Survival and unique clinical practices of extremely preterm infants born at 22-23 weeks' gestation in Japan: a national survey.

OBJECTIVES: To investigate prognosis and clinical practices of infants born at 22-23 weeks' gestational age (wkGA) in Japan. DESIGN: A national institutional-level electronic questionnaire surveys performed in September 2021. SETTING: All perinatal centres across Japan. PATIENTS: Infants born at 22-23 wkGA in 2018-2020. MAIN OUTCOME MEASURES: Proportion of active resuscitation and survival at neonatal intensive care unit (NICU) discharge, and various clinical practices. RESULTS: In total, 255 of 295 NICUs (86%) responded. Among them, 145 took care of infants born at 22-23 wkGA and answered the questions regarding their outcomes and care. In most NICUs (129 of 145 (89%)), infants born at 22+0 wkGA can be actively resuscitated. In almost half of the NICUs (79 of 145 (54%)), infants born at ≥22+0 wkGA were always actively resuscitated. Among 341 and 757 infants born alive at 22 and 23 wkGA, respectively, 85% (291 of 341) and 98% (745 of 757) received active resuscitation after birth. Among infants actively resuscitated at birth, 63% (183 of 291) and 80% (594 of 745) of infants born at 22 and 23 wkGA survived, respectively. The survey revealed unique clinical management for these infants in Japan, including delivery with caul in caesarean section, cut-cord milking after clamping cord, immediate intubation at birth, hydrocortisone use for chronic lung disease, analgesia/sedation use for infants on mechanical ventilation, routine echocardiography and brain ultrasound, probiotics administration, routine glycerin enema and skin dressing to prevent pressure ulcers. CONCLUSIONS: Many 22-23 wkGA infants were actively resuscitated in Japan and had a high survival rate. Various unique clinical practices were highlighted.

Reversible cerebral vasoconstriction syndrome shows different clinical pictures at different times during the perinatal period: Two case reports.

OBJECTIVE: With the development of diagnostic imaging, a new clinical entity called reversible cerebral vasoconstriction syndrome (RCVS), which is considered to be a cause of secondary headache, has emerged. We herein present two cases of RCVS with different patterns of clinical progression. CASE REPORT: Case 1 occurred during labor, whereas case 2 occurred after delivery. Neither case presnted thunderclap headache at the onset of symptoms. Hypertensive disorders of pregnancy did not occur during the pregnancy or the puerperium in either case. Neurological symptoms following mild headache (Case 1: coma; Case 2: paralysis of the right extremities) were observed. CONCLUSION: Even when a patient has no risk factors for RCVS and had no severe headache, it is important not to miss any of the neurological symptoms. Magnetic resonance imaging (MRI) strongly supports the diagnosis, even during pregnancy. In addition, the diagnosis should always be reviewed while excluding eclampsia.

Nationwide status of progestogen treatment to prevent spontaneous preterm birth: A questionnaire survey for childbirth healthcare facilities in Japan.

AIM: This study aimed to investigate the current status of progestogen treatment for pregnant women at a high risk for preterm birth (PTB) in childbirth healthcare facilities in Japan. METHODS: A web-based nationwide questionnaire survey regarding progestogen use for prevention of PTB was conducted among childbirth healthcare facilities from 2019 to 2021. RESULTS: Valid responses were obtained from 528 facilities (25.2% of those surveyed), including 155 tertiary perinatal facilities (making up 92.3% of all tertiary perinatal care facilities). In the survey period, progestogen treatment was implemented in 207 facilities (39.2%) for PTB prevention. Regarding types of progestogens, 17α-hydroxyprogesterone caproate was used in 170 facilities (82.1%), with a low dose (125 mg/week) administered in 62.9% of the facilities to comply with the regulations of the national health insurance system, although 250 mg/week is considered the best dose. Vaginal progesterone was used in 36 facilities (17.4%), although the cost of vaginal progesterone was not covered by health insurance. Of the facilities not administering progestogen treatment, approximately 40% expressed that vaginal progesterone would be their first choice for PTB prevention in daily practice if it would be covered by health insurance in the future. CONCLUSIONS: Due to the current regulations of the Japanese health insurance system, 17α-hydroxyprogesterone caproate, rather than vaginal progesterone, was mainly used for PTB prevention. Despite global evidence supporting vaginal progesterone as the approach with the highest efficacy, only a limited number of facilities have utilized it due to the current drug use regulations in Japan.

Cervical cerclage for short cervix at 24 to 26 weeks of gestation: systematic review and meta-analysis of randomized controlled trials using individual patient-level data.

OBJECTIVE: This study aimed to determine whether cervical cerclage for a transvaginal ultrasound-detected short cervical length after 24 weeks of gestation in singleton pregnancies reduces the risk for preterm birth. DATA SOURCES: Ovid MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials were searched using the following terms: "cerclage, cervical," "uterine cervical incompetence," "obstetrical surgical procedures," "cervix uteri," "randomized controlled trial," and "controlled clinical trial." STUDY ELIGIBILITY CRITERIA: All randomized controlled trials comparing cerclage placement with no cerclage in singleton gestations with a transvaginal ultrasound-detected short cervical length ≤25 mm between 24+0/7 and 29+6/7 weeks of gestation were eligible for inclusion. METHODS: Individual patient-level data from each trial were collected. If an eligible trial included patients with both multiple and singleton gestations with a short cervical length detected either before or after 24+0/7 weeks of gestation, only singletons who presented at or after 24+0/7 weeks were included. The primary outcome was preterm birth <37 weeks' gestation. Secondary outcomes included preterm birth <34, <32, and <28 weeks' gestation, gestational age at delivery, latency, preterm prelabor rupture of membranes, chorioamnionitis, and adverse neonatal outcomes. Individual patient-level data from each trial were analyzed using a 2-stage approach. Pooled relative risks or mean differences with 95% confidence intervals were calculated as appropriate. RESULTS: Data from the 4 eligible randomized controlled trials were included. A total of 131 singletons presented at 24+0/7 to 26+6/7 weeks of gestation and were further analyzed; there were no data on patients with a cerclage at 27+0/7 weeks' gestation or later. Of those included, 66 (50.4%) were in the cerclage group and 65 (49.6%) were in the no cerclage group. The rate of preterm birth <37 weeks' gestation was similar between patients who were randomized to the cerclage group and those who were randomized to the no cerclage group (27.3% vs 38.5%; relative risk, 0.78; 95% confidence interval, 0.37-1.28). Secondary outcomes including preterm birth <34, <32, and <28 weeks' gestation, gestational age at delivery, time interval from randomization to delivery, preterm prelabor rupture of membranes, and adverse neonatal outcomes such as low birthweight, very low birthweight, and perinatal death were similar between the 2 groups. Planned subgroup analyses revealed no statistically significant differences in the rate of preterm birth <37 weeks' gestation between the 2 groups when compared based on cervical length measurement (≤15 mm or ≤10 mm), gestational age at randomization (24+0/7 to 24+6/7 weeks or 25+0/7 to 26+6/7 weeks), or history of preterm birth. CONCLUSION: Cervical cerclage did not reduce or increase the rate of preterm birth among singleton pregnancies with a short cervical length detected after 24 weeks of gestation. Because there was a 22% nonsignificant decrease in preterm birth associated with cerclage, which is a similar amount of risk reduction often associated with ultrasound-indicated cerclage before 24 weeks' gestation, further randomized controlled trials in this patient population are warranted.

Review, role of lactoferrin in preventing preterm delivery.

Prevention of preterm birth (PTB) is a global challenge and is one of the most important issues to be addressed in perinatal care. The hypothesis that ascending lower genital infection leads to PTB has been tested in numerous in vitro and in vivo studies. For patients with intractable vaginitis or high-risk patients with successive PTBs, mainly due to intra-uterine infection, the vaginal flora is enhanced to increase systemic immunity and locally propagate Lactobacillus species. It has been shown that the administration of lactoferrin (LF), a prebiotic with minimum side effects, may be effective in suppressing PTB. This hypothesis has been evaluated in this review using various relevant test examples. The findings suggest that LF may play a role in inflammatory protection in pregnant human cervical tissue. The antibacterial and anti-cytokine effects of LF in human-derived mucus-producing cervical cell lines were also demonstrated. It was also clarified that LF suppresses PTB and improves the prognosis of pups in inflammation-induced PTB animal models. Thus, we have identified that LF, a prebiotic contained in breast milk, can be clinically applied to suppress PTB in humans and to prevent PTBs in high-risk pregnancies.

Effects of prophylactic vaginal progesterone administration on mild cervical shortening (TROPICAL study): a multicenter, double-blind, randomized trial.

Vaginal progesterone reduces the preterm birth frequency among high-risk women with a cervical length ≤25 mm at midtrimester. However, the strategy may promote no substantial reduction in overall preterm birth rates, because such high-risk women are only approximately 2% of all pregnant women, which restrict the number of participants. Our purpose was to determine whether prophylactic vaginal progesterone administration can preserve cervical length and reduce preterm birth rates among women with mild cervical shortening.This multicenter, parallel-arm, double-blind, randomized, placebo-controlled trial involved vaginal progesterone administration (200 mg daily from 16 to 33 weeks of gestation) among asymptomatic women with a singleton pregnancy and a sonographic cervical length of 25 to <30 mm between 16 and 23 weeks of gestation. The primary and secondary endpoints were cervical shortening rates at 34 weeks of gestation and preterm birth rates, respectively. The trial was registered at the University Hospital Medical Information Network (UMIN000013518) in Japan.Between April 2014 and March 2018, 119 women were randomly assigned to the progesterone group (n = 59) and the placebo group (n = 60). No significant differences in the frequency of women with a cervical length ≥20 mm at 34 weeks of gestation were observed between both groups. All preterm births occurred after 34 weeks of gestation, except for one patient in the placebo group. The progesterone group had a lower rate of preterm birth before 37 weeks than the placebo group (3.4% vs. 15.0%, respectively; p < .05).Despite having no effect on preserving cervical length, prophylactic vaginal progesterone administration reduced preterm birth frequency among women with mild cervical shortening. Our results are suggesting that women with mild cervical shortening are at risk for late preterm birth and the need for expanding progesterone treatment indications to include not only high-risk but also low-risk populations.

Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: A Japanese nationwide retrospective cohort study.

Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO4) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm infants in a retrospective cohort study. We used a nationwide obstetrical database from 2014. A total of 4,622 live preterm infants born at 32-36 gestational weeks participated. Fourteen risk factors based on both clinical relevance and univariate analysis were adjusted in multivariable logistic regression analyses. Neonatal hyperkalemia and hypoglycemia occurred in 7.6% (284/3,732) and 32.4% (1,458/4,501), respectively. Occurrence of hyperkalemia was associated with concomitant usage of ritodrine and MgSO4 compared with no usage (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.09-2.15). Occurrence of hypoglycemia was associated with ritodrine alone (aOR 2.58 [CI 2.21-3.01]) and with concomitant usage of ritodrine and MgSO4 (aOR 2.59 [CI 2.13-3.15]), compared with no usage, and was associated with long-term usage (≥ 48 hours) of ritodrine and cessation directly before delivery. In conclusion, in late preterm infants, usage of ritodrine together with MgSO4 was associated with occurrence of critical neonatal hyperkalemia, and long-term usage of ritodrine and cessation directly before delivery were associated with neonatal hypoglycemia.

Transvaginal cervicoisthmic cerclage for patients with extremely high-risk history of preterm delivery.

Transvaginal cervicoisthmic cerclage was carried out in 12 such patients who were at high-risk of premature delivery. Patients who underwent transvaginal cervicoisthmic cerclage had undergone conization, cervical radical hysterectomy or another form of extensive cervical resection, or had a history of third-trimester miscarriage or premature delivery despite having previously undergone cervical cerclage several times for cervical incompetence. There were seven cases of pregnancy after extensive conization, and four had a history of failed cervical cerclage. Two of these cases were the same individual, who became pregnant twice after extensive conization and gave birth to a live infant each time. The mean age at surgery was 35.7 years, and cerclage was performed at 11-19 weeks' gestation. All of the infants survived to hospital discharge. Transvaginal cervicoisthmic cerclage may be considered effective for patients with the history of recurring pregnancy loss due to previous failure of prophylactic cerclage.

Randomized trial of the efficacy of intravaginal ulinastatin administration for the prevention of preterm birth in women with a singleton pregnancy and both cervical shortening and inflammation of lower genital tract.

AIM: To assess the preventive effect on preterm birth of intravaginal ulinastatin (urinary trypsin inhibitor; UTI) administration during the mid-trimester in women with singleton pregnancy and both cervical shortening and lower genital infections. METHODS: Pregnant women with a short cervical length < 25 mm between 16 and 26 weeks of gestation and who had been diagnosed with a lower genital infection were randomly assigned for intravaginal UTI administration or placebo. All of the women were screened for infection or inflammation of the lower genital tract, and women with negative results were excluded. RESULTS: Of the 92 patients with a short cervical length who were assessed for eligibility for this study, 86 singleton patients were enrolled. All patients were randomized to one of two treatment groups: patients administered UTI (n = 35) and placebo (n = 35). There were no differences between the two groups in the incidence of preterm delivery before 28, 30, 32, 34 and 37 weeks of gestation and in perinatal outcomes. CONCLUSION: For women diagnosed with a short cervical length < 25 mm) between 16 and 26 weeks of gestation and lower genital infection, who were at risk of preterm birth, administration of transvaginal UTI with vaginal irrigation showed no apparent benefit. Future research on the efficacy of UTI should evaluate modified modes of UTI application.

Effects of lactoferrin in 6 patients with refractory bacterial vaginosis.

We previously reported that lactoferrin (LF) could be effective for preventing preterm delivery and intrauterine infections, based on data derived from mice and rabbits. Here we describe 6 women with a history of multiple pregnancy losses or preterm delivery and refractory bacterial vaginosis, who received prebiotic LF therapy and delivered an infant normally. Five of the women were pregnant and one was not at the time of this study. The Ethics Committee at Showa University Hospital and Showa University Koto Toyosu Hospital approved the therapeutic protocol. Vaginal suppositories and oral prebiotic LF were administered to patients who were refractory to conventional treatment for vaginosis and had a history of late miscarriages and very early preterm delivery due to refractory vaginitis and chorioamnionitis. LF significantly improved the vaginal bacterial flora. Lactobacillus, which was detectable in the vaginas of all patients after one month of LF therapy, gradually became dominant. The findings from these 6 patients suggest that administering LF to humans could help prevent refractory vaginitis, cervical inflammation, and preterm delivery.

Improving the Accuracy of Diagnosing Placenta Previa on Transvaginal Ultrasound by Distinguishing between the Uterine Isthmus and Cervix: A Prospective Multicenter Observational Study.

OBJECTIVE: To clarify whether distinguishing between the uterine isthmus and cervix can improve the accuracy of diagnosing placenta previa at term. METHODS: A multicenter prospective observational study was conducted among pregnant women with suspected placenta previa at 20-24 weeks' gestation. Subjects were divided into the open isthmus group and closed isthmus group. The accuracy of diagnosing placenta previa at term was compared between the 2 groups. RESULTS: We screened 9,341 patients, and 53 (0.6%) met the inclusion criteria. Nineteen cases with an open isthmus and 34 with a closed isthmus were followed. The accuracy for diagnosing placenta previa or a low-lying placenta at term was 94.7% in the open isthmus group and 26.5% in the closed isthmus group (p < 0.001). Elective or emergency Cesarean section was required in 100% of cases in the open isthmus group and 20.6% in the closed isthmus group (p < 0.001). CONCLUSION: A high prediction rate of placenta previa was obtained by using transvaginal ultrasound at 20-24 weeks' gestation after the isthmus opened by carefully distinguishing between the cervix and isthmus.

Randomized trial of ultrasound-indicated cerclage in singleton women without lower genital tract inflammation.

AIM: This is the first report of a randomized trial of cerclage on pure cervical shortening without vaginosis or cervicitis. The objective of our multicenter randomized controlled trial was to assess the benefits of ultrasound-indicated cervical cerclage in the mid-trimester to prevent preterm birth in women who have no signs of infection or inflammation of the lower genital tract. MATERIAL AND METHODS: Women with a short cervical length < 25 mm between 16 and 26 weeks of gestation were randomly assigned to receive a Shirodkar cerclage, McDonald cerclage, or bedrest (no cerclage). Before being randomly assigned to one of the three groups, all women were screened for infection/inflammation of the lower genital tract; those with positive results were excluded from the study. The ratio of preterm delivery as a primary end-point was evaluated in the groups. RESULTS: A total of 106 singleton patients with a short cervical length were assessed for study eligibility; 106 patients were randomized to the three treatment options. Ultimately, 98 patients (in the Shirodkar [n = 34], McDonald [n = 34] and bedrest [n = 30] groups) were analyzed. No differences in preterm delivery or perinatal outcomes were found between the three groups. Significantly fewer patients in the Shirodkar group required hospitalization for treatment of threatened preterm labor when compared to patients in the bedrest group. CONCLUSION: For women with a short cervical length < 25 mm between 16 and 26 weeks of gestation, Shirodkar cerclage might be considered to reduce the occurrence of threatened preterm labor.

Decidual polyps are associated with preterm delivery in cases of attempted uterine cervical polypectomy during the first and second trimester.

OBJECTIVE: To clarify which types of cervical polyp removed during the first and second trimester are associated with the risk of spontaneous abortion and preterm delivery. METHODS: Pregnant females who underwent attempted polypectomy of cervical polyps during pregnancy and delivered singleton infants between 2005 and 2011 were evaluated. The clinical courses and outcomes of preterm delivery after polypectomy stratified according to the pathologic diagnosis of the polyps were retrospectively reviewed. The removed polyps were classified into decidual polyps and endocervical polyps. RESULTS: The pathological diagnoses included 41 decidual polyps and 42 endocervical polyps. No malignant polyps were found. The removal of decidual polyps during pregnancy carried a higher risk of spontaneous abortion (12.2% versus 0%, p = 0.026) and preterm delivery (34.2% versus 4.8%, p = 0.001) than that of endocervical polyps. According to the multivariate logistic regression analysis, risk factors for preterm delivery before 37 weeks' gestation were the presence of decidual polyps and a history of preterm delivery. CONCLUSIONS: The risk of abortion and preterm delivery associated with polypectomy during pregnancy is greater in patients with decidual polyps. It might be safer not to remove cervical polyps during pregnancy, except in cases in which the polyps are suspected to be malignant.

Administration of oral and vaginal prebiotic lactoferrin for a woman with a refractory vaginitis recurring preterm delivery: appearance of lactobacillus in vaginal flora followed by term delivery.

Lactoferrin (LF) is one of the prebiotics present in the human body. A 38-year-old multiparous woman with poor obstetrical histories, three consecutive preterm premature rupture of membrane at the 19th, 23rd and 25th week of pregnancy, was referred to our hospital. She was diagnosed as having refractory vaginitis. Although estriol vaginal tablets were used for 4 months, the vaginitis was not cured. We administrated vaginal tablets and oral agents of prebiotic LF, resulting in a Lactobacillus predominant vaginal flora. When she was pregnant, she continued to use the LF, and the Lactobacillus in the vaginal flora was continuously observed during pregnancy. An elective cesarean section was performed at the 38th week of pregnancy. When the administration of LF was discontinued after the delivery, Lactobacillus in the vaginal flora was disappeared.

Incidence and prediction of outcome in hypoxic-ischemic encephalopathy in Japan.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most critical pathologic conditions in neonatal medicine due to the potential for neurological deficits in later life. We investigated the incidence of term infants with moderate or severe HIE in Japan and identified prognostic risk factors for poor outcome in HIE. METHODS: Data on 227 infants diagnosed with moderate or severe HIE and born between January and December 2008 were collected via nationwide surveys from 263 responding hospitals. Using logistic regression, we examined the relationship between maternal, antepartum, intrapartum, and neonatal risk factors and clinical outcome at 18 months following birth. RESULTS: In Japan, the incidence of moderate or severe HIE was 0.37 per 1000 term live births. Outborn births, low Apgar score at 5 min, use of epinephrine, and low cord blood pH were intrapartum factors significantly associated with neurodevelopmental delay and death at 18 months. Serum lactate, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase (all, P < 0.001) and creatine kinase (P = 0.002) were significantly higher in infants with poor outcome compared to those with favorable outcomes. Abnormal brain magnetic resonance imaging (MRI), an important prognostic factor, was significantly associated with poor outcome (odds ratio, 11.57; 95% confidence interval: 5.66-23.64; P < 0.001). CONCLUSIONS: Risk factors predicting poor outcome in HIE include outborn birth, low Apgar score at 5 min, use of epinephrine, laboratory abnormalities, and abnormal MRI findings.

A case of aggressive angiomyxoma of the vulva.

Aggressive angiomyxoma (AA) is a rare mesenchymal neoplasm of the female pelvis and vulva, which has a tendency for local recurrence. AA is occasionally misdiagnosed as Bartholin's gland cyst or abscess, lipoma, simple labial cyst, or soft tissue tumors. We describe a case of AA on the outside of the left labium majus pudendi in a 28-year-old female. We were able to make the preoperative diagnosis of AA by magnetic resonance imaging (MRI) and ultrasound (US), and to perform complete surgical excision with a transperineal minimally invasive approach. The novelty of this case is the use of ultrasound for the diagnostic workup of the perineal tumor and determination of the incision line.

Retrospective cohort study: a comparison of two different management strategies in patients with preterm premature rupture of membranes.

PURPOSE: Perinatal outcomes were compared before and after changes in the treatment policy to improve the management for preterm PROM (pPROM). METHODS: This is a retrospective analysis of 99 cases of pPROM diagnosed between 27 and 34 weeks of gestation, which were managed according to the following two different protocols. Group A (47 cases): tocolytic therapy was continued to prevent preterm delivery until clinical chorioamnionitis (CAM) was diagnosed between January 2000 and June 2004. Group B (52 cases): labor was induced or cesarean section performed when oligohydramnios was diagnosed and/or elevation elastase (EL) of amnion was detected by amniocentesis between July 2004 and July 2009. The outcomes of the cases in each group were compared with regard to the extension of pregnancy period, reasons for delivery, perinatal complications, stage of pathological CAM and funisitis (FUN), neonatal serum IgM concentration, mortality, and morbidity. RESULTS: The incidences of pathological CAM and FUN were significantly lower in Group B than in Group A. The concentration of neonatal serum IgM was also significantly lower in Group B than in Group A. CONCLUSIONS: The addition of oligohydramnios and elevation EL of amnion as indicative factors of intrauterine infection might lead to a reduction in the severity of fetal infection in cases of pPROM.

Recombinant human lactoferrin inhibits matrix metalloproteinase (MMP-2, MMP-3, and MMP-9) activity in a rabbit preterm delivery model.

AIM: To investigate the effect of recombinant human lactoferrin (rh-LF) on the expression of matrix metalloproteinase as a marker of cervical maturation, using a rabbit preterm delivery model in which preterm labor was induced by bacteria. METHODS: We used cervical tissues that had been excised in a previous study in which rabbits were randomly assigned to receive either inoculation with Escherichia coli (E. coli) or saline solution and to receive pretreatment with or without rh-LF inserted into the cervix two hours before bacterial inoculation (Condition A: saline + saline; Condition B: rh-LF + E. coli; Condition C: saline +E. coli). E. coli, saline solution, and rh-LF were inserted into the cervix using a hysteroscope and a sterile polyethylene cannula. Both cervices of the rabbit uterus, which is bicorpus-bicolli, were taken out and preserved, and expression of matrix metalloproteinases MMP-2,-3, and -9 in the cervix was evaluated using Western blot. RESULTS: MMP-2,-3, and -9 levels in the cervix under Conditions A and B were significantly lower than that under Condition C. CONCLUSIONS: These results suggest that the prevention of preterm delivery by rh-LF in a rabbit model has been achieved through inhibition of cervical maturation promoted by matrix metalloproteinase activity.