Cell-mediated and humoral immune responses to human cytomegalovirus in pregnant women with vertically transmitted infection following primary infection: A case report.

Human cytomegalovirus (HCMV) is the major cause of neurological sequelae in infants. Immune control of primary HCMV infection appears to depend on the interaction between humoral and cell-mediated immune responses. We report the case of an HCMV-transmitter mother observed with dissociation between humoral and cell-mediated immune responses. The patient had immunoglobulin (Ig) G and M positivity at 11 weeks of gestation and showed fetal hyperechoic bowel and minimal ascites at 21 weeks of gestation. At 25 weeks of gestation, the polymerase chain reaction result for HCMV using amniotic fluid was positive. The numbers of spots in the enzyme-linked immunosorbent spot (ELISPOT) assay at 25, 36, and 39 weeks of gestation were three, five, and six spots/2 × 105 peripheral blood mononuclear cells, respectively. Furthermore, IgG avidity indexes (AIs) at 21, 25, 36, and 39 weeks of gestation were 37.6, 49.7, 72.5, and 74.3, respectively. At 40+1 weeks of gestation, the patient delivered a symptomatic infected newborn with a weight of 2,384 g (-2.6 SD) and a head circumference of 30 cm (-2.6 SD). The neonate had a petechial rash and bilateral hearing loss although did not show liver dysfunction or thrombocytopenia. Cranial magnetic resonance imaging revealed mild ventriculomegaly, left lateral/parietal polymicrogyria, and a punctate white matter lesion. This case showed that IgG AI increased with increasing gestational age, whereas the numbers of spots in the ELISPOT assay had no change. The dissociation between humoral and cell-mediated immune responses may be characteristic of the immune response of a transmitter mother.

Prevalence of congenital cytomegalovirus infection according to the type of maternal infection in Japan.

INTRODUCTION: Variable rates of cytomegalovirus (CMV) seropositivity in mothers from different individual's background may translate to distinct epidemiological patterns of congenital CMV infection. METHODS: The prospective cohort study was conducted in Japan to evaluate the prevalence of vertical transmission rate according to the type of maternal infection. Post hoc power as a follow-up analysis was evaluated to compare the statistical power with other studies from France, Finland and Brazil. One thousand one hundred sixty-three pregnant women were measured IgG, IgM and IgG avidity index. The urine samples of neonates of these women were evaluated using polymerase chain reaction to diagnose the vertical transmission. RESULTS: The prevalence of congenital CMV infection in the study population was 0.4%. The proportions of patients with primary and nonprimary infections were 60% and 40%, respectively, with a maternal seroprevalence of 82.5%. The rate of vertical transmission among the seronegative pregnant women before pregnancy was statistically higher than that among the seropositive pregnant women before pregnancy (p < 0.05), with a study power of 52.7%. The same difference was observed in France and Finland for maternal seroprevalence of 61% and 72% and statistical power of 56.9% and 66.7%, respectively. CONCLUSION: The maternal seroprevalence of the present study conducted in Japan was much higher than that of studies in France and Finland. Nevertheless, seronegative pregnant women had a higher risk of vertical transmission before pregnancy.

Low Maternal Immunoglobulin G Avidity and Single Parity as Adverse Implications of Human Cytomegalovirus Vertical Transmission in Pregnant Women with Immunoglobulin M Positivity.

Human cytomegalovirus (CMV) is the leading cause of neurological sequelae in infants. Understanding the risk factors of primary CMV infection is crucial in establishing preventive strategies. Thus, we conducted a retrospective cohort study to identify risk factors of vertical transmission among pregnant women with immunoglobulin (Ig) M positivity. The study included 456 pregnant women with IgM positivity. Information on age, parity, occupation, clinical signs, IgM levels, and IgG avidity index (AI) was collected. The women were divided into infected and non-infected groups. The two groups showed significant differences in IgM level, IgG AI, number of women with low IgG AI, clinical signs, and number of pregnant women with single parity. In the multiple logistic regression analysis, pregnant women with single parity and low IgG AI were independent predictors. Among 40 women who tested negative for IgG antibody in their previous pregnancy, 20 showed low IgG AI in their current pregnancy. Among the 20 women, 4 had vertical transmission. These results provide better understanding of the risk factors of vertical transmission in pregnant women with IgM positivity.

A case of facial cellulitis caused by group B streptococcus in an extremely low birthweight infant.

Group B streptococcus (GBS) is an important pathogen that causes neonatal sepsis and meningitis, which have high mortality and morbidity. Cellulitis is a rare presentation of late-onset neonatal GBS infection. We report the case of an extremely low birthweight infant with facial cellulitis caused by late-onset GBS infection. A 590-g male neonate was delivered by Cesarean section at 23 gestational weeks due to intrauterine GBS infection. Although he was effectively treated with 2 weeks of antimicrobial therapy for early-onset GBS sepsis, he subsequently developed facial and submandibular cellulitis caused by GBS at 44 days of age. He was treated with debridement and antibiotic therapy, and after 2 months his facial involvement had improved, but cosmetic issues remained. Neonatal GBS infection requires a prompt sepsis workup followed by the initiation of empiric antibiotic therapy. Additionally, lifesaving surgical debridement is sometimes necessary for cellulitis, even in premature infants.

Differences in levels of rubella hemagglutination inhibition antibody titers according to birth cohort.

INTRODUCTION: This study aimed to examine the immunity level against rubella in pregnant women of different birth cohorts. METHODS: In total, 512 pregnant women who visited a primary clinic between May 2019 and March 2020 were enrolled. Information in terms of the patients' hemagglutination inhibition (HI) titers, birthdate, obstetrical history, and vaccination history were collected. Participants were divided into three generational groups according to the vaccination policy in Japan. Publicly funded vaccination was administered twice as part of a routine program in group A (n = 11), once as part of a routine program and once in a catch-up program in group B (n = 181), and once in group C (n = 320). RESULTS: All groups had some women with negative rubella HI antibody titers (7.6% of all the women, 18.2% of group A, 9.4% of group B, and 6.3% of group C) and those with rubella HI antibody titers of ≤1:16 (45.1% of all women, 90.9% of group A, 56.4% of group B, and 37.2% of group C). Rubella HI antibody titers differed between the groups; group C had higher titers than that in group B. In groups B and C, the proportions of women with rubella HI antibody titers of ≤1:16 were not statistically different between primipara and multipara. CONCLUSIONS: Our study showed that an increase in immunity to rubella, a vaccine-preventable disease, is nevertheless required among childbearing women to prevent rubella and congenital rubella syndrome.

A multiple regression model for predicting a high cytomegalovirus immunoglobulin G avidity level in pregnant women with IgM positivity.

OBJECTIVE: To establish a model to predict high cytomegalovirus (CMV) immunoglobulin (Ig)G avidity index (AI) using clinical information, to contribute to the mental health of CMV-IgM positive pregnant women. METHODS: We studied 371 women with IgM positivity at ≤14 w of gestation. Information on the age, parity, occupation, clinical signs, IgM and G values, and IgG AI was collected. The IgG AI cut-off value for diagnosing congenital infection was calculated based on a receiver operating characteristic curve analysis. Between-group differences were assessed using the Mann-Whitney U-test or χ2 analysis. The factors predicting a high IgG AI were determined using multiple logistic regression. RESULTS: The women were divided into high or low IgG AI groups based on an IgG AI cut-off value of 31.75. There were significant differences in the IgG and IgM levels, age, clinical signs, and the number of women with one parity between the two groups. In a multiple logistic regression analysis, IgM and the number of women with one parity were independent predictors. This result helped us establish a mathematical model that correctly classified the IgG AI level for 84.6% of women. CONCLUSION: We established a highly effective model for predicting a high IgG AI immediately after demonstrating IgM positivity.

Characteristics and influence of Mycoplasma/Ureaplasma cultures in amniotic fluid on perinatal outcomes.

AIM: To investigate the effects of Mycoplasma/Ureaplasma cultured in amniotic fluid on perinatal characteristics in preterm delivery between 22 and 33 weeks of gestation. METHODS: The study was conducted in a tertiary perinatal center and involved 38 pregnant women who had undergone amniocentesis to evaluate intrauterine infection due to preterm labor or premature rupture of membranes. The subjects were divided into three groups based on the culture results: negative (Negative Group, n = 24), positive for Mycoplasma/Ureaplasma (M/U Group, n = 6), and positive for other pathogens (Other Pathogens Group, n = 8). One-way analysis of variance was used to compare the three groups. RESULTS: The incidence of histological chorioamnionitis and neonatal sepsis was significantly different among the three groups (the Negative Group and the Other Pathogens Group, P < 0.01; the M/U Group and the Other Pathogens Group, P = 0.03). In the M/U Group, no infants had sepsis, severe intraventricular hemorrhage, cystic periventricular leukomalacia, or poor neurological outcomes, but one infant developed bronchopulmonary dysplasia and needed home oxygen treatment. Although one died of gastrorrhexis, the remaining five patients had normal brain magnetic resonance imaging findings and developed normally. CONCLUSION: The presence of Mycoplasma/Ureaplasma isolated from amniotic fluid did not cause neonatal sepsis or poor prognosis. In some infants, there was no histological chorioamnionitis in the placenta. These pathogens thus seem to be less invasive than any other microbes with respect to perinatal outcomes.

A cross-sectional study on maternal anxiety levels after cytomegalovirus screening.

Purpose: we aimed to estimate the anxiety levels of pregnant women following maternal serum screening for CMV infection.Materials and methods: In this case-control study conducted from April 2016 to June 2017, we enrolled all pregnant women referred to our hospital who were CMV immunoglobulin (Ig) M antibody positive (IgM-positive group, n = 51); further, those who were CMV IgG positive but IgM negative (IgM-negative group, n = 51) during the same period were included as study controls. Data were collected on patient characteristics, CMV IgM levels, and whether patients were accompanied by their partners during the first hospital visit after CMV IgM testing. The State-Trait Anxiety Inventory was used to assess anxiety levels.Results: Both groups were age matched [mean age (years): IgM-positive, 30 ± 4.2 and IgM-negative, 29.9 ± 4.6]. The mean state-anxiety score was higher in the IgM-positive group (53 ± 9.6) than in the IgM-negative group (38.5 ± 7.0, p < .05) with no between-group differences in trait-anxiety scores. Similarly, a higher number of women were accompanied by their partners in the IgM-positive group. The state-anxiety scores and CMV IgM levels were not correlated in the IgM-positive group.Conclusion: Counseling support is essential for IgM-positive pregnant women following serum screening, and the screening should be avoided if support systems are unavailable.

Oral diatrizoate acid for meconium-related ileus in extremely preterm infants.

BACKGROUND: Intestinal disorders are common in very low-birthweight infants. The purpose of this study was to evaluate the impact of prophylactic oral Gastrografin® (diatrizoate acid) on meconium-related ileus (MRI) in extremely preterm infants. METHODS: This was a retrospective case-control study of infants born extremely preterm at <28 weeks of gestation and treated with diatrizoate acid (prophylactic group) or not (control group) in the periods 2007-2014 and 2000-2009, respectively. In the 2007-2014 period, 120 infants received prophylactic diatrizoate acid solution. From the 165 infants in the control group, we selected 120 infants matched for gestational age. Cases of death before 72 h of life or congenital abnormalities were excluded. Intestinal disorders, time until full enteral feeding, duration of hospital stay, mortality rate, and neurodevelopmental outcome were compared. RESULTS: MRI occurred in six infants in the control group and in none of the infants in the prophylactic group (P = 0.039). Median time until full enteral feeding was 25 versus 22 days (P < 0.01), hospital stay was 142 versus 126 days (P < 0.01), and mortality rate for infants aged 24-27 weeks was 8.2% versus 0% (P = 0.021), respectively. CONCLUSIONS: Prophylactic oral diatrizoate acid reduced MRI in extremely preterm infants without side-effects and decreased the mortality rate of infants born at 24-27 weeks, and is thus beneficial in extremely preterm infants.

Fetal left ventricular non-compaction cardiomyopathy with ascites: A case report.

Here we report a case of fetal left ventricular non-compaction cardiomyopathy with ascites and cardiac dysfunction at a gestational age of 34+5  weeks. Laboratory tests did not reveal any sign of viral infection in utero. A female neonate weighing 2436 g was delivered by emergency cesarean section due to non-reassuring fetal status. Postnatal echocardiography confirmed left ventricular non-compaction cardiomyopathy with severe cardiac failure. Although she was treated effectively during the acute period by continuous flow peritoneal dialysis, surgical ligation of a patent ductus arteriosus, and inhaled nitric oxide, she died on day 41 of life. Symptoms of severe cardiac dysfunction appeared antenatally in this patient and the outcome was poor.

Maternal immunoglobulin G avidity as a diagnostic tool to identify pregnant women at risk of congenital cytomegalovirus infection.

BACKGROUND: The immunoglobulin (Ig) G avidity index (AI) is useful to detect primary cytomegalovirus (CMV) infection. However, because IgG matures with time, this index is not useful to detect a primary infection, unless measured at an appropriate time. OBJECTIVES: We aimed to clarify the difference between using IgG AI and IgM positivity according to the stage of pregnancy to identify congenital CMV infection risk. STUDY DESIGN: We collected the serum samples from 1115 pregnant women who underwent maternal screening for primary infection (n = 956) and were referred to our hospital because of CMV IgM positivity (n = 155) or had abnormal fetal ultrasonography findings (n = 4). The same sera samples were used to measure CMV IgM, IgG, and IgG AI. An IgG AI of <35% was defined as low. Neonatal urine collected within 5 days after birth was examined by polymerase chain reaction to confirm congenital infection. RESULTS: Fourteen mothers gave birth to infected neonates. The sensitivity, specificity, and negative predictive values of the low IgG AI group with IgM-positive samples to discriminate between women with congenital infection at ≤14 weeks of gestation were 83.3, 83.8, and 99.1, respectively, which were higher than those of other subjects. Uni- and multivariate analyses revealed that IgM positivity and low IgG AI were independent variables associated with congenital infection at any stage of pregnancy, except low IgG AI at ≥15 weeks of gestation. CONCLUSION: Low IgG AI with IgM positivity at ≤14 weeks of gestation was a good indicator of congenital infection, which should prove useful in obstetric practice.

Did antepartum hypoxic insult caused by fetal vessel thrombosis influence the procalcitonin level in umbilical blood? A case report.

We report a case of marked elevation of the procalcitonin level in umbilical blood and neonatal blood at birth. The mother did not perceive fetal motion. Antepartum fetal heart rate monitoring showed a loss of variability and absence of acceleration. No fetal breathing movement, fetal movement, or fetal tone were observed by ultrasonography. The female neonate was delivered by cesarean section at 25 weeks of gestation, with birthweight 774 g. The umbilical arterial pH value at birth was 7.29. Mild elevation in interleukin-6 and tumor necrosis factor-α in umbilical blood were observed. Cytochrome c showed a high level in umbilical and neonatal blood at birth. Placental histopathology revealed multiple fetal vessel thrombosis in the large stem villi and chorionic vessels. The neonate showed no infectious signs throughout the neonatal period. Computed tomography at 3 months of age revealed atrophy in the cerebrum and cerebellum. At 1 year after birth, the infant showed spastic quadriplegia. In this case, antepartum asphyxia due to fetal vessel thrombosis may have influenced the elevation of procalcitonin level in umbilical blood and neonatal blood at birth.

Perinatal morbidity and mortality for extremely low-birthweight infants: A population-based study of regionalized maternal and neonatal transport.

AIM: The aim of this study was to clarify the mortality and long-term outcomes of extremely low-birthweight infants according to the process of maternal or infant transport and indications for maternal transport. MATERIAL AND METHODS: We conducted a population-based study between 2005 and 2009. The collected data included the process and indications for maternal or neonatal transport, maternal and infant characteristics and the prognosis of extremely low-birthweight infants. Intergroup comparisons were made using the Mann-Whitney U-test, while multiple group comparisons were made using the Kruskal-Wallis test followed by the post-hoc paired t-test according to the Dunn procedure. Comparisons of the cumulative survival rates based on postnatal age according to the process of maternal or neonatal transport were performed using a Kaplan-Meier survival analysis and the log-rank test. RESULTS: The study subjects included 195 infants from 189 mothers following 50,632 deliveries during the study period. Overall, 32 (16.4%) infants died and 33 (20.2%) infants had neurological impairments. The rates of mortality and handicaps among the infants in the maternal transport group were 15.2% and 23.2%, respectively, compared to 25% and 44%, respectively, in the neonatal transport group. There were no differences in the prognoses of the infants according to the process of maternal transport, although more premature neonates were managed in the tertiary center. There were no differences in the cumulative survival rates based on the institution that managed the neonate. The incidence of a poor prognosis was significantly higher among the infants born from mothers transported to the tertiary center due to bulging membranes (P = 0.047). All mothers with placental abruption were transported to the nearest secondary center. CONCLUSION: The morbidity and mortality of extremely low-birthweight infants demonstrated a low incidence following the regionalization of high-risk pregnancies in our region. Further reductions in severe neonatal morbidities may depend on reducing the rate of neonatal transport.

Prospective study of the MD-twin score for antepartum evaluation of monochorionic diamniotic twins and its correlation with perinatal outcomes.

AIM: To assess the outcome of monochorionic diamniotic (MD) twins with the aid of the MD-twin score. METHODS: We enrolled 112 MD-twin women in a tertiary perinatal center from 1997 to 2009. The MD-twin score was prospectively applied once per week to women who did not have twin-to-twin transfusion syndrome (TTTS) after 26 weeks of gestation. The MD-twin score consists of five variables: (i) fetal weight discordance; (ii) amniotic fluid discordance; (iii) hydrops fetalis; (iv) umbilical cord insertion; and (v) fetal heart rate monitoring. Normal was assigned a value of 0, abnormal was assigned 1, and total score was used for evaluation. Women with scores of 2 at 26 weeks gestation were managed expectantly until the score reached 3. Outcome measures were fetal death, neonatal death and neurological sequelae. The incidence of poor outcome according to score was investigated. The characteristics of MD twins with poor outcome were investigated. RESULTS: MD-twin scores were applied to 90 women. Among them, 79 had scores of 2 or less and all had good outcomes. There were 11 women with a score of 3, four of whom had adverse outcome for at least one twin. Neonates born to women with scores of 0-2 had good outcomes without respect to birthweight percentile, while neonates with scores of 3 had poor outcomes when their birthweight percentile was less than the third percentile. CONCLUSION: The MD-twin score is applicable to 90% of MD twins without TTTS. An MD-twin score of 2 is reassuring, while a score of 3 indicates increased risks for adverse outcome.

Protein C deficiency as the major cause of thrombophilias in childhood.

Genetic predisposition of thromboembolism depends on the racial background. Factor V Leiden (G1691A) and factor II mutation (G20210A) are the leading causes of inherited thrombophilias in Caucasians, but are not found in Asian ancestries. Protein S (PS), protein C (PC) and antithrombin (AT) activity are reportedly low in 65% of adult Japanese patients with deep vein thrombosis. Approximately half of the patients with each deficiency carry the heterozygous mutation of PS (PROS1; 20%), PC (PROC; 10%), and AT genes (SERPINC1: 5%). Recently, several studies have revealed an outline of inherited thrombophilias in Japanese children. Congenital thrombophilias in 48 patients less than age 20 years consisted of 45% PC deficiency, 15% PS deficiency and 10% AT deficiency, along with other causes. All PS- and AT-deficient patients had a heterozygous mutation of the respective gene. On the other hand, PC-deficient patients were considered to carry the homozygous or compound heterozygous mutation in 50%, the heterozygous mutation in 25%, and unknown causes in the remaining 25% of patients. Half of unrelated patients with homozygous or compound heterozygous PROC mutations carried PC-nagoya (1362delG), while their parents with its heterozygous mutation were asymptomatic. Most of the PC-deficient patients developed intracranial lesion and/or purpura fulminans within 2 weeks after birth. Non-inherited PC deficiency also conveyed thromboembolic events in early infancy. The molecular epidemiology of thrombosis in Asian children would provide a clue to establish the early intervention and optimal anticoagulant therapy in pediatric PC deficiency.

Mortality rates for extremely low-birthweight infants: a regional, population-based study in Japan during 2005-2009.

AIM: We investigated neonatal and infant mortality rates for extremely low-birthweight infants and clarified clinical factors associated with death. MATERIAL AND METHODS: A population-based study was conducted for 195 infants born from 2005 to 2009. RESULTS: The infant mortality rate was 28.6%, 21.7%, 34.2%, 6.7%, 6.3%, 13%, and 4.8% at 22, 23, 24, 25, 26, 28, and ≥28 weeks, respectively. The infant mortality rate according to birthweight was 50%, 9%, 31%, 16.7%, 19.4%, 7.5%, and 2.9% for <400 g, 400-499 g, 500-599 g, 600-699 g, 700-799 g, 800-899 g, and 900-999 g, respectively. Log-rank tests revealed a significant difference in the cumulative survival rates according to gestational age (P < 0.001). In the 24-week group, this rate in a tertiary center was higher than in a non-tertiary center (P = 0.001). The mortality of infants born by cesarean section (73%) was lower than that of infants born vaginally (P < 0.05). Multiple regression analyses show that the significant factors associated with death were 22-24 weeks of gestational age, management at non-tertiary centers, and multiple births. CONCLUSION: Survival of infants (<1000 g) depends on gestational age, centralization and multiple births.

Congenital infantile fibrosarcoma in a very low-birth-weight infant.

We describe a prenatally diagnosed case with congenital infantile fibrosarcoma, which is a rare malignant tumor, of which there have been only 14 cases reported in the English literature. A giant mass on the left thigh was detected at 24 weeks' gestation by prenatal ultrasonography. Because of its rapid growth and nonreassuring fetal status in utero, the baby was delivered by cesarean delivery at 27 weeks' gestation. The case was complicated by hemorrhagic anemia, coagulopathy, and cardiac failure, and a tumor resection was performed on day 3. As of age 2.5 years, he was healthy without evidence of recurrence. Because some fetal cases with congenital infantile fibrosarcoma have a poor prognosis, termination of pregnancy at an appropriate time and postnatal early treatment are crucial for successful treatment.

Case report and review of delayed-interval delivery for dichorionic, diamniotic twins with normal development.

We report a case of delayed-interval delivery of a dichorionic, diamniotic twin pregnancy with the survival of both twins. The patient presented at 22 weeks and 1 day of gestation with vaginal bleeding and preterm labor. Five days later, the first twin was born. The second twin remained in utero. The management consisted of careful monitoring of both maternal and fetal status. Nine days later, the second twin was delivered vaginally. Both twins received full resuscitation and immediate life-support intervention; at 7 years of age both twins exhibited normal development.

Perinatal death and neurological damage as a sequential chain of poor outcome.

OBJECTIVE: We investigated the risk factors of perinatal death and neurological damage. METHODS: Perinatal death and neurological damage were retrospectively investigated using a population-based study of 108 024 deliveries from 1998 to 2007. Main factors studied were asphyxia, growth restriction and preterm delivery < 34 weeks of gestation, since these three factors were most often associated with poor prognosis. The impact of each factor was identified by multiple regression analyses. RESULTS: There were 459 perinatal deaths (4.3/1000) and 220 neurological damages (2.0/1000). Preterm delivery accounted for 50% of perinatal deaths and neurological damage, whereas it constituted 2.6% of total births. Multiple regression analyses showed that prematurity < 34 weeks (10-fold), asphyxia (10-fold) and growth restriction (2-fold) were independent and significant risk factors associated with poor outcomes, and that the magnitude was similar throughout the three consecutive critical events of fetal death, neonatal death and neurological damage. CONCLUSIONS: Prematurity < 34 weeks, asphyxia and growth restriction are independent and persistent risk factors from perinatal death to neurological damage.

Application of a fetal scalp electrode for continuous fetal heart rate monitoring during an ex utero intrapartum treatment.

Fetal monitoring is required to avoid hypoxic injury during ex utero intrapartum treatment (EXIT). We performed a tracheostomy under EXIT in a case of suspected airway obstruction caused by a cervical teratoma. The scalp electrode was applied for continuous fetal heart rate monitoring. This device enabled us to promptly deal with fetal bradycardia caused by cord compression. We describe here the usefulness of the fetal scalp electrode for fetal monitoring under EXIT.