Challenges in Cardiology Research in Pregnancy
Challenges in Cardiology Research in Pregnancy
Research in pregnancy is challenging as it involves a special 'vulnerable' group due to the involvement of the mother and the fetus. These challenges, which are inherent in studying pregnancy in physiologic and pathologic states, have contributed to the scant research in pregnancy. Until recently, most studies in pregnancy were nonrandomized and retrospective in nature, representing prevailing clinical standards of practice and clinicians' biases. Prospective studies were generally limited to single centers, comprising of small sample sizes and were observational in nature, rather than randomized studies involving therapy. Ethical and legal factors, research mandates, patient factors, the protracted nature of pregnancy, institutional commitment to research, interdisciplinary clinical and research collaboration, funding support, administrative issues and the level of involvement of national cardiac and obstetric and gynecological societies have been barriers to research in pregnancy in developed countries. Even prospective observational studies are difficult to perform due the difficulties involved with obtaining consent, study recruitment and follow-up. Misconceptions regarding research have led to a lack of participation by women. The longitudinal nature of prospective studies in pregnancy, the problems associated with enrolling women before pregnancy and in the first trimester and the failure to understand the commitment required by the patient, as well as many social factors, have led to increased drop-out rates during pregnancy, as well as difficulty with follow-up in the post-partum state. These factors, along with the failure to supplement funding support due to longer study periods than anticipated, have led to studies of small sample sizes. Understanding patient factors that lead to a lack of participation in research or dropping out following initial consent could help make research participation more conducive for pregnant women. The involvement of national societies in the planning and funding of multicenter studies, interdepartmental and interinstitutional collaboration, institutional and extramural funding support and patient incentives are crucial for shortening study duration and ensuring adequacy of sample sizes for successful research in pregnancy. National health service structures, such as those found in Europe and Canada, makes multicenter collaboration for prospective studies more feasible than for countries such as the USA, in which the fees-for-service system is used. Utilization of telemedicine and handheld ultrasound systems and participation in prospective multicenter registries could not only improve the clinical care of pregnant women in underdeveloped countries, but also provide a platform for research during pregnancy. Multicenter and even global registries supported by European cardiac societies have been formed recently that are beginning to bring forth much-needed data regarding pathological states, such as peripartum cardiomyopathy and pregnancy in congenital heart disease. Such studies are largely confined to non-US countries and have started seeing participation from underdeveloped countries. Studies on pregnancy in connective tissue disorders, older women, post-chemoradiation therapy or organ transplantation and in the HIV state remain limited.
Pregnancy is a somewhat understudied condition in both physiologic and pathologic states. Until recently, most studies in pregnancy were either case reports or retrospective evaluations of clinical experience from single centers or meta-analyses of retrospective studies. Among the limited prospective studies available during pregnancy, most studies were observational in nature and evaluated physiological changes in normal pregnancies or in the presence of pathologic conditions such as hypertension, diabetes or pre-eclampsia. Most of such prospective studies were limited to Caucasian women. Prospective studies in women of lower socioeconomic status or in non-white populations have been sparse, limiting the generalizability of experience as well as contributing to ongoing health disparities. The single-center nature of such studies limits sample sizes and reduced the generalizability of their findings due to the nature of the study cohort. Interventional prospective studies are few; they are all in the area of anticoagulation and are all from Europe. The issue of anticoagulation during pregnancy in women with prosthetic heart valves affects a small minority of pregnant women; nevertheless, this is probably going to become a more frequent issue due to a growing number of children with congenital heart disease (CHD) reaching adulthood. The best anticoagulation regimen for pregnant women with prosthetic heart valves remains unclear, and resulted in variation in guidelines across the globe on the type and level of anticoagulation to be used. The use of warfarin throughout pregnancy has been favored in Europe, whereas until recently, treatment with unfractionated or low-molecular-weight heparin (LMWH) has been favored in the USA with or without warfarin during the middle of pregnancy. The new ACC/AHA valve guidelines (11) now favor use of warfarin giving it a class IIa recommendation in the second and third trimester of pregnancy. The levels of international normalized ratio (INR) or partial thromboplastin time (PTT) that are needed in order to prevent thromboembolic complications remain unclear. The only prospective, randomized therapeutic study comparing LMWH with unfractionated heparin had to be stopped prematurely due to an increased incidence of thromboembolism in patients on LMWH, despite the use of a therapeutic dose of LMWH as per the protocol and derived from the sparse literature at the time regarding adequate dose in pregnancy. A lack of adequate 'trough' levels of antithrombin activity appears to have contributed to the adverse events that led to the termination of the trial. Risk of bleeding complications in the fetus precludes aggressive dosing regimens of anticoagulants. Retrospective studies reporting on increased thromboembolic complications in patients on unfractionated heparin consist of patients who either did not have PTT monitoring at all or whose PTT was grossly subtherapeutic. Given the anticipated increase in women with CHD and prosthetic heart valves who will become pregnant, questions regarding the type of valve and the level and type of anticoagulation are going to become increasingly important, and data to answer these questions will need to be collected. While the more recent valve guidelines assist with decision making for the clinicians, most of the recommendations including class I recommendations in pregnancy are based on level of evidence C.
Abstract and Introduction
Abstract
Research in pregnancy is challenging as it involves a special 'vulnerable' group due to the involvement of the mother and the fetus. These challenges, which are inherent in studying pregnancy in physiologic and pathologic states, have contributed to the scant research in pregnancy. Until recently, most studies in pregnancy were nonrandomized and retrospective in nature, representing prevailing clinical standards of practice and clinicians' biases. Prospective studies were generally limited to single centers, comprising of small sample sizes and were observational in nature, rather than randomized studies involving therapy. Ethical and legal factors, research mandates, patient factors, the protracted nature of pregnancy, institutional commitment to research, interdisciplinary clinical and research collaboration, funding support, administrative issues and the level of involvement of national cardiac and obstetric and gynecological societies have been barriers to research in pregnancy in developed countries. Even prospective observational studies are difficult to perform due the difficulties involved with obtaining consent, study recruitment and follow-up. Misconceptions regarding research have led to a lack of participation by women. The longitudinal nature of prospective studies in pregnancy, the problems associated with enrolling women before pregnancy and in the first trimester and the failure to understand the commitment required by the patient, as well as many social factors, have led to increased drop-out rates during pregnancy, as well as difficulty with follow-up in the post-partum state. These factors, along with the failure to supplement funding support due to longer study periods than anticipated, have led to studies of small sample sizes. Understanding patient factors that lead to a lack of participation in research or dropping out following initial consent could help make research participation more conducive for pregnant women. The involvement of national societies in the planning and funding of multicenter studies, interdepartmental and interinstitutional collaboration, institutional and extramural funding support and patient incentives are crucial for shortening study duration and ensuring adequacy of sample sizes for successful research in pregnancy. National health service structures, such as those found in Europe and Canada, makes multicenter collaboration for prospective studies more feasible than for countries such as the USA, in which the fees-for-service system is used. Utilization of telemedicine and handheld ultrasound systems and participation in prospective multicenter registries could not only improve the clinical care of pregnant women in underdeveloped countries, but also provide a platform for research during pregnancy. Multicenter and even global registries supported by European cardiac societies have been formed recently that are beginning to bring forth much-needed data regarding pathological states, such as peripartum cardiomyopathy and pregnancy in congenital heart disease. Such studies are largely confined to non-US countries and have started seeing participation from underdeveloped countries. Studies on pregnancy in connective tissue disorders, older women, post-chemoradiation therapy or organ transplantation and in the HIV state remain limited.
Introduction
Pregnancy is a somewhat understudied condition in both physiologic and pathologic states. Until recently, most studies in pregnancy were either case reports or retrospective evaluations of clinical experience from single centers or meta-analyses of retrospective studies. Among the limited prospective studies available during pregnancy, most studies were observational in nature and evaluated physiological changes in normal pregnancies or in the presence of pathologic conditions such as hypertension, diabetes or pre-eclampsia. Most of such prospective studies were limited to Caucasian women. Prospective studies in women of lower socioeconomic status or in non-white populations have been sparse, limiting the generalizability of experience as well as contributing to ongoing health disparities. The single-center nature of such studies limits sample sizes and reduced the generalizability of their findings due to the nature of the study cohort. Interventional prospective studies are few; they are all in the area of anticoagulation and are all from Europe. The issue of anticoagulation during pregnancy in women with prosthetic heart valves affects a small minority of pregnant women; nevertheless, this is probably going to become a more frequent issue due to a growing number of children with congenital heart disease (CHD) reaching adulthood. The best anticoagulation regimen for pregnant women with prosthetic heart valves remains unclear, and resulted in variation in guidelines across the globe on the type and level of anticoagulation to be used. The use of warfarin throughout pregnancy has been favored in Europe, whereas until recently, treatment with unfractionated or low-molecular-weight heparin (LMWH) has been favored in the USA with or without warfarin during the middle of pregnancy. The new ACC/AHA valve guidelines (11) now favor use of warfarin giving it a class IIa recommendation in the second and third trimester of pregnancy. The levels of international normalized ratio (INR) or partial thromboplastin time (PTT) that are needed in order to prevent thromboembolic complications remain unclear. The only prospective, randomized therapeutic study comparing LMWH with unfractionated heparin had to be stopped prematurely due to an increased incidence of thromboembolism in patients on LMWH, despite the use of a therapeutic dose of LMWH as per the protocol and derived from the sparse literature at the time regarding adequate dose in pregnancy. A lack of adequate 'trough' levels of antithrombin activity appears to have contributed to the adverse events that led to the termination of the trial. Risk of bleeding complications in the fetus precludes aggressive dosing regimens of anticoagulants. Retrospective studies reporting on increased thromboembolic complications in patients on unfractionated heparin consist of patients who either did not have PTT monitoring at all or whose PTT was grossly subtherapeutic. Given the anticipated increase in women with CHD and prosthetic heart valves who will become pregnant, questions regarding the type of valve and the level and type of anticoagulation are going to become increasingly important, and data to answer these questions will need to be collected. While the more recent valve guidelines assist with decision making for the clinicians, most of the recommendations including class I recommendations in pregnancy are based on level of evidence C.
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