Treatment of Refractory/High-Risk Pregnancies With Antiphospholipid Syndrome: A Systematic Review of the Literature
Frontiers in pharmacology. 2022;13:849692
Different treatment protocols have been employed to manage heparin/low-dose aspirin refractory or high-risk pregnancies in antiphospholipid antibody syndrome (APS) pregnancies. A systematic review of the literature on additional treatments used in refractory and/or high-risk APS pregnancies was conducted. Records from February 2006 to October 2021 were retrieved from PubMed, Web of Science, Cochrane, and the www.clinicaltrials.gov platform. Twenty-one studies met our eligibility criteria. Live birth rate is this study's primary endpoint, while pregnancy complications and adverse events are secondary endpoints. A total of 434 pregnancies, 162 (37.3%) refractory and 272 (62.7%) high-risk/refractory pregnancies, were included. Both IVIG <2 gr/kg/monthly/HCQ/LDS and PEX/IA ± LDS led to 100% viable infants in refractory APS. Furthermore, HCQ 200-400 mg showed a higher live birth rate than HCQ + LDS (88.6% vs. 82.7%). Following treatment protocol with HCQ 200-400 mg and IVIG <2 gr/kg/monthly/HCQ/LDS, pregnancy complications rates of 16.7 and 83.3% were registered, respectively. Pravastatin 20 mg, IA weekly + IVIG 2 gr/monthly, and PEX weekly + IVIg 2 gr/kg/monthly showed higher live birth rates in high-risk APS pregnancies of 100, 100 and 92%, respectively, whereas the lower severe pregnancy complications were reported in pregnancies treated with PEX weekly + IVIg 2 gr/kg/monthly (11.1%). One (0.6%) case of dermatitis during treatment with HCQ was observed. The results of this study showed that HCQ 200-400 mg and PEX weekly + IVIG 2 gr/kg/monthly achieved a higher live birth rate in refractory APS and high-risk/refractory APS, respectively. The results presented provide clinicians with up-to-date knowledge in the management of APS pregnancies according to risk stratification.
Efficacy of intravenous immunoglobulin in the treatment of recurrent spontaneous abortion: a systematic review and meta-analysis
American journal of reproductive immunology (New York, N.Y. : 1989). 2022
OBJECTIVE we aimed to evalute the efficacy of IVIG in the treatment with patients with recurrent spontaneous abortion (RSA). METHODS Pubmed, Embase, Web of science, Cochrane library we searched for randomized controlled (RCTs) about effect of IVIG on RSA from inception to August 20, 2021. Values of standardized mean differences (SMD) were determined for continuous outcomes. RESULTS A total of fifteen articles involving 902 patients were included in meta-analysis. Compared with the control group, IVIG can increase the live birth rate of recurrent spontaneous abortion patients[OR = 3.06, 95%CI(1.23, 7.64, P = 0.02]. However, recurrent abortion was divided into primary and secondary abortion for subgroup analysis, and there was no statistical difference. Besides, IVIG can also increase the expression in peripheral blood CD3+[OR = 0.4, 95%CI(-2.47, 3.15, P = 0.81],CD4+[OR = 1.16, 95%CI(-4.60, 6.93, P = 0.69], and decrease the expression of CD8+[OR = -1.78, 95%CI(-5.30, 1.75, P = 0.32], but there is no statistical significance. CONCLUSIONS IVIG can significantly increase the live birth rate of recurrent spontaneous abortion. However, the evidence needs further verification and the curative effect is uncertain. It is necessary to further explore the pathogenesis of recurrent abortion and the mechanism of IVIG in the treatment of recurrent spontaneous abortion. Besides, more high-quality randomized controlled trials suitable for population, race, dosage and timing of IVIG in the treatment of recurrent abortion are needed to confirm its effectiveness, and effective systematic evaluation is also needed to evaluate its use benefit. This article is protected by copyright. All rights reserved.
Describing the impact of maternal hyperimmune globulin and valaciclovir on the outcomes of CMV infection in pregnancy: a systematic review
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022
Cytomegalovirus is the leading infectious cause of congenital neurological disabilities. Valaciclovir and CMV hyperimmune globulin may reduce vertical transmission and sequelae in neonates. A systematic review on valaciclovir and CMV hyperimmune globulin in preventing vertical transmission or reducing sequelae in neonates was conducted to 3 September 2021. Valaciclovir as a preventative strategy was supported by a well-conducted randomised controlled trial. Evidence supporting valaciclovir as a treatment strategy was limited to observational studies at moderate risk of bias. CMV hyperimmune globulin was not supported as a preventative strategy in two RCTs, which contrasted with observational studies. Evidence favouring CMV hyperimmune globulin as a treatment strategy was limited to observational studies at moderate risk of bias. The role of valaciclovir and CMV hyperimmune globulin in CMV infection in pregnancy is still being defined. Valaciclovir to prevent vertical transmission has the highest quality evidence in favour of use.
Application of Tissue Engineering and Regenerative Medicine in Prelabor Rupture of Membranes: a Review of the Current Evidence
Reproductive sciences (Thousand Oaks, Calif.). 2021
Preterm prelabor rupture of membranes (PPROM) is the main cause of preterm delivery, resulting in increased perinatal morbidity and mortality. Several techniques have been studied for the healing of ruptured membranes, with some success. Before new techniques using tissue/organ engineering are applied in clinical practice, these techniques must be validated in clinical trials. To address this issue, the objective of this study was to summarize the current literature on interventions to seal or heal the amniotic membranes after PPROM. An electronic search was conducted using the keywords "fetal membranes," "premature rupture," "amnion," "tissue engineering," "fibrin tissue adhesive," "regenerative medicine," "tissue adhesive," "wound healing," and "fetoscopy" through the MEDLINE, Embase, and Cochrane CENTRAL databases, with the limitation of English-language studies. Through a review of the identified studies, it was found that spontaneous healing of the fetal membrane has not been successful. Several efforts have been made to seal membranes before or after rupture using different methods, including amniopatches, collagen, tissue patches, fibrin sealant, mussel-mimetic sealant, engineered cell matrix, and immunological supplements. However, most studies have been conducted in ex vivo or in vivo settings, so the safety and applicability of these techniques to spontaneous rupture of membranes in clinical settings have not been sufficiently tested. Overall, the current evidence is limited regarding the safety and effectiveness of interventions against PPROM.
Endometriosis with infertility: a comprehensive review on the role of immune deregulation and immunomodulation therapy
American journal of reproductive immunology (New York, N.Y. : 1989). 2020;:e13384
BACKGROUND Endometriosis is a multifactorial pathology dependent on intrinsic and extrinsic factors, but the immune deregulation seems to play a pivotal role. In endometriosis-associated infertility this could raise the benefit of immunomodulatory strategies to improve the results of ART. In this review, we will describe (1) sera and peritoneal fluid cytokines and immune markers; (2) autoantibodies; (3) immunomodulatory treatments in endometriosis with infertility. METHODS The literature research was conducted in Medline, Embase and Cochrane Library with keywords: "endometriosis", "unexplained miscarriage", "implantation failure", "recurrent implantation failure » and « IVF-ICSI », « biomarkers of autoimmunity", "TNF-α", "TNF-α antagonists", "infliximab", "adalimumab", "etanercept", "immunomodulatory treatment", "steroids", "intralipids", "intravenous immunoglobulins", "G-CSF", "pentoxyfylline". RESULTS Several studies analyzed the levels of pro-inflammatory cytokines in sera and peritoneal fluid of endometriosis-associated infertility, in particular TNF-α. Various autoantibodies have been found in peritoneal fluid and sera of infertile endometriosis women even in the absence of clinically defined autoimmune disease, as antinuclear, anti-SSA and antiphospholipid autoantibodies. In few uncontrolled studies, steroids and TNF-α antagonists could increase the pregnancy rates in endometriosis-associated infertility, but well-designed trials are lacking. CONCLUSION Endometriosis is characterized by increased levels of cytokines and autoantibodies. This suggests the role of inflammation and immune cell deregulation in infertility associated to endometriosis. The strategies of immunomodulation to regulate these immune deregulations are poorly studied and well-designed studies are necessary.
Prevention of recurrent miscarriage in women with antiphospholipid syndrome: A systematic review and network meta-analysis
OBJECTIVES To compare and rank currently available pharmacological interventions for the prevention of recurrent miscarriage (RM) in women with antiphospholipid syndrome (APS). METHODS A search was performed using PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, CNKI, ClinicalTrials.gov, and the UK National Research Register on December 15, 2019. Studies comparing any types of active interventions with placebo/inactive control or another active intervention for the prevention of RM in patients with APS were considered for inclusion. The primary outcomes were efficacy (measured by live birth rate) and acceptability (measured by all-cause discontinuation); secondary outcomes were birthweight, preterm birth, preeclampsia, and intrauterine growth retardation. The protocol of this study was registered with Open Science Framework (DOI: 10.17605/OSF.IO/B9T4E). RESULTS In total, 54 randomized controlled trials (RCTs) comprising 4,957 participants were included. Low-molecular-weight heparin (LMWH) alone, aspirin plus LMWH or unfractionated heparin (UFH), aspirin plus LMWH plus intravenous immunoglobulin (IVIG), aspirin plus LMWH plus IVIG plus prednisone were found to be effective pharmacological interventions for increasing live birth rate (ORs ranging between 2.88 to 11.24). In terms of acceptability, no significant difference was found between treatments. In terms of adverse perinatal outcomes, aspirin alone was associated with a higher risk of preterm birth than aspirin plus LMWH (OR 3.92, 95% CI 1.16 to 16.44) and with lower birthweight than LMWH (SMD -808.76, 95% CI -1596.54 to -5.07). CONCLUSIONS Our findings support the use of low-dose aspirin plus heparin as the first-line treatment for prevention of RM in women with APS, and support the efficacy of hydroxychloroquine, IVIG, and prednisone when added to current treatment regimens. More large-scale, high-quality RCTs are needed to confirm these findings, and new pharmacological options should be further evaluated.
Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage-A Systematic Review
Transfusion medicine reviews. 2020
Fibrinogen levels drop early in postpartum hemorrhage (PPH), and low fibrinogen levels predict outcomes. There is increasing interest in replacing fibrinogen early in severe PPH and this systematic review's aim was to assess if early fibrinogen replacement therapy improves outcomes in severe PPH. We searched the following databases from inception to June 2019: CDSR and CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed, Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index-Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal. We included randomized (RCT) and well-designed controlled observational studies where fibrinogen replacement therapy was given early (within 90 minutes of bleeding) compared with standard protocol in pregnant women > 24 weeks' gestation who developed PPH, defined as estimated blood loss ≥500 mL up to 24 hours post-delivery. Two independent reviewers extracted and reviewed the data on the primary outcome of allogeneic blood transfusion at 24 hours after intervention and secondary outcomes including all-cause mortality, rate of thrombosis, and the need for surgical and non-surgical interventions. We identified 5 eligible studies: 2 completed (total of 299 women) RCTs comparing fibrinogen concentrate with placebo, and 3 ongoing RCTs. There was no completed study assessing cryoprecipitate transfusion. There was variation of: timings of intervention administration; severity of PPH; fibrinogen doses and use of tranexamic acid. There was insufficient evidence that early administration of fibrinogen in PPH reduces the need for allogeneic blood transfusion at 24 hours (risk ratio 0.83 (95% CI 0.54-1.26), P = 0.38) (2 trials, 299 participants) or improves other outcomes. Both studies were underpowered to answer our outcomes. There is a lack of evidence that early fibrinogen replacement therapy improves outcomes in PPH. Future studies are needed to address this, underpinned by data on the optimal fibrinogen dose, protocol-driven approaches versus targeted therapy, and cost-effectiveness of cryoprecipitate versus fibrinogen concentrate therapy in PPH.
Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: A systematic literature review
Haemophilia : the official journal of the World Federation of Hemophilia. 2019
INTRODUCTION Hereditary fibrinogen disorders (HFD) are rare quantitative or qualitative fibrinogen anomalies, including afibrinogenaemia (A), hypofibrinogenaemia (H), dysfibrinogenaemia (D) and hypodysfibrinogenaemia (HD). As fibrinogen plays an essential role in pregnancy, we addressed the issue of obstetrical and postpartum complications in women with HFD. METHODS A systematic literature review, restricted to English manuscripts, was conducted according to the PRISMA guidelines. We searched through the MEDLINE database for English articles, published from January 1985 until November 2018, focusing on pregnancy in A, H, D and HD. A total of 198 articles were identified, 15 articles were added from other sources. Overall, 213 articles were screened and 54 were included in the final analysis. RESULTS A total of 188 pregnancies from 70 women were analysed. About half of pregnancies resulted in miscarriage; more specifically in 15 (42.9%), 36 (46.8%), 27 (42.9%) and 4 (30.8%) of A, H, D and HD patients, respectively. Preterm complications were also frequent (33.5%). Metrorrhagia, mainly in the first trimester, was observed in 21.7% of the pregnancies. Placenta abruption was reported in 5 (14.3%), 4 (5.2%), 5 (7.9%) and 1 (7.7%) of A, H, D and HD, respectively. A total of 24 (12.7%) deliveries were complicated by postpartum thrombotic events (3.2%) or postpartum haemorrhage (9.6%). A fibrinogen replacement therapy was introduced in 30% of pregnancies, as prophylaxis (81.1%) or on demand (18.9%). CONCLUSION These results suggest that women with HFD are at high risk of obstetrical and postpartum complications. Prospective international registries may allow to identify more precisely the incidence of obstetrical and postpartum adverse outcomes and their management.
The effectiveness of IVIG therapy in pregnancy and live birth rate of women with recurrent implantation failure (RIF): A systematic review and meta-analysis
Journal of reproductive immunology. 2019;134-135:28-33
Recurrent implantation failure (RIF), as a challenging problem in human reproduction, is widely improved by intravenous immunoglobulin (IVIG), especially in patients with immunologic abnormalities. In this meta-analysis, we evaluated the results of the studies in which RIF women were treated with IVIG, and pregnancy, live birth, miscarriage and implantation rate were assessed as the result of treatment. A systematic search was conducted in MEDLINE (PubMed), Embase, Cochrane Library, Google Scholar, ProQuest and clinicaltrail.gov. Two cohorts, two cross-sectional and one quasi experimental studies were included in this study. Four out of five studies were included in meta-analysis and remained one study was narratively discussed. Data analysis was conducted by RevMan 5.2 software. Our meta-analysis results demonstrated that there was a significant difference in the pregnancy rate of cohorts (OR = 1.82, 95% CI = 1.14-2.89, P = 0.01) and cross-sectional studies (OR = 11.12, 95% CI = 6.43-19.23, P < 0.00001), live birth rate of cohorts (OR = 2.17, 95% CI = 1.30-3.61, P = 0.003) and cross-sectional studies (OR = 7.57, 95% CI = 4.53-12.64, P < 0.00001) in the IVIG group when compared to the control group, but there was no significant difference in the miscarriage rate. In conclusion, IVIG may be a beneficial therapeutic strategy in RIF patients selected according to relevant immunological disturbances. However, final conclusions on the efficiency of the treatment must await prospective, randomized controlled trials of sufficient size.
Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses
Acta Obstetricia Et Gynecologica Scandinavica. 2018
INTRODUCTION Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss. MATERIAL AND METHODS We searched Medline, Embase, the Cochrane Library and identified 1415 publications. This systematic review included 21 randomized controlled trials regarding acetylsalicylic acid, low-molecular-weight heparin, progesterone, intravenous immunoglobulin or leukocyte immune therapy in women with ≥3 consecutive miscarriages of unknown cause. The study quality was assessed and data was extracted independently by at least two authors. RESULTS No significant difference in live birth rate was found, neither when acetylsalicylic acid was compared with low-molecular-weight heparin nor with placebo. Meta-analyses of low-molecular-weight heparin vs. control found no significant differences in live birth rate; risk ratio (RR) 1.47 (95% CI 0.83-2.61). Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate; RR 1.18 (95% CI 1.09-1.27) but not when started after conception. Intravenous immunoglobulin showed no effect on live birth rate compared with placebo; RR 1.07 (95% CI 0.91-1.26). Paternal immunization compared with autologous immunization showed a significant difference in outcome; RR 1.8 (95% CI 1.34-2.41), although the studies were small and at high risk of bias. CONCLUSION The literature does not allow advice on any specific treatment for idiopathic recurrent pregnancy loss, with the exception of progesterone from ovulation. We suggest that any treatment for recurrent pregnancy loss should be used within the context of a randomized controlled trial. This article is protected by copyright. All rights reserved.