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1.
High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss
Yamada, H., Deguchi, M., Saito, S., Takeshita, T., Mitsui, M., Saito, T., Nagamatsu, T., Takakuwa, K., Nakatsuka, M., Yoneda, S., et al
Journal of reproductive immunology. 2023;158:103977
Abstract
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.
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Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial
Yamada H, Deguchi M, Saito S, Takeshita T, Mitsui M, Saito T, Nagamatsu T, Takakuwa K, Nakatsuka M, Yoneda S, et al
EClinicalMedicine. 2022;50:101527
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Editor's Choice
Abstract
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.
PICO Summary
Population
Women with unexplained recurrent pregnancy loss (n= 99).
Intervention
High dose of intravenous immunoglobulin (IVIG), (n= 50).
Comparison
Placebo (physiological saline), (n= 49).
Outcome
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.
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Application of hepatitis B immunoglobulin in prevention of mother-to-child transmission of chronic hepatitis B in HBsAg- and HBeAg-positive mother
Luo Q, Wang H, Fang JW, Gu ZW, Song DJ, Chen Y, Chen GD, Zhao B, Sun C, Ma Y, et al
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2021;:1-6
Abstract
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.
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Early and Systematic Administration of Fibrinogen Concentrate in Postpartum Haemorrhage Following Vaginal Delivery: The FIDEL Randomized Controlled Trial
Ducloy Bouthors AS, Mercier FJ, Grouin JM, Bayoumeu F, Corouge J, Le Gouez A, Rackelboom T, Broisin F, Vial F, Luzi A, et al
BJOG : an international journal of obstetrics and gynaecology. 2021
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Editor's Choice
Abstract
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.
PICO Summary
Population
Patients with persistent post-partum haemorrhage after vaginal delivery enrolled in the FIDEL trial (n= 437).
Intervention
Fibrinogen concentrate (n= 224).
Comparison
Placebo (n = 213).
Outcome
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.
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Treatment with intravenous immunoglobulin increases the level of small EVs in plasma of pregnant women with recurrent pregnancy loss
Jorgensen MM, Baek R, Sloth J, Varming K, Christiansen OB, Ditlevsen NE, Rajaratnam N
J Reprod Immunol. 2020;140:103128
Abstract
Extracellular vesicles (EVs), which are small cell-derived compartments, take part in numerous different physiological processes. The contents of EVs reveal the cell of origin and indicates pathophysiological states in different diseases. In pregnancy disorders, changes have been reported in the composition, bioactivity and concentration of placental and non-placental EVs. The purpose of this study was to monitor the effects on EVs in patients receiving intravenous immunoglobulin (IVIG) or placebo (albumin) treatment due to recurrent pregnancy loss (RPL). In a placebo-controlled trial study of IVIG treatment, plasma collected from 39 women with RPL were investigated using the Extracellular Vesicle Array (EV Array). Plasma was sampled consecutively (from gestational week (GW) 5) and the protein phenotypes of the smaller EVs (sEVs) were analyzed for the presence of 34 markers. The levels of sEVs or changes in their levels in early pregnancy were correlated with treatment. There was statistically significant increased levels of sEVs in patients who received IVIG versus placebo. In conclusion, the treatment with high-doses of IVIG clearly boosted the production and release of sEVs to the circulation; however, the biological role of this boost remains to be clarified in further studies.
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Efficacy of Nucleotide/Nucleoside Analogues and Hepatitis B Immunoglobulin Therapy in Blocking Mother-to-Child Transmission of Hepatitis B in an Eastern Chinese Group
Sun X, Wang C, Wang B, Yang X, Xu H, Shen M, Zhu K
Infectious diseases in obstetrics and gynecology. 2020;2020:4305950
Abstract
The objective of this study was to investigate the efficacy and potential side-effects of nucleotide/nucleoside analogues and hepatitis B immunoglobulin injection of newborns in blocking mother-to-child transmission of hepatitis B virus in the middle and late pregnancy period. 238 cases of enrolled pregnant women were divided into the Telbivudine group, the Tenofovir group, the Lamivudine group, and the hepatitis B immunoglobulin (HBIG) group. Enrolled patients received corresponding therapies. Clinical and laboratory data were collected. Results showed that the levels of HBV DNA of the enrolled pregnant women in the Telbivudine, Tenofovir, and Lamivudine groups decreased rapidly after 12 weeks of drug intervention compared with those in the control. HBsAg positive rate in newborns and in children 24 weeks after birth was 0/60, 0/60, 0/60, 3/30, and 11/28 in the Telbivudine, Tenofovir, Lamivudine, HBIG, and control groups, respectively. No significant side-effects were identified after following up to 12 months after birth. Our results show that routine HBV vaccine plus HBIG injections is insufficient in blocking mother-to-child HBV transmission. Administration of nucleotide/nucleoside analogues or HBIG at pregnancy is suggested to maximize the blocking of vertical HBV transmission.
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Histological analysis of term placentas from hyperimmune globulin-treated and untreated mothers with primary cytomegalovirus infection
Gabrielli L, Bonasoni M P, Foschini M P, Silini E M, Spinillo A, Revello M G, Chiereghin A, Piccirilli G, Petrisli E, Turello G, et al
Fetal Diagnosis and Therapy. 2018;:1-7.
Abstract
BACKGROUND The Congenital Human Cytomegalovirus Infection Prevention (CHIP) study, a randomized, blinded, placebo-controlled trial, demonstrated that the efficacy of hyperimmune globulin (HIG) was not different from that of placebo regarding transmission of cytomegalovirus (CMV) from mothers to newborns. Our aim was to analyze histologically HIG effects on placentas collected for the CHIP study. MATERIALS AND METHODS Virological and histological analyses were performed on 40 placentas from transmitter and nontransmitter HIG-treated and untreated mothers by assessing the number of CMV-positive cells, tissue viral load, tissue damage, and compensatory mechanisms. RESULTS The HIG and placebo groups showed no significant differences in the number of CMV-positive cells (median number in 10 fields at 10 high-power fields: 2.5 vs. 2, p = 0.969) and viral load (median load: 5 copies/5 ng vs. 10.5 copies/5 ng, p = 0.874). Regarding histological examination, the scores of parameters related to tissue damage and hypoxic parenchymal compensation were higher in transmitters except for chorangiosis, with statistically significant differences observed for chronic villitis (p = 0.007), calcification (p = 0.011), and the total score of tissue damage (p < 0.001). The HIG and placebo groups showed no significant differences for all tissue damage and compensation parameters and overall scores. DISCUSSION HIGs are not able to reduce placental viral load and histological damage, which was significantly associated only with infection.
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Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial
Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, Weeks AD, Sanders J, Aawar N, Townson J, et al
British Journal of Anaesthesia. 2017;119((3)):411-421.
Abstract
Background: Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. Methods: Women with PPH 1000-1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. Results: Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3-1.7), P =0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th-75th centile) of 1 (0-4.5) unit of allogeneic blood products and had an additional 300 (100-350) ml blood loss whereas those who received placebo also received 3 (0-6) units of allogeneic blood products and had 700 (200-1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. Conclusions: Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre -1 , but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis. Trial registration: ISRCTN46295339 ( http://www.isrctn.com/ISRCTN46295339 , last accessed 5 July 2017), EudraCT 2012-005511-11 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11 , last accessed 5 July 2017).
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Usefulness of hemostatic sealants for minimizing ovarian damage during laparoscopic cystectomy for endometriosis
Choi C, Kim WY, Lee DH, Lee SH
The Journal of Obstetrics and Gynaecology Research. 2017;44((3):):532-539
Abstract
AIM: We aimed to evaluate the impact of topical hemostatic sealants and bipolar coagulation during laparoscopic ovarian endometriotic cyst resection on ovarian reserve by comparing the rates of decrease in anti-Mullerian hormone (AMH). METHODS A randomized prospective data collection was made on women aged 19-45 years who planned to have laparoscopic ovarian cystectomy at one of two institutions (n = 80), Kangbuk Samsung Hospital, Seoul, Korea or National Health Insurance Service Ilsan Hospital, Goyang, Korea, from January 2014 to April 2016. Patients were randomly divided into two groups treated with either a topical hemostatic sealant or bipolar coagulation for hemostasis. The hemostatic group was randomized to the FloSeal or TachoSil subgroups. Preoperative and 3-month postoperative AMH levels were checked and the rates of decrease of AMH were compared. All patients enrolled were treated with dienogest (Visanne) for 6-12 months. None were lost to follow-up at postoperative 3 months, but about one-third of the patients had been lost to follow-up by 6-12 months. RESULTS AMH was significantly decreased in both groups 3 months postoperatively; however, the rate of decrease in the bipolar coagulation group was greater than that in the hemostatic sealant group, 41.9% (interquartile range [IQR], 22.29-65.24) versus 18.1% (IQR, 10.94-29.90), P = 0.007. Between the two hemostatic subgroups, there was no significant difference in AMH decrease rate, 14.95% (IQR, 11.34-21.21) versus 18.1% (IQR 9.76-40.70), P = 0.204. CONCLUSION Hemostatic sealants may be an alternative to bipolar coagulation for preservation of ovarian reserve after laparoscopic ovarian cystectomy for endometriosis.
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Single dose Anti-D prophylaxis in pregnancy: is it time to change?
Pennell C
Haematology Society of Australia and New Zealand. 2016;:146.. 145.