High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss.

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.

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.

A successfully treated case of an acute presentation of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) with decreased ADAMTS13 during late stage of pregnancy.

We herein report the case of a 28-year-old pregnant woman with an acute presentation of remarkable petechiae on her lower extremities and severe thrombocytopenia (16 000/mm3 ) at the 35th week of gestation. Although idiopathic thrombocytopenic purpura was initially suspected, subsequent examinations revealed that her ADAMTS13 (a Disintegrin And Metalloprotease, with ThromboSpondin type 1 repeats, member 13) titer was extremely decreased, while she was negative for antibodies against ADAMTS13. Infusion of fresh frozen plasma was immediately performed, and the platelet count was observed to increase. However, severe pregnancy-induced hypertension and proteinuria emerged at 36 weeks and 2 days of gestation, and a male infant was delivered by emergency cesarean section on the 37th week of gestation. The postnatal development was uncomplicated. After delivery, although the mother's platelet count and ADAMTS13 activity decreased temporarily, both values increased following fresh frozen plasma transfusion. This case showed interesting aspects of congenital thrombocytopenic purpura (Upshaw-Schulman syndrome) in pregnancy. Moreover, the rapid measurement of the patient's ADAMTS13 activity and the subsequent accurate diagnosis of congenital thrombocytopenic purpura made it possible to treat the patient with fresh frozen plasma infusion and avoid contraindicated platelet infusion. Close cooperation between obstetricians, hematologists and pediatricians is necessary to achieve successful outcomes in cases of thrombocytopenic purpura during pregnancy.

Enlarged uterine fibroid forming uterine diverticulum during pregnancy: a case report.

BACKGROUND: Although uterine fibroids are a common gynecologic neoplasm, uterine diverticulum accompanied by a uterine fibroid is unique. In addition, pregnancy complicated with uterine diverticulum is extremely rare. We experienced a case of a uterine fibroid that was associated with a uterine diverticulum that enlarged during pregnancy and puerperium. CASE PRESENTATION: A 25-year-old nulligravida woman had an abnormal uterine cavity surrounded by myomatous mass. After natural conception, the mass and pouch had enlarged during pregnancy. Six months after elective cesarean delivery, she underwent laparotomy because of abdominal pain caused by the myomatous mass and the fluid inside. The tumor was connected to the midline of the posterior wall of the normal uterus. The resected tumor was pathologically diagnosed as leiomyoma and diverticulum. CONCLUSIONS: Pregnancy can stimulate uterine fibroids to form uterine diverticula. Resection of the diverticulum and fibroid is a useful option for symptomatic patients with desired future fertility.

Biology of the vernix caseosa: A review.

The vernix caseosa is a complex membranous structure comprising 80% water, 10% protein, and 10% lipids including barrier lipids such as ceramides, free fatty acids, phospholipids and cholesterol, synthesized partly by fetal sebaceous glands during the last trimester of pregnancy in an antero-posterior and dorsoventral manner. Because of its lipid content, vernix is hydrophobic and protects the skin from excessive water exposure during the development of the stratum corneum. The vernix caseosa has various functions during fetal transition from an intrauterine to an extrauterine environment, including lubrication of the birth canal during parturition, barrier function to prevent water loss, temperature regulation, for innate immunity and for intestinal development. This review discusses the evidence supporting the prenatal and postnatal functions of vernix caseosa, along with its structure, composition, and physical and biological characteristics. Understanding the biology of the vernix may facilitate improved care of preterm infants immediately post-partum.

The analysis of chromosomal abnormalities in patients with recurrent pregnancy loss, focusing on the prognosis of patients with inversion of chromosome (9).

PURPOSE: Inversion of chromosome 9 (inv[9]) is considered to be a normal variant, and the inv(9) in patients or husbands with recurrent pregnancy loss (RPL) is believed to be harmless. However, there are few reports concerning the outcomes of pregnancy in patients with RPL when the patient or their partner has inv(9). In this study, we analyzed the outcomes of pregnancy in this patient population. METHODS: Chromosomal karyotyping was performed for 2006 couples with RPL (two or more consecutive early pregnancy losses including non-visualized cases) with their informed consent. The frequency of various chromosomal abnormalities in the patient population was then analyzed, and the outcomes of pregnancy in patients with inv(9) were investigated. RESULTS: The frequency of inv(9) in the overall population was 2.6% (52/2006). Thus far, 32 patients have conceived repetitively, resulting in live births in 23 cases and early pregnancy losses in nine cases. Four of the nine cases obtained a good outcome in the subsequent pregnancy. Thus, a successful outcome was obtained in 27 of the 32 (84.4%) cases. CONCLUSIONS: This study suggests that inv(9) has no adverse influence on subsequent pregnancy.

Treatment for patients with recurrent fetal losses positive for anti-cardiolipin beta2 glycoprotein I antibody using Sairei-to (Chai-ling-tang) and low-dose aspirin.

AIM: Recently, it is widely recognized that positivity for anti-phospholipid antibodies is a causative factor for a range of reproductive failures. Anti-cardiolipin beta2 glycoprotein I antibody (anti-CL-beta2-GPI) is a representative anti-phospholipid antibody, which strongly correlates with the development of thrombotic events and diversity of adverse pregnancies. In this series, we aimed to elucidate effective treatment for patients with recurrent fetal losses positive for anti-CL-beta2-GPI using Japanese-modified Chinese herbal medicine. METHODS: Twenty-one patients with recurrent fetal losses who were positive for anti-CL-beta2-GPI were treated with the Japanese-modified Chinese herbal medicine, Sairei-to (Chai-ling-tang), and low-dose aspirin with or without adrenal corticosteroid hormone. Of the 21 patients, the value of anti-CL-beta2-GPI ranged from 1.9 to 3.4 in 10 patients, and it was over 3.5 in 11 patients. RESULTS: Of the 21 patients treated with the current protocol, the pregnancy successfully continued in 17 patients (success rate: 81.0%). Of the four patients who showed repeated abortion, chromosome abnormality of chorionic villi was observed in two; thus, the success rate would be 89.5% (17 of 19 cases) on excluding these cases from the evaluation. CONCLUSION: The efficacy of the current treatment adopting the modified Japanese version of the Chinese herbal medicine Sairei-to for patients with recurrent fetal losses positive for anti-CL-beta2-GPI was indicated.

Microdissection testicular sperm extraction in five Japanese patients with non-mosaic Klinefelter's syndrome.

CASES: Microdissection testicular sperm extraction (micro-TESE) was performed on five Japanese men with non-mosaic Klinefelter's syndrome (KS) and non-obstructive azoospermia in the authors' department. Here is reported the operative results and partner's clinical course for two cases where spermatozoa could be acquired. Also encountered was a man with non-mosaic KS with the partial deletion of azoospermia factor (AZF)b. Because this is rare, it is reported in detail in the context of the previous literature. This case series describes the first experience of micro-TESE by gynecologists in the current department. OUTCOME: The egg collection date was adjusted to the micro-TESE day by using the modified ultra-long method. Intracytoplasmic sperm injection (ICSI) was implemented for two men whose spermatozoa were acquired by micro-TESE, with these progressing to the blastocyst stage. Subsequently, one case conceived after the transfer of fresh embryos and a healthy baby was delivered. However, spermatozoa could not be retrieved from the man with non-mosaic KS who was harboring the partial deletion of AZFb. CONCLUSION: These findings suggest that ovulation induction by using the modified ultra-long method with micro-TESE and ICSI on the same day represents an effective treatment option for men with non-mosaic KS. As there are cases where AZF deletion is recognized among patients with non-mosaic KS, screening before micro-TESE is strongly recommended.

The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy.

OBJECTIVES: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. METHODS/MATERIALS: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. RESULTS: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. CONCLUSIONS: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby.

Effectiveness of fetal cardiac screening for congenital heart disease using a combination of the four-chamber view and three-vessel view during the second trimester scan.

AIM: We aimed to assess the accuracy and effectiveness of fetal cardiac screening for congenital heart disease (CHD) during the second trimester by general obstetricians in a non-selected population. METHODS: In this multicenter, prospective cohort study of fetal cardiac screening, four-chamber and three-vessel views were recorded by obstetricians at 18-21 gestational weeks (GW). A total of 3005 fetuses that were scheduled for delivery at our institution were included. RESULTS: Thirty-seven newborns were born with CHD (1.2%). On excluding 23 cases of ventricular septal defects, the prenatal detection rate of CHD was 42.8%. Although six cases (75.0%) of severe structural abnormality were diagnosed prenatally, the prenatal detection rate of valvular abnormalities was 0%. CONCLUSION: One-point ultrasound screening of the fetal heart using a combination of four-chamber and three-vessel views at 18-21 GW by general obstetricians in a non-selected population may be useful for detecting severe structural abnormalities but not valvular abnormalities. However, this limitation may be improved by conducting another fetal cardiac screening at approximately 30 GW along with the routine use of color Doppler.

Case with pyoderma gangrenosum abruptly emerging around the wound of cesarean section for placenta previa with placenta accrete.

A 39-year-old woman underwent emergency cesarean section (CS) due to placenta previa totalis with massive bleeding. Two major problems emerged in this patient after CS was carried out. One was partial retention of the placenta due to placenta accreta. Another major and more serious problem was pyoderma gangrenosum (PG) widely appearing at the skin of the abdomen around the CS wound. Conservative treatment was performed for the retained placenta, and it had completely disappeared by 76 days after the CS. The diagnosis of PG was promptly made in consultation with a plastic surgeon and a dermatologist when a wide ulcer emerged around the CS wound, and high-dose prednisolone was administered as treatment. At 90 days following the CS, near-complete epithelialization was achieved. This extremely rare case reflects the importance of rapid diagnosis and treatment of PG.

Complex chromosomal rearrangements in couples affected by recurrent spontaneous abortion.

OBJECTIVE: To determine the proportion of couples affected by recurrent spontaneous abortion in which one partner carries balanced translocations among three chromosomes. METHODS: In a retrospective study, G-banded chromosome complements were analyzed for couples affected by recurrent spontaneous abortion who were referred to Niigata University Hospital, Japan, between January 1, 1990, and December 31, 2011. The frequency of couples in whom one of the partners carried balanced translocations among three chromosomes was determined, and the clinical outcomes for affected couples who subsequently achieved term pregnancies were reviewed. RESULTS: Of 1415 couples with recurrent spontaneous abortion during the study period, there were two (0.1%) in which one of the partners (the woman in both cases) carried balanced translocations among three chromosomes. Both couples achieved a subsequent pregnancy that continued successfully and resulted in a phenotypically normal neonate. CONCLUSION: The frequency of balanced translocations among three chromosomes was estimated to be approximately 0.1% in a population affected by recurrent spontaneous abortion. With appropriate treatment based on careful examinations, affected couples can go on to achieve a successful pregnancy outcome.

Successful management of severe intrahepatic cholestasis of pregnancy: report of a first Japanese case.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a cholestasis condition caused by elevated levels of serum bile acids that mainly occurs in the third trimester of pregnancy. Maternal symptoms include pruritus; elevation of transaminases, biliary enzymes, and bilirubin levels; and abnormal liver function tests. Fetal symptoms include spontaneous preterm labor, fetal distress, and intrauterine death. It is more prevalent in the Caucasians and is rarely found in Asian countries, including Japan. The etiology of ICP has been reported as involving various factors such as, environmental factors, hormone balance, and genetic components. The genetic factors include single-nucleotide polymorphisms (SNPs) in the genes of canalicular transporters, including ABCB4 and ABCB11. It has also been reported that the combination of these SNPs induces severe cholestasis and liver dysfunction. CASE PRESENTATION: Here, we report for the first time a 24-year Japanese case of severe ICP diagnosed by typical symptoms, serum biochemical analysis, and treated with the administration of ursodeoxycholic acid which improved cholestasis and liver injury and prevented fetal death. The sequence analysis showed SNPs reported their association with ICP in the ABCB11 (rs2287622, V444A) and ABCB4 (rs1202283, N168N) loci. CONCLUSION: The risk of ICP has been reported to be population-specific, and it is rare in the Japanese population. Our case was successfully treated with ursodeoxycholic acid and the genetic sequence analysis has supported the diagnosis. Because genetic variation in ABCB4 and ABCB11 has also been reported in the Japanese population, we need to be aware of potential ICP cases in pregnant Japanese women although further studies are necessary.

Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene.

We present a case of a patient whose L1CAM gene in X-chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X-linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.

Two cases of recurrent abortion in which isodicentric chromosome 15 was observed in the husbands.

We report two cases of women positive for anticardiolipin antibodies who experienced recurrent abortion whose husbands had isodicentric chromosome 15 aberrations who eventually had successful pregnancies. Two women were referred to our hospital due to their medical history of recurrent abortion. Both were diagnosed as being positive for anticardiolipin antibodies and their husbands with isodicentric chromosome 15. After both patients were treated with a Japanese herbal medicine (Sairei-to) and low-dose aspirin for the positive anticardiolipin antibodies, they delivered appropriate-for-date infants at term gestation. Although both husbands were revealed to have isodicentric chromosome 15, and coincidentally both wives were positive for anticardiolipin antibodies, their next pregnancies continued uneventfully as a result of the treatment.

Twins with neonatal pemphigus vulgaris born to a mother with pemphigus vulgaris: a case report.

Dichorionic diamniotic twins were born at 37 weeks of gestation by cesarean section to a 34-year-old primigravid Japanese woman because the first twin was in breech presentation. The mother had been diagnosed with pemphigus vulgaris prior to her pregnancy. In addition to a high antidesmoglein 3 autoantibody titer, flaccid bullae and erosions on both of the twins' lips and in their oral cavities at 13 days of age led to the diagnosis of neonatal pemphigus vulgaris. This case highlights the need for awareness that pemphigus vulgaris may not occur immediately after birth.

Pregnancy complicated by uterine sacculation due to a huge myoma.

Uterine sacculation is rare complication affecting the pregnant uterus, and is difficult to diagnose. Sacculation consists of a transitory pouch or sac-like structure caused by inverted uterine polarity. Vaginal delivery is difficult, and even cesarean section can be difficult because of peculiar risks associated with uterine sacculation. We report a pregnant patient with posterior sacculation due to a huge myoma in the lower anterior uterine segment. Sacculation, especially that complicated by a huge myoma, is very difficult to accurately diagnose and makes cesarean section surgery challenging. Because of the myoma in our present case, opening the lower uterine segment was impossible with cesarean section. The uterus was instead opened by corporeal vertical cesarean section. Myomectomy was not performed and the giant myoma thus remained. Postoperative assessment revealed the uterus to still be retroverted. The giant myoma was the cause of sacculation in this case.

Changes in fetal circulation associated with congenital heart disease and their effects on fetal growth.

OBJECTIVE: Our aim was to investigate the association between fetal growth and cerebrovascular resistance in fetuses with congenital heart disease (CHD). METHODS: Fetal echocardiography was performed to measure the biparietal diameter, abdominal circumference, femur length, estimated fetal body weight, middle cerebral artery (MCA) resistance index (RI) and umbilical artery (UA) RI in 44 fetuses with CHD and 140 normal fetuses at a gestational age of 28-34 weeks. RESULTS: Fetuses with CHD exhibited significantly lower values for femur length, estimated fetal body weight at the third trimester, body weight, length, and chest circumference at birth than normal controls. The percentages of fetuses showing MCA RI values <10th percentile and UA RI values >90th percentile were significantly higher in the CHD group than in the control group. However, there were no significant differences in any biometric parameters measured between cases with MCA RI values ≥10th percentile and values <10th percentile. CONCLUSIONS: Growth restriction and blood flow changes were observed significantly more frequently in fetuses with CHD than in those without CHD. Further studies are necessary to clarify the association between fetal growth and dynamic changes in fetal circulation.

Successful twin pregnancy in a patient with parkin-associated autosomal recessive juvenile parkinsonism.

BACKGROUND: Pregnancy in patients with Parkinson disease is a rare occurrence. To the best of our knowledge, the effect of pregnancy as well as treatment in genetically confirmed autosomal recessive juvenile parkinsonism (ARJP) has never been reported. Here, we report the first case of pregnancy in a patient with ARJP associated with a parkin gene mutation, ARJP/PARK2. CASE PRESENTATION: A 27-year-old woman with ARJP/PARK2 was diagnosed as having a spontaneous dichorionic/diamniotic twin pregnancy. Exacerbation of motor disability was noted between ovulation and menstruation before pregnancy as well as during late pregnancy, suggesting that her parkinsonism might have been influenced by fluctuations in the levels of endogenous sex hormones. During the organogenesis period, she was only treated with levodopa/carbidopa, although she continued to receive inpatient hospital care for assistance in the activities of daily living. After the organogenesis period, she was administered sufficient amounts of antiparkinsonian drugs. She delivered healthy male twins, and psychomotor development of both the babies was normal at the age of 2 years. CONCLUSION: Pregnancy may worsen the symptoms of ARJP/PARK2, although appropriate treatments with antiparkinsonian drugs and adequate assistance in the activities of daily living might enable successful pregnancy and birth of healthy children.