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. 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. 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). A high dose of IVIG in very early pregnancy improved pregnancy outcome in women with four or more RPLs of unexplained aetiology. The Japan Blood Products Organization.

Acute infection with Toxoplasma gondii during pregnancy can cause congenital toxoplasmosis. The aim of this study was to evaluate whether screening with the use of IgG avidity and multiplex nested PCR methods was effective to detect a high-risk pregnancy. In a prospective study, serum T. gondii IgG avidity was measured in consecutive 146 pregnant women testing positive for T. gondii antibody and either positive or equivocal for IgM. Multiplex nested PCR for T. gondii DNA on amniotic fluid, maternal blood, and umbilical cord blood were performed with informed consent. A total of 51 (34.9%) women presented with low IgG avidity (35%) indices. Amniotic fluid obtained at amniocentesis or birth yielded positive PCR results in nine women with low IgG avidity indices. Of these nine women, three had congenital toxoplasmosis. None of women with high or border line IgG avidity indices had a positive PCR result in the amniotic fluid or congenital toxoplasmosis. No congenital toxoplasmosis was detected in women whose amniotic fluids yielded negative PCR results. Ingestion of raw or undercooked meat was found to be the main risk factor for acute T. gondii infection. Congenital toxoplasmosis screening with a combination of IgG avidity in the maternal blood and multiplex nested PCR in the amniotic fluid was useful for detecting a high risk pregnancy and diagnosing congenital toxoplasmosis.

Cytomegalovirus (CMV) infection is the most common cause of congenital viral infections in humans. The unusual structure of the placenta plays a pivotal role in CMV transmission from mothers to fetuses. The aim of this study was to evaluate the histopathological findings of placentas with congenital CMV infections. We obtained placental specimens from 35 women who had newborns with congenital CMV infections. Placental specimens, extraplacental membranes, and umbilical cords were stained with hematoxylin and eosin, and subjected to immunohistochemical analysis. We evaluated the localization of CMV-infected cells and other histological parameters. Thirty (86%) of the 35 placentas tested positive for CMV-infected cell proteins by immunohistochemistry. A majority of CMV-positive cells were present in fibroblasts and endothelial cells in the villi. The number of CMV-infected cells was inversely correlated to gestational age at delivery. The frequency of chronic villitis (65% vs. 11%; p < 0.01) and changes of the villi (38% vs. 0%; p < 0.05) in the placentas from mothers with symptomatic congenital CMV infections was higher than those observed in samples from mothers with asymptomatic congenital infections. The frequency of changes of the decidua (43% vs. 5%; p < 0.01) in the placentas from mothers with non-primary CMV infections was higher than those from mothers with primary infections. Chronic villitis and changes of the villi were associated with symptomatic congenital CMV infections. The changes of the decidua were associated with congenital CMV infections, in mothers with non-primary CMV infections.

The aim of this study was to evaluate whether chronic endometritis (CE) and uterine endometrium microbiota were associated with repeated implantation failures (RIFs) and recurrent pregnancy losses (RPLs). In this prospective study, uterine endometrial specimens were obtained from 24 women with RIF, 27 with RPL, and 29 fertile control women. Immunohistochemical staining of CD138 for CE and 16S ribosomal RNA (rRNA) sequencing analysis for uterine endometrium microbiota were performed simultaneously. To assess CE, Liu’s method, McQueen scores and plasma cell count/10 mm² were used. The frequency of CE (plasma cells > 5.15/10 mm²) was higher in women with RPL (29.6%) than in fertile controls (6.8%, p < 0.05). The plasma cell count/10 mm² in women with RPL (median 1.53, range 0–252.6, p < 0.01) and women with RIF (median 0.6, range 0–6.98, p < 0.05) was higher than in fertile controls (median 0, range 0–29). The uterine endometrium microbiota in women with RPL or RIF was not significantly different from that in fertile controls. However, the relative dominance rate of Lactobacillus iners (median 4.7%, range 0–99.9 vs. median 0%, range 0–100, p < 0.001) and the positive rate of Ureaplasma species (36.3% vs. 8.6%, p < 0.05) were higher in 11 women with CE than in 69 women without CE. The results suggest that CE may be involved in the pathophysiology of RPL and RIF. Lactobacillus iners and Ureaplasma species may be associated with the etiology of CE.

It was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8–14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of preeclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7–18.1) and body mass index (BMI) ≥ 25 kg/m² (4.3, 1.1–13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0–14.3) and BMI ≥ 25 kg/m² (4.0, 1.3–10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.