepted uncertainty regarding the pregnancy outcome and were will‑ Moderate Patel 2012 [44]] [Bates 2016 [41], 2007 [45]; Patel 2012 [44]] ing to take heparin as it was felt they were taking- action on the management Eckman2015 [47]] When you want to have a baby … nothing of their condition. Most of the women from the qualitative data were using -94.5 ­(RSQb) will stop you LMWH to prevent pregnancy loss, hence higher risk perception than when used [Hordern 2015 [42]] Definitely gives me piece of mind during to prevent DVT (as shown by the non-utility values; women at lower risk were Non-utility: Median pregnancy; without it I would feel very nerv- less willing to take the medication). Risk perception is correlated with willing to (%) of risk reduc‑ ous about developing another DVT take LMWH tion of LMWH to be willing to take (instrument [ref ]) 3 (probability Very Low trade-off ) [Bates 2016 [41], Eckman 2015 [47]] Page 11 of 18 Table 2 (continued) Mixed-methods Quantitative outcomes Qualitative findings Mixed-methods findings Certainty of themes [ref] (Confirmation, Expansion, Discordance) the evidence Beliefs towards Non-utility: Mean Certainty of the Theme(s) [ref ], representative quote CERQUAL assess‑ medication (± a) Necessity- evidence ment Moderate [Guimicheva 2019 concerns differ‑ [40]; Patel 2012 ential (instrument [44]; Hordern 2015 [ref ]) [42]; Anderson 1993 [43]; Skeith + (BMQ- Scale) Very Low Concerns about medication Moderate Confirmation 2021 [46]; Martens [Guimicheva 2019 [Skeith 2021 [46]; Martens 2007 [45]; Patel Patients focused on safety issues. Women place a higher priority on the impact 2007 [45]; Patel [40]; Patel 2012 2012 [44]] LMWH has on the unborn baby compared with any impact the medicine may 2012 [44]] [44]] I wanted a baby so bad, I was like I don’t care, have on them I’ll do it… the chance of it harming me… León‑García et al. BMC Pregnancy and Childbirth Non-utility Values: Certainty of the Theme(s) [ref ], representative quote CERQUAL assess‑ Reasons for not evidence ment being adherent when using LMWH (% of women) (instrument [ref ]) (2022) 22:747 -Bruising (25 ­(RSQb) Concerns about medication Expansion [Hordern 2015 [42]] Very Low [Skeith 2021 [46]; Martens 2007 [45]; Patel Moderate Other concerns provided by the qualitative data were regarding withholding Moderate -Forgetting 2012 [44]] injections before delivery and a scheduled labor (16.6(RSQb So, then you’ re worried because labor it isn’ t [Hordern 2015 [42]] always planned, right, and what if … I mean -Fear or dislike what if I went into labor at 33 [weeks] and of needles I took [LMWH] yesterday or I took it today (16.6(RSQb) and I would worry that I would go into labor; [Hordern 2015 [42]] what would ultimately happen, being on the medication and going into labor Non-utility Values: Certainty of the Theme(s) [ref ], representative quote CERQUAL assess‑ Preference for evidence ment route of adminis‑ tration (Instrument, % of women) ([ref ]) Teflon catheter Very Low Experience of using LMWH during Confirmation ­(RSQb) = 83.3 pregnancy Moderate Women from both datasets agreed that they preferred devices that would Moderate [Anderson 1993] [Skeith 2021 [46]; Martens 2007 [45]; Patel facilitate administration of injections [43] 2012 [44]] If there was a way to get injections for enoxa- parin via an epipen type device it would be much more tolerable Page 12 of 18 Table 2 (continued) Mixed-methods Quantitative outcomes Qualitative findings Mixed-methods findings Certainty of themes [ref] (Confirmation, Expansion, Discordance) the evidence Preferred amount Non-utility Certainty of the Theme(s) [ref ], representative quote CERQUAL assess‑ of information Values: Adequate evidence ment regarding LMWH information [Hordern 2015 [42]; regarding LMWH Skeith 2021 [46]; (Instrument, % of Martens 2007 [45]; women) ([ref ]) Patel 2012 [44]] Whether Information needs to inform the decision Discordance woman had Very Low [Martens 2007 [45]; Patel 2012 [44]] Low While quantitative data showed that patients felt well-informed about their Low received enough I have no issues injecting if it is safeguard- decision; in qualitative data the majority of women felt they had not received León‑García et al. BMC Pregnancy and Childbirth information ing mine and the baby’s health but I lack enough information to address their concerns. Women expressed feeling regarding LMWH some faith in the safety/side-effects/ general confused about how VTE could affect their baby, how it could compromise their ­(RSQb) = 83.8 effects of the medicine. Published informa- own health and why it was particularly relevant during pregnancy [Hordern 2015 [42]] tion on Clexane seems to be contradictory Patient involvement in the decision- making (2022) 22:747 [Skeith 2021 [46]; Martens 2007 [45]; Patel 2012 [44] ] I do not have a problem doing injections and was aware of the possibility of the injections before becoming pregnant. However, I think other women might benefit from more time and support around the use of Clexane in their pregnancy Patient involvement in the decision- Expansion making Moderate Qualitative data informed that women felt involved in the decision-making; Moderate [Skeith 2021 [46]; Martens 2007 [45]; Patel healthcare professionals are an important role in support the decision-making 2012 [44]] process I felt pretty involved. I didn’t feel like pressured into taking [LMWH] if I did get pregnant. It was really up to me to say I want to take the injections or not… I felt involved in the decision Would have liked Information needs to inform the decision Discordance more information Very Low [Martens 2007 [45]; Patel 2012 [44]] Low Datasets are in discordance in whether it was an informed decision-making pro‑ Low or training before No, I don’t remember being given any cess. Injection administration technique was an important need of information leaving hospital information and you are insecure about ­(RSQb) = 16.6 the whole subject, so you are not prepared [Hordern 2015 [42]] to ask questions because you don’t know what to ask a ( ±): Positive values ratio means that women place higher value to the necessity of medication than concern; for negative values it would be the opposite (BMQ scale) b RSQ Researchers self-developed questionnaire Page 13 of 18 León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 14 of 18 Discussion populations included women using LMWH to prevent miscarriage (women with thrombophilia) and women Main findings using it as thromboprophylaxis to prevent recurrent Our mixed methods systematic review is the first to VTE. Risk perceptions differ according to the condition assess preferences of women towards using LMWH for which LMWH was going to be used for. This was evi- during pregnancy. We included seven studies: five stud- dent in one of the studies that included both populations; ies [40–44, 47] were conducted among women who had those with thrombophilia had higher risk perception vs a history of VTE, in which heparin was used for VTE those with a prior VTE [44]. Thus, we were unable to prevention and/or treatment in the ante- and/or post- meta-analyze preferences for each population group: pre- partum period. The other two qualitative studies [45, 46] vious VTE event, unprecedented thrombophilia throm- were conducted in women with thrombophilia, where bosis, and previous obstetric complications. Despite LMWH was used to reduce risk of miscarriage. these limitations, by leveraging both qualitative and After quantitative and qualitative datasets were quantitative data, our review was able to demonstrate a merged, four mixed- methods findings were identified relationship between level of VTE risk and willingness to reporting on women’s preferences towards using LMWH take LMWH. during pregnancy. Another limitation of our review was the lack of con- For all included women (women with a previous VTE sideration for other VTE treatment options like aspirin event, unprecedented thrombophilia thrombosis, and (ASA), which is recommended by various obstetrician previous obstetric complications), datasets confirmed societies [8, 51–53] to reduce obstetric complications each other in that: 1) the majority of women considered such as preeclampsia. Despite that, we included only that benefits of treatment outweighed the inconvenience LMWH because it is the unique anticoagulant show- of daily injections; and 2) main concerns were about ing safety for the baby as it does not cross the placenta. medication safety and the need to give injections. Quan- The encouraged use of the combination LMWH with titative outcomes expanded on the qualitative findings ASA [51, 53] by obstetricians should be noted and future in that: 3) women who perceived a higher risk of VTE research should address women’s preferences for this (those who had an unprovoked previous VTE and those combination, especially in women at high risk [9, 52]. with thrombophilia) were more willing to take LMWH. As noted in other reviews of values and preferences Finally, we found a discrepancy between the datasets [13, 54], we were able to collect and analyze quantitative regarding: 4) the amount of information preferred to data more easily than qualitative data. As measures are make the decision; however, qualitative data expanded inconsistent and we lack a specific framework to guide to clarify this discrepancy. Women expressed feeling the analysis of qualitative data, we opted to use an open confused about how VTE could affect their baby, how it coding approach for extracted data, which is the gold could compromise their own health, and why it was par- standard methodology to study phenomena in qualita- ticularly relevant during pregnancy. Therefore, informed tive methods [28, 33]. In addition, we used a validated decisions are preferred and the role of clinicians to sup- search strategy that was designed to include qualitative port their decision-making process was highlighted for studies containing preferences [29] to ensure the identifi- women with multiple risk factors for VTE: previous VTE cation of the full body of qualitative evidence. Therefore, event, unprecedented thrombophilia thrombosis, and a strength of this systematic review was our demonstra- previous obstetric complications. tion that qualitative methods are useful to inform on The overall quality of the evidence was moderate. the context, the grounds by which the decision is made; and address issues like level of information is needed to Limitations, strengths and previous research inform the decision, what is the preferred level of patient Our review has several limitations. There are still very involvement, and the role of the healthcare professional few studies, including very few women, in this field. As in supporting the decision [46]. a result of this limitation in the body of evidence, we Assessing the certainty of the evidence is critical in only captured preferences for women at risk for VTE or understanding how our findings support suggestions pregnancy loss during pregnancy. We were not able to to use shared decision-making in clinical practice and identify preferences in other conditions such as women guideline development. Although, there are specific with heart valve prostheses [8, 9, 49, 50]. In addition to quality of evidence appraisal tools for mixed- methods the limited number of published studies, another reason systematic reviews, these methods still face the chal- to downgrade the quality of the evidence in our review lenge of assessing integrated findings [55]; hence, we is inconsistency across studies. For example, for out- assessed independently the certainty of the evidence for comes such as “willingness to take LMWH” the patient both datasets using the GRADE approach, which has León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 15 of 18 specific guidance for the topic. We used specific guide- More research is needed on specific qualitative frame- lines to assess the evidence about values and preferences works to assess preferences delivered through qualitative described in quantitative findings [34, 35], and used instruments, such as interviews or clinical observations GRADE-CERqual to judge qualitative evidence. [34, 35, [63]. For example, one study [46] included in this review 56]. Finally, we selected findings with the highest cer- reported that the husband of a pregnant women was very tainty to inform the quality of our mixed- methods find- concerned about the safety of LMWH and its effect on ings [39]. his wife’s health. ‘What other people think I should do’ An important strength of this review is the mixed-meth- is an aspect that can affect the decision. Burke’s motives ods integrative approach, which expanded our findings, by pentad framework was used to deductively categorize increasing the ability of data analyzed and subsequently patient reflections by their reasons, as to why their care used to inform policy and practice [25]. The design of this plans made sense in the context of thromboprophylaxis review leverages qualitative and quantitative data to help in atrial fibrillation decision-making [64]. us confirm and expand on findings, as well identify dis- In addition, further guidance from the GRADE-CER- cordances between the types of data. Other mixed-meth- QUAL group is also needed to assess certainty of the evi- ods systematic reviews [13, 54, 57] assessing preferences dence in mixed methods reviews that integrates findings using different methods to analyze outcomes, rarely inte- coming from different methodologies. The CERQUAL grated data from quantitative and qualitative datasets to methodology to assess the relevance and adequacy improve understanding of the phenomena [25]. The con- domains [65, 66] may help clarify when findings coming duction of an integrative analysis contributes to the field of from different study designs are complementary or dis- mixed methods research [15] and specifically in the field of cordant among studies [38]. systematic reviews [28, 58]. Also, attempting to integrate data and findings from the individual components is con- Conclusion sidered adequate criteria in Good Reporting of A Mixed This mixed-method systematic review showed among Methods Study (GRAMMS) [14]. women at risk for recurrent VTE during pregnancy and pregnancy loss, LMWH prophylaxis was preferred to Implications for practice and research watchful waiting due to its perceived net clinical ben- Venous thromboembolism is recognized as a leading efit. However, more evidence is needed in women at cause of maternal death in high income countries and the lower risk of VTE in pregnancy as the certainty of this use of LWHM is the gold standard preventive and treat- evidence was only moderate. Integrating data from dif- ment strategy [10, 59]. However, the efficacy of LMWH ferent sources of evidence, and representing them in a in pregnancy continues to be uncertain, mainly due to joint manner helps us better understand women’s pref- the high rate of refusals in RCT [60–62] over 20% of the erences and contributes to the field of mixed-methods included participants. Clinicians included in these trials research. Our results may inform clinical practice showed to be dedicated, well-informed, and experienced guidelines and support a shared decision-making pro- counselors. However more research is needed on wom- cess in the clinical encounter for the management of en’s preferences for VTE prophylaxis during pregnancy VTE in the context of pregnancy. (specially in high risk and for preventive purposes) to support this clinical decision-making. Our findings can Supplementary Information support recommendations [12, 52] regarding the types The online version contains supplementary material available at https://​doi.​ of information pregnant women at risk of VTE need to org/​10.​1186/​s12884-​022-​05042-x. participate in a SDM process and raise awareness among Additional file 1. obstetricians and anesthesiologists that potential risks Additional file 2. are high and prepare them for timely adaptation of medi- Additional file 3. cation when necessary [10]. These factors have been shown to influence the decision-making process [46], and their clarification is especially important in low risk set- Acknowledgements Montserrat León- García is a doctoral candidate for the Ph.D. in Methodology tings (i.e., women with a prior history of VTE associated of Biomedical Research and Public Health, Universitat Autònoma de Barcelona, with a non-hormonal temporary provoking risk factor), Barcelona, Spain; and this review will be part of her thesis dissertation. The in which we showed lower levels of willingness to take authors wish to acknowledge and thank Yang Song, Ena Pery Niño de Guzmán Quis, Claudia Valli, Claudio Rocha for their contributions on abstract screening antithrombotic treatment [41, 47]. This is particularly rel- and guidance on approaching mixed-methods methods. We thank Ivan Solá evant when using systematic reviews to inform the devel- for his help on conducting and executing the search strategy. opment of tools used to support SDM [19]. León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 16 of 18 Authors’ contributions References CrediT authorship contribution statement. ML-G: Conceptualization, Meth‑ 1. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ. odology, Formal analysis, Data curation, Investigation, Writing – original draft, Trends in the incidence of venous thromboembolism during pregnancy Visualization, Project administration. BH: Conceptualization, Methodology, For‑ or postpartum: A 30-year population-based study. Ann Intern Med. mal analysis, Writing – review & editing. AM: Formal analysis, Writing – review 2005;143(10):697–707. & editing. MR: Methodology, Writing – review & editing. KB: Methodology, 2. Bailly J, Jacobson BF, Louw S. Safety and efficacy of adjusted-dose enoxa‑ Visualization, Writing – review & editing. LP-P: Conceptualization, Methodol‑ parin in pregnant patients with increased risk for venous thromboem‑ ogy, Writing – re- view & editing, Supervision. FX: Methodology, Writing bolic disease. Int J Gynaecol and Obstet. 2019;145(1):70–5. – review & editing, Project administration. IP: Methodology, Writing – review 3. MBRRACE-UK. Saving lives, improving mother’s care report. MBRRACE-UK. & editing. ME: Methodology, Writing – review & editing. SB: Methodology, Writ‑ Midwifery. 2019;31:1–85. ing – review & editing. AS: Conceptualization, Methodology, Formal analysis, 4. Nahas R, Saliba W, Elias A, Elias M. The prevalence of thrombophilia Data curation, Visualization, Writing – review & editing, Supervision. PA-C: in women with recurrent fetal loss and outcome of anticoagulation Conceptualization, Methodology, Data curation, Writing – re- view & editing, therapy for the prevention of miscarriages. Clin Appl Thromb/Hemost. Supervision, Project administration, Funding acquisition. The author(s) read 2018;24(1):122–8. and approved the final manuscript. 5. Zheng J, Chen Q, Fu J, Lu Y, Han T, He P. Critical appraisal of international guidelines for the prevention and treatment of pregnancy-associated Authors’ information venous thromboembolism: a systematic review. BMC Cardiovasc Disord. Montserrat León- García is a doctoral candidate for the Ph.D. in Methodology 2019;19(1):1–10. of Biomedical Research and Public Health, Universitat Autònoma de Barcelona, 6. Romualdi E, Dentali F, Rancan E, Squizzato A, Steidl L, Middeldorp S, et al. Barcelona, Spain. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Hae‑ Funding most. 2013;11(2):270–81. ML received a doctoral award from Health Institute Carlos III (Grant number: 7. Sucker C. Prophylaxis and therapy of venous thrombotic events in preg‑ F18/00014). This study has been funded by Instituto de Salud Carlos III (Grant nancy and the postpartum period. GebFra Science. 2020;80:48–59. number: PI17/01874), and Co-funded by the European Regional Development 8. Rodger MA, Carrier M, le Gal G, Martinelli I, Perna A, Rey E, et al. Meta- Fund “A way to make Europe”. analysis of low-molecular-weight heparin to prevent recurrent placenta- mediated pregnancy complications. Blood. 2014;123(6):822–8. Availability of data and materials 9. Skeith L, Rodger M. Anticoagulants to prevent recurrent placenta- All data generated or analysed during this study are included in this published mediated pregnancy complications: is it time to put the needles away? article [and its supplementary information files]. Preserve search strings are Thromb Res. 2017;151:S38-42. available in searchRxiv https://​searc​hrxiv.​org/). 10. Leffert L, Butwick A, Carvalho B, Arendt K, Bates SM, Friedman A, et al. The society for obstetric anesthesia and perinatology consensus statement on the anesthetic management of pregnant and postpartum women Declarations receiving thromboprophylaxis or higher dose anticoagulants. Anesth Analg. 2018;126(3):928–44. Ethics approval and consent to participate 11. MacLean S, Mulla S, Akl EA, Jankowski M, Vandvik PO, Ebrahim S, et al. Not applicable. Patient values and preferences in decision making for antithrombotic therapy: a systematic review - antithrombotic therapy and prevention of Consent for publication thrombosis, 9th ed: American college of chest physicians evidence-based Not applicable. clinical practice guidelines. Chest. 2012;141(2 SUPPL.):e1S-e23S. 12. Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James Competing interests AH, et al. American society of hematology 2018 guidelines for manage‑ Nothing to declare. ment of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317–59. Author details 13. Etxeandia-Ikobaltzeta I, Zhang Y, Brundisini F, Florez ID, Wiercioch W, 1 Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain. Nieuwlaat R, et al. Patient values and preferences regarding VTE disease: a 2 Department of Pediatrics, Obstetrics, Gynaecology and Preventive Medi‑ systematic review to inform American society of hematology guidelines. cine, Universidad Autónoma de Barcelona, Barcelona, Spain. 3 Knowledge Blood Adv. 2020;4(5):953–68. and Evaluation Research Unit, Department of Medicine, Mayo Clinic, Roches‑ 14. O’Cathain A, Murphy E, Nicholl J. The quality of mixed methods studies in ter, MN, USA. 4 Cytel Inc, Toronto, ON, Canada. 5 Department of Health Research health services research. J Health Serv Res Policy. 2008;13(2):92–8. Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada. 15. Fetters MD, Molina-Azorin JF. New requirements to include the methodo‑ 6 Division of Health Care Delivery Research, Mayo Clinic, Rochester, MN, USA. logical contribution in articles published in the journal of mixed methods 7 Evaluation Unit (SESCS), Canary Islands Health Service (SCS), Tenerife, Spain. research. J Mixed Methods Res. 2019;13:138–42. 8 Research Network On Health Services in Chronic Diseases (REDISSEC), 16. Sale JEM, Marwah A, Naeem F, Yu W, Meadows L. Evidence of patient Tenerife, Spain. 9 Network for Research On Chronicity, Primary Care, and Health beliefs, values, and preferences is not provided in osteoporosis clinical Promotion (RICAPPS), Tenerife, Spain. 10 Centre for Health Economics practice guidelines. Osteoporos Int. 2019;30(7):1325–37. and Policy Analysis, McMaster University, Hamilton, ON, Canada. 11 Department 17. Chong CAKY, Chen IJ, Naglie G, Krahn MD. How well do guidelines of Obstetrics and Gynecology, Ramón y Cajal Hospital, Madrid, Spain. 12 Faculty incorporate evidence on patient preferences? J Gen Intern Med. of Medicine, Alcalá de Henares University, Madrid, Spain. 13 Division of General 2009;24(8):977–82. Internal Medicine and Center for Clinical Effectiveness, University of Cincinnati 18. Selva A, Sanabria AJ, Niño de Guzman E, Ballesteros M, Selva C, Valli C, School of Medicine, Cincinnati, OH, USA. 14 Department of Medicine, McMaster et al. Colorectal cancer guidelines seldom include the patient perspec‑ University, Hamilton, ON, Canada. 15 Clinical Epidemiology and Cancer tive. J Clin Epidemiol. 2019;116:84–97. Screening, Corporació Sanitaria Parc Taulí, Sabadell, Barcelona, Spain. 16 CIBER 19. Humphries B, León-Garcia M, Bates S, Guyatt G, Eckman M, Souza RD, of Epidemiology and Public Health, CIBERESP, Madrid, Spain. et al. Decision Analysis in SHared decision making for Thromboprophy‑ laxis during Pregnancy (DASH-TOP): a sequential explanatory mixed Received: 7 July 2022 Accepted: 9 September 2022 methods pilot study protocol. BMJ Open. 2021;11:1–12. 20. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. British Med J. 2021;372(n71):1–20. 21. Creswell JW, Plano Clark VL. Designing and Conducting Mixed Methods Research [Internet]. Third Edit. SAGE Publications, Inc; 2017. 520 p. León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 17 of 18 Available from: https://​us.​sagep​ub.​com/​en-​us/​nam/​desig​ning-​and-​ 43. Anderson DR, Ginsberg JS, Brill-Edwards P, Demers C, Burrows RF, Hirsh condu​cting-​mixed-​metho​ds-​resea​rch/​book2​41842 J. The use of an indwelling Teflon catheter for subcutaneous heparin 22. Guetterman TC, Fetters MD, Creswell JW. Integrating quantitative and administration during pregnancy. Arch Intern Med. 1993;153:841–4. qualitative results in health science mixed methods research through https://​doi.​org/​10.​1038/​nrcar​dio.​2015.​172. joint displays. Ann Fam Med. 2015;13(6):554–61. 44. Patel JP, Auyeung V, Patel RK, Marsh MS, Green B, Arya R, et al. Women’s 23. Sandelowski M, Voils CI, Barroso J. Defining and Designing Mixed Research views on and adherence to low-molecular-weight heparin therapy during Synthesis Studies. Res sch [Internet]. 2006;13(1):29. Available from: https://​ pregnancy and the puerperium. J Thromb Haemost. 2012;10(12):2526–34. www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC36​24763/​pdf/​nihms​412728.​pdf 45. Martens TZ, Emed JD. The experiences and challenges of pregnant 24. Tashakkori A, Teddlie C. Sage Handbook of Mixed Methods in Social & women coping with thrombophilia. J Obstet Gynecol Neonatal Nurs. Behavioral Research. 2nd ed. Thousand Oaks, CA: Sage Publications; 2010. 2007;36(1):55–62. 25. Pearson A, White H, Bath-Hextall F, Salmond S, Apostolo J, Kirkpatrick P. A 46. Skeith L, Rodger MA, Bates SM, Gonsalves C, Karovitch A, Taylor TS. Part mixed-methods approach to systematic reviews. Int J Evid Based Healthc. of the Ritual: Exploring Patient and Physician Decision Making Regarding 2015;13(3):121–31. Anticoagulation Use in Obstetric Antiphospholipid Syndrome. Thromb 26. Fetters MD, Curry LA, Creswell JW. Achieving integration in mixed meth‑ Haemost. 2021;121(10):1353–60. ods designs - Principles and practices. Health Services Res. 2013;48(6 47. Eckman MH, Alonso-Coello P, Guyatt GH, Ebrahim S, Tikkinen KAO, Lopes PART2):2134–56. LC, et al. Women’s values and preferences for thromboprophylaxis during 27. Moseholm E, Rydahl-Hansen S, Lindhardt B, Fetters MD. Health-related pregnancy: a comparison of direct-choice and decision analysis using quality of life in patients with serious non-specific symptoms undergoing patient specific utilities. Thromb Res. 2015;136(2):341–7. evaluation for possible cancer and their experience during the process: a 48. Horne R, Weinman J, Hankins M. The beliefs about medicines ques‑ mixed methods study. Qual Life Res. 2017;26(4):993–1006. tionnaire: the development and evaluation of a new method for 28. Sandelowski M, Barroso J. Focus on research methods toward a metasyn‑ assessing the cognitive representation of medication. Psychol Health. thesis of qualitative findings on motherhood in HIV-positive women. Res 1999;14(1):1–24. Nurs Health. 2003;26(2):153–70. 49. Kai S, Fujita Y, Sato Y, Kido S, Hidaka N, Sakamoto I, et al. Pregnancy man‑ 29. Selva A, Solà I, Zhang Y, Pardo-hernandez H, Haynes RB, García LM, aged by unfractionated heparin after mechanical aortic valve replace‑ et al. Development and use of a content search strategy for retrieving ment. J Matern Fetal Neonatal Med. 2020;33(6):1030–2. studies on patients ’ views and preferences. Health Qual Life Outcomes. 50. McLintock C. Anticoagulant therapy in pregnant women with mechani‑ 2017;15(126):1–9. cal prosthetic heart valves: No easy option. Thromb Res. 2011;127(Suppl. 30. Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis 3):S56–60. S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: 51. The American College of Obstetricians and Gynecologists. ACOG Practice Reporting guideline. BMJ. 2020;368:1–6. bulletin clinical management guidelines for obstetrician-gynecologists 31. Zhang Y, Morgan RL, Alonso-Coello P, Wiercioch W, Bała MM, Jaeschke inherited thrombophilias in pregnancy. Obstet Gynecol. 2018;132(1):e18– RR, et al. A systematic review of how patients value COPD outcomes. Eur 34. Available from: https://​journ​als.​lww.​com/​green​journ​al Respir J. 2018;52(1):180222. 52. Wu P, Poole TC, Pickett JA, Bhat A, Lees CC. Current obstetric guidelines 32. Aromataris E, Munn Z. JBI Manual for Evidence Synthesis. JBI, 2020. [Inter‑ on thromboprophylaxis in the United Kingdom: evidence based medi‑ net]. 2020. Available from: https://​wiki.​jbi.​global/​displ​ay/​MANUAL/​8.3+​ cine? Eur J Obstetr Gynecol Reprod Biol. 2013;168(1):7–11. The+​JBI+​appro​ach+​to+​mixed+​method+​syste​matic+​revie​ws 53. NICE clinical guideline 107. Hypertension in pregnancy the manage‑ 33. Pearson A, Robertson-malt S, Rittenmeyer L. Synthesizing qualitative ment of hypertensive disorders during pregnancy. 2010. Available from: evidence evidence. 2011. www.​nice.​org.​uk 34. Zhang Y, Coello PA, Guyatt GH, Yepes-Nuñez JJ, Akl EA, Hazlewood G, 54. Hiligsmann M, Bours SPG, Boonen A. A review of patient preferences for et al. GRADE guidelines: 20. Assessing the certainty of evidence in the osteoporosis drug treatment. Curr Rheumatol Rep. 2015;17(61):1–10. importance of outcomes or values and preferences—inconsistency, 55. Hong QN, Gonzalez-Reyes A, Pluye P. Improving the usefulness of a imprecision, and other domains. J Clin Epidemiol. 2019;111:83–93. tool for appraising the quality of qualitative, quantitative and mixed 35. Zhang Y, Alonso-Coello P, Guyatt GH, Yepes-Nuñez JJ, Akl EA, Hazlewood methods studies, the mixed methods appraisal tool. J Eval Clin Pract. G, et al. GRADE guidelines: 19. Assessing the certainty of evidence in the 2018;24(3):459–67. importance of outcomes or values and preferences—Risk of bias and 56. Lewin S, Booth A, Glenton C, Munthe-Kaas H, Rashidian A, Wainwright M, indirectness. J Clin Epidemiol. 2019;111:94–104. et al. Applying GRADE-CERQual to qualitative evidence synthesis find‑ 36. CASP Qualitative Checklist. Critical appraisal skills programme part of ings: Introduction to the series. Implementation Science. 2018;13:1–70. better value healthcare Ltd. 2018. Available from: www.​casp-​uk.​net 57. Valli C, Rabassa M, Johnston BC, Kuijpers R, Prokop-Dorner A, Zajac J, et al. 37. Noyes J, Booth A, Moore G, Flemming K, Tunçalp Ö, Shakibazadeh E. Health-related values and preferences regarding meat consumption a Synthesising quantitative and qualitative evidence to inform guidelines mixed-methods systematic review. Ann Intern Med. 2019;171(10):742–55. on complex interventions: clarifying the purposes, designs and outlining 58. Gough D. Qualitative and mixed methods in systematic reviews. Syst Rev. some methods. BMJ Global Health. 2019;4(Supplement1):1–14. 2015;4:1–3. 38. Lewin S, Bohren M, Rashidian A, Munthe-Kaas H, Glenton C, Colvin 59. Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James CJ, et al. Applying GRADE-CERQual to qualitative evidence synthesis AH, et al. American Society of Hematology 2018 guidelines for manage‑ findings-paper 2: how to make an overall CERQual assessment of confi‑ ment of venous thromboembolism: venous thromboembolism in the dence and create a summary of qualitative findings table. Implementa‑ context of pregnancy. Blood Adv. 2018;2(22):3317–59. tion Science. 2018;13(Suppl 1):1–70. 60. de Vries JIP, van Pampus MG, Hague WM, Bezemer PD, Joosten JH. Low- 39. Cuello-Garcia CA, Santesso N, Morgan RL, Verbeek J, Thayer K, Ansari MT, molecular-weight heparin added to aspirin in the prevention of recurrent et al. GRADE guidance 24 optimizing the integration of randomized and early-onset pre-eclampsia in women with inheritable thrombophilia: the non-randomized studies of interventions in evidence syntheses and FRUIT-RCT. J Thromb Haemost. 2012;10(1):64–72. health guidelines. J Clin Epidemiol. 2022;142:200–8. 61. Rodger MA, Hague WM, Kingdom J, Kahn SR, Wells PS. Dalteparin for 40. Guimicheva B, Patel JP, Roberts LN, Subramanian D, Arya R. Women’s pregnant women with thrombophilia - authors’ reply. Vol. 385, The Lan‑ views, adherence and experience with postnatal thromboprophylaxis. cet. Lancet Publishing Group; 2015;385(9969):690. Thromb Res. 2019;173:85–90. 62. Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, et al. Dalteparin 41. Bates SM, Alonso-Coello P, Tikkinen KAO, Ebrahim S, Lopes LC, McDonald for the prevention of recurrence of placental-mediated complications SD, et al. Women’s values and preferences and health state valuations for of pregnancy in women without thrombophilia: a pilot randomized thromboprophylaxis during pregnancy: a cross-sectional interview study. controlled trial. J Thromb Haemost. 2009;7(1):58–64. Thromb Res. 2016;140:22–9. 63. Booth A. Searching for qualitative research for inclusion in systematic 42. Hordern CE, Bircher CW, Prosser-Snelling EC, Fraser FK, Smith RP. Patient reviews: A structured methodological review. Syst Rev. 2016;5(1):63–70. compliance with postnatal thromboprophylaxis: an observational study. J 64. Kunneman M, Hargraves IG, Sivly AL, Branda ME, LaVecchia CM, Labrie Obstet Gynaecol. 2015;35(8):793–6. NHM, et al. Co-creating sensible care plans using shared decision making: León‑García et al. BMC Pregnancy and Childbirth (2022) 22:747 Page 18 of 18 patients’ reflections and observations of encounters. Patient Educ Couns. 2021;105(6):1539–44. 65. Noyes J, Booth A, Lewin S, Carlsen B, Glenton C, Colvin CJ, et al. Applying GRADE-CERQual to qualitative evidence synthesis findings-paper 6: How to assess relevance of the data. Implementation Science. 2018;13:51–61. 66. Glenton C, Carlsen B, Lewin S, Munthe-Kaas H, Colvin CJ, Tunçalp Ö, et al. Applying GRADE-CERQual to qualitative evidence synthesis findings- paper 5: how to assess adequacy of data. Implementation Science. 2018;13:43–50. 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