Comparative effectiveness and safety of 36 therapies or interventions for pregnancy outcomes with recurrent implantation failure: a systematic review and network meta-analysis
Journal of assisted reproduction and genetics. 2023
PURPOSE To investigate the effectiveness and safety of 36 different therapies for recurrent implantation failure (RIF) patients. METHODS We searched PubMed, Embase, the Cochrane Library (CENTRAL), Web of Science, and China National Knowledge Internet (CNKI) from inception to August 24, 2022, with language in both English and Chinese. Randomized controlled trials (RCTs) and observational studies that provided data with one of pregnancy outcomes on RIF patients were included in the network meta-analysis (NMA). The odds ratios (OR) and 95% credible interval (CrI) on pregnancy outcomes were summarized by NMA with a random-effects model. We also analyzed data from only RCTs and compared whether the optimal treatment is the same for different failed embryo transfer attempts. RESULTS The total of 29,906 RIF patients from 154 clinical studies (74 RCTs and 80 non-RCTs) were included in the NMA. In terms of implantation rate (IR), growth hormone (GH) (OR: 3.32, 95% CrI: 1.95-5.67) is the best treatment in all included studies; IVIG+PBMC (5.84, 2.44-14.1) is the best for clinical pregnancy rate (CPR); hyaluronic acid (HA) (12.9, 2.37-112.0) for live birth rate (LBR); and aspirin combined with glucocorticoids (0.208, 0.0494-0.777) for miscarriage rate (MR). The two-dimensional graphs showed that GH could maximize IR and CPR simultaneously; HA and GH could simultaneously increase IR and LBR to a large extent; HA could maximize IR and minimize MR. CONCLUSION IVIG+PBMC, GH, and embryo medium enriched with HA could significantly improve pregnancy outcomes in patients with RIF. It appears that combination therapy is a potential administration strategy. TRIAL REGISTRATION This study has been registered on PROSPERO (CRD42022353423).
High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss
Journal of reproductive immunology. 2023;158:103977
The aim was to evaluate whether natural killer (NK) cells and regulatory T (Treg) cells were involved in mechanisms underlying beneficial effects of a high dose of intravenous immunoglobulin (IVIG) on recurrent pregnancy losses (RPL) of unexplained etiology. In a double-blind, randomized, placebo-controlled trial of IVIG (400 mg/kg, for 5 days in 4-6 weeks of gestation) in women with RPL, blood samples were collected pre-infusion, one week after infusion (1 w), and eight weeks of gestation/when miscarried (8 w). Levels of NK and Treg cells in peripheral blood were compared between women with IVIG (n = 50) and placebo (n = 49), and between women with IVIG who gave live birth (n = 29) and those who had miscarriage with normal chromosome (n = 12). Effector Treg cell percentages in IVIG group at 1 w (mean 1.43 % vs. 1.03 %) and at 8 w (1.91 % vs. 1.18 %) were higher than those in placebo group (p < 0.01). Total Treg cell percentages in IVIG group at 1 w (4.75 % vs. 4.08 %) and at 8 w (5.55 % vs. 4.47 %) were higher than those in placebo group (p < 0.05). In women with live birth, total Treg cell percentages increased at 8 w (5.52 %, p < 0.001) compared with pre-infusion (4.54 %) and 1 w (4.47 %), while NK cell activity decreased at 1 w (20.18 %, p < 0.001) compared with pre-infusion (26.59 %). IVIG increased Treg cell percentages and suppressed NK cell activity very early in pregnancy, and these were associated with subsequent live birth. Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG.
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.
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.
Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial
BACKGROUND There is no effective treatment for women with unexplained recurrent pregnancy loss (RPL). We aimed to investigate whether treatment with a high dose of intravenous immunoglobulin (IVIG) in early pregnancy can improve pregnancy outcomes in women with unexplained RPL. METHODS In a double-blind, randomised, placebo-controlled trial, women with primary RPL of unexplained aetiology received 400 mg/kg of IVIG daily or placebo for five consecutive days starting at 4-6 weeks of gestation. They had experienced four or more miscarriages except biochemical pregnancy loss and at least one miscarriage of normal chromosome karyotype. The primary outcome was ongoing pregnancy rate at 22 weeks of gestation, and the live birth rate was the secondary outcome. We analysed all women receiving the study drug (intention-to-treat, ITT) and women except those who miscarried due to fetal chromosome abnormality (modified-ITT). This study is registered with ClinicalTrials.gov number, NCT02184741. FINDINGS From June 3, 2014 to Jan 29, 2020, 102 women were randomly assigned to receive IVIG (n = 53) or placebo (n = 49). Three women were excluded; therefore 50 women received IVIG and 49 women received placebo in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (31/50 [62·0%] vs. 17/49 [34·7%]; odds ratio [OR] 3·07, 95% CI 1·35-6·97; p = 0·009) and the live birth rate (29/50 [58·0%] vs. 17/49 [34·7%]; OR 2·60, 95% CI 1·15-5·86; p = 0·03) in the IVIG group were higher than those in the placebo group in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (OR 6·27, 95% CI 2·21-17·78; p < 0·001) and the live birth rate (OR 4·85, 95% CI 1·74-13·49; p = 0·003) significantly increased in women who received IVIG at 4-5 weeks of gestation as compared with placebo, but these increases were not evident in women who received IVIG at 6 weeks of gestation. Four newborns in the IVIG group and none in the placebo group had congenital anomalies (p = 0·28). INTERPRETATION A high dose of IVIG in very early pregnancy improved pregnancy outcome in women with four or more RPLs of unexplained aetiology. FUNDING The Japan Blood Products Organization.
Women with unexplained recurrent pregnancy loss (n= 99).
High dose of intravenous immunoglobulin (IVIG), (n= 50).
Placebo (physiological saline), (n= 49).
The ongoing pregnancy rate at 22 weeks of gestation (31/50 [62·0%] vs. 17/49 [34·7%]; and the live birth rate (29/50 [58·0%] vs. 17/49 [34·7%] in the IVIG group were higher than those in the placebo group. The ongoing pregnancy rate at 22 weeks of gestation and the live birth rate significantly increased in women who received IVIG at 4-5 weeks of gestation as compared with placebo, but these increases were not evident in women who received IVIG at 6 weeks of gestation. Four newborns in the IVIG group and none in the placebo group had congenital anomalies.
Intravenous immunoglobulins improve live birth rate among women with underlying immune conditions and recurrent pregnancy loss: a systematic review and meta-analysis
Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology. 2022;18(1):23
Intravenous immunoglobulin (IVIG) is increasingly used as a treatment for recurrent pregnancy loss (RPL) despite lack of clear evidence on efficacy. Recent data suggest IVIG might be more effective in a subgroup of women with an aberrant immunological profile. Therefore, a systematic review and meta-analysis of studies on the effectiveness of IVIG treatment on pregnancy outcome among women with RPL and underlying immunological conditions (e.g., elevated NK cell percentage, elevated Th1/Th2 ratio, diagnosis with autoimmune disorders) was conducted. Eight non-randomized controlled trials, including 478 women (intervention: 284; control: 194), met eligibility criteria. Meta-analysis showed that treatment with IVIG was associated with a two-fold increase in live birth rate (RR 1.98, 95% CI 1.44-2.73, P < 0.0001). The effect of IVIG was particularly marked in the subgroup of studies including patients based on presence of elevated (> 12%) NK-cell percentage (RR 2.32, 95% CI 1.77-3.02, P < 0.0001) and when starting intervention prior to or during cycle of conception (RR 4.47, 95% CI 1.53-13.05, P = 0.006). In conclusion, treatment with IVIG may improve live birth rate in women with RPL and underlying immune conditions. However, these results should be interpreted with caution as studies are limited by low number of participants and the non-randomized design, which represent seriously biases. Future randomized controlled trials in women with RPL and underlying immune conditions are needed before using IVIG in a clinical setting.
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.
Early and Systematic Administration of Fibrinogen Concentrate in Postpartum Haemorrhage Following Vaginal Delivery: The FIDEL Randomized Controlled Trial
BJOG : an international journal of obstetrics and gynaecology. 2021
OBJECTIVE To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management. DESIGN Multicentre, double-blind, randomized placebo-controlled trial. SETTING 30 French hospitals. POPULATION patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins. METHODS Within 30 min after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo. MAIN OUTCOME MEASURES Failure as composite primary efficacy endpoint: at least 4 g/dL of haemoglobin decrease and/or transfusion of at least 2 units of packed red blood cells within 48h following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures, and maternal morbidity-mortality within 6±2 weeks after delivery. RESULTS 437 patients were included : 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346mL) and plasma fibrinogen (4.1 ± 0.9g/L) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the Fibrinogen and placebo groups, respectively (OR=0.99) after adjustment for centre and baseline plasma fibrinogen; (95%CI: [0.66;1.47]; p=0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged in the Fibrinogen group and decreased by 0.56 g/L in the placebo group. No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group, versus two in the placebo group. CONCLUSIONS As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs, and postpartum anaemia, but prevented plasma fibrinogen decrease without any subsequent thromboembolic events.
Patients with persistent post-partum haemorrhage after vaginal delivery enrolled in the FIDEL trial (n= 437).
Fibrinogen concentrate (n= 224).
Placebo (n = 213).
At inclusion, blood loss (877 ± 346mL) and plasma fibrinogen (4.1 ± 0.9g/L) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the fibrinogen and placebo groups, respectively after adjustment for centre and baseline plasma fibrinogen. No significant differences in secondary efficacy outcomes were observed. The mean plasma fibrinogen was unchanged in the fibrinogen group and decreased by 0.56 g/L in the placebo group. No thromboembolic or other relevant adverse effects were reported in the fibrinogen group, versus two in the placebo group.
Application of hepatitis B immunoglobulin in prevention of mother-to-child transmission of chronic hepatitis B in HBsAg- and HBeAg-positive mother
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2021;:1-6
The aim of our study was to compare the efficacy of two dosages of hepatitis B immunoglobulin (HBIG) combined with HBV vaccine (HBVac) to prevent mother-to-child transmission (MTCT) of hepatitis B in HBsAg- and HBeAg-positive mother. We enrolled 331 mother-infant pairs with HBsAg- and HBeAg-positive maternal state from the Women's Hospital School of Medicine of Zhejiang University. Newborns were randomly distributed into two groups according to the dosages of HBIG injection: 100 IU and 200 IU. Newborns from both groups were injected with HBVac in the same doses. We compared the immune outcomes between the two groups and explore the influencing factors of immune outcomes through regression analysis. There was no statistically significant relationship between HBsAg serological transmission of newborns and dosages of HBIG in HBsAg- and HBeAg-positive mother (p > .05). The Logistic regression showed that high DNA load is a risk factor for passive-active immunoprophylaxis failure for both 100 IU and 200 IU group, but higher-dosage HBIG is not necessary for higher-viral-load pregnant women with HBsAg- and HBeAg-positive. In conclusion, combined application of HBVac and a single dose of 100 IU HBIG can achieve the ideal MTCT interruption results for HBsAg- and HBeAg-positive pregnant women.IMPACT STATEMENTWhat is already known on this subject? Passive-active immunoprophylaxis is proved to be effective in preventing mother-to-child transmission of hepatitis B. Hepatitis B vaccine combined with 100 IU or 200 IU immunoglobulin is mostly recommended in China.What do the results of this study add? At present, there is still a lack scientific basis for improving existing strategies and measures to prevent mother-to-child transmission of hepatitis B in China.What are the implications of these findings for clinical practice and/or further research? 100 IU and 200 IU immunoglobulin show equivalent blocking effect, and combined use of hepatitis B vaccine and 100 IU immunoglobulin is more cost-effective.