Effects and safety of COVID-19 vaccination on assisted reproductive technology and pregnancy: A comprehensive review and joint statements of the KSRM, the KSRI, and the KOSAR.

Humanity is in the midst of the coronavirus disease 2019 (COVID-19) pandemic, and vaccines-including mRNA vaccines-have been developed at an unprecedented speed. It is necessary to develop guidelines for vaccination for people undergoing treatment with assisted reproductive technology (ART) and for pregnancy-related situations based on the extant laboratory and clinical data. COVID-19 vaccines do not appear to adversely affect gametes, embryos, or implantation; therefore, active vaccination is recommended for women or men who are preparing for ART. The use of intravenous immunoglobulin G (IVIG) for the treatment of immune-related infertility is unlikely to impact the effectiveness of the vaccines, so COVID-19 vaccines can be administered around ART cycles in which IVIG is scheduled. Pregnant women have been proven to be at risk of severe maternal and neonatal complications from COVID-19. It does not appear that COVID-19 vaccines harm pregnant women or fetuses; instead, they have been observed to deliver antibodies against severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) to the fetus. Accordingly, it is recommended that pregnant women receive COVID-19 vaccination. There is no rationale for adverse effects, or clinical cases of adverse reactions, in mothers or neonates after COVID-19 vaccination in lactating women. Instead, antibodies to SARS-CoV-2 can be delivered through breast milk. Therefore, breastfeeding mothers should consider vaccination. In summary, active administration of COVID-19 vaccines will help ensure the safe implementation of ART, pregnancy, and breastfeeding.

Is cervical cancer a risk factor for colorectal neoplasia? Prevalence of colorectal adenoma in Korean patients with cervical cancer.

BACKGROUND/AIMS: The relationship between colorectal neoplasia and cervical cancer has not been evaluated. This study aimed to assess the prevalence of colorectal adenoma in patients with cervical cancer and compare it with that of control subjects. METHODOLOGY: Between January 2005 and December 2009, the medical records of patients diagnosed with cervical cancer were retrospectively reviewed. Patients undergoing sigmoidoscopy or colonoscopy for the preoperative evaluation of the colon were enrolled in this study. Age-matched female healthy subjects who underwent colonoscopy for screening purposes were included as control subjects. We compared demographic and clinicopathological characteristics between the groups. RESULTS: Overall, 285 patients with cervical cancer and 284 healthy subjects were included (age, 56.93±11.92 vs. 56.10±9.31 years). The mean body weight, body mass index (BMI), the incidence of diabetes mellitus and impaired fasting glucose were not statistically different between the 2 groups. The prevalence of colorectal adenoma was not different between the patient and control groups, regardless of examination extent. Multivariate analysis showed that age and BMI were significant independent risk factors for colorectal adenomatous polyps (age, p<0.001; BMI, p=0.002). CONCLUSION: There might not be any significant association between cervical cancer and colorectal adenomatous polyps.

Successful laparoscopic surgery of accessory cavitated uterine mass in young women with severe dysmenorrhea.

Accessory cavitated uterine mass (ACUM) is a rare and unique condition seen in young women. We report cases of ACUMs in two patients, a 14-year-old girl and a 25-year-old woman, both with complaints of severe dysmenorrhea that had started at menarche and had progressively worsened since. A large cystic lesion was localized in the anterolateral wall of the myometrium separate from the endometrium, which was difficult to distinguish from congenital uterine anomalies. Laparoscopic excision of the ACUMs was successful and completely resolved the dysmenorrhea. Early investigation of severe dysmenorrhea in young women can provide appropriate management and relieve symptoms.

Maternal and fetal safety of intravenous immunoglobulin in women with reproductive failure.

PROBLEM: Intravenous immunoglobulin G (IVIG) is an emerging regimen for women with reproductive failures (RF) during- or pre-pregnancy who have aberrant cellular immune reactions. Studies investigating teratogenicity of IVIG have been limited. Herein, we evaluated the fetal teratogenicity of IVIG and IVIG-related obstetric complications. METHOD OF STUDY: Women who used IVIG during pregnancy due to RF with cellular immune aberrances were enrolled from four medical centers in Korea. The pregnancy outcomes were collected. RESULTS: A total of 370 RF women who used IVIG during their pregnancy were enrolled. Most of the patients started the IVIG therapy before 12 weeks of gestation and 229 women continued IVIG treatment beyond 12 weeks of gestation. The mean age of the subjects was 34.8 years and the mean total dosage of IVIG was 125.3 g. A total of 307 women had livebirths and six of them were twins. Of 301 singleton livebirths, obstetric complications were developed as follows: preterm births (12.0%), gestational diabetes (7.0%), preeclampsia (4.0%), placental abruption (1.3%), placenta previa (4.3%), and placenta accrete (1.7%). Total six cases (1.99%) had major fetal anomalies in livebirths. The incidence of birth defects is similar to those of the general population in Korea and the previous report in infertile women. No IVIG -related viral contamination was noted. CONCLUSION: IVIG use during pregnancy did not increase obstetric complications and fetal teratogenicity. This study can be an evidence of maternal and fetal safety of IVIG administration during pregnancy.

A New Thermo-Responsive Hyaluronic Acid Sol-Gel to Prevent Intrauterine Adhesions after Hysteroscopic Surgery: A Randomized, Non-Inferiority Trial.

PURPOSE: To investigate the efficacy and safety of a newly developed thermo-responsive sol-gel, ABT13107, for reducing the formation of intrauterine adhesions (IUAs) after hysteroscopic surgery. MATERIALS AND METHODS: In this multicenter, prospective, randomized trial (Canadian Task Force classification I), 192 women scheduled to undergo a hysteroscopic surgery at one of the eight university hospitals in South Korea were randomized into the ABT13107 group or the comparator (Hyalobarrier®) group in a 1:1 ratio. During hysteroscopic surgery, ABT13107 or Hyalobarrier® was injected to sufficiently cover the entire intrauterine cavity. RESULTS: The patients returned to their respective sites for safety assessments at postoperative weeks 1 and 4 and for efficacy assessments at postoperative week 4. The post-surgery incidence of IUAs was 23.4% in the ABT13107 group and 25.8% in the comparator group; this difference met the criteria for ABT13107 to be considered as not inferior to the comparator. No differences were found in the extent of adhesions, types of adhesions, or the cumulative American Fertility Society score between the two treatment groups. Most adverse events were mild in severity, and no serious adverse events occurred. CONCLUSION: ABT13107, a new anti-adhesive barrier containing hyaluronic acid, was not inferior to the highly viscous hyaluronic acid anti-adhesive barrier, Hyalurobarrier® in IUA formation after hysteroscopic surgery (Clinical trial registration No. NCT04007211).

Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.

The task force of the Korean Society for Reproductive Immunology recommends intravenous immunoglobulin G treatment in women with reproductive failure, including recurrent pregnancy loss and/or repeated implantation failure, who show cellular immune factors such as abnormal natural killer cell levels, natural killer cell cytotoxicity, and/or type 1 T helper immunity.

Etiologic characteristics and index pregnancy outcomes of recurrent pregnancy losses in Korean women.

OBJECTIVE: The goal of this study was to evaluate the etiologies and clinical outcomes of Korean recurrent pregnancy loss (RPL) patients. And also, we investigated the differences between primary and secondary RPL patients, between two and three or more pregnancy losses. METHODS: One hundred seventy eight women diagnosed as RPL were enrolled. We performed chromosomal analysis, thyroid stimulating hormone, prolactin, blood glucose, plasminogen activator inhibitor-1, natural killer cell proportion, anticardiolipin antibodies, antiphospholipid antibodies, lupus anticoagulant, anti-ß2glycoprotein-1 antibodies, antinuclear antibody, protein C, protein S, antithrombin III, homocysteine, MTFHR gene, factor V Leiden mutation, and hysterosalphingography/hysteroscopic evaluation. RESULTS: The mean age was 34.03±4.30 years, and mean number of miscarriages was 2.69±1.11 (range, 2 to 11). Anatomical cause (13.5%), chromosomal abnormalities (5.6%), and endocrine disorders (34.3%) were observed in RPL women. Elevated natural killer cell and antiphospholipid antibodies were observed in 43.3% and 7.3% each. Among of 178 women, 77 women were pregnant. After management of those women, live birth rate was 84.4% and mean gestational weeks was 37.63±5.12. Women with three or more RPL compared with women with two RPL had more common anatomical cause such as intrauterine adhesions and lower rates of spontaneous pregnancy. Compare with secondary RPL women, immunological abnormalities were more common in primary RPL. However, miscarriage rates were not different. CONCLUSION: Immunological factor including autoimmune and alloimmune disorders was most common etiology of RPL. Inherited thrombophilia showed different patterns with other ethnic countries. Miscarriage rates were not different between primary and secondary RPL, or between two and three or more miscarriages group.

Surgical impact on serum anti-Müllerian hormone in women with benign ovarian cyst: A prospective study.

OBJECTIVE: The aim of this study was to evaluate the surgical impact of benign ovarian mass on ovarian reserve as measured by serum follicle stimulating hormone (FSH), estradiol (E2) and anti-Müllerian hormone (AMH) levels, antral follicle count (AFC) and ovarian volumes. In addition, the differences in ovarian reserve impairment between endometrioma cystectomy and non-endometrioma cystectomy were investigated. METHODS: In this prospective study, 22 patients of reproductive age (range, 18.35 years) with benign ovarian masses were enrolled to undergo laparoscopic cystectomy. Of whom 12 had endometriomas and 10 had non-endometriomas. On early follicular phase (day 3) of the cycle preceding the operation and three months after the laparoscopic cystectomy, serum levels of FSH, E2 and AMH, AFC and ovarian volumes were measured in all patients. Data were analyzed with Mann-Whitney U-test and Wilcoxon rank test using SPSS ver. 12.0 for statistic analysis. RESULTS: Median level of serum AMH was significantly decreased from 5.48 ng/mL (interquartile range [IQR], 2.80-7.47) before cystectomy to 2.56 ng/mL (IQR, 1.74-4.32) 3 months postoperation (P<0.05). On the other hand, no significant differences in FSH, E2, AFC and ovarian volumes were found between the preoperative and three months postoperative levels. In a subgroup analysis of the pathologic type of the ovarian cyst, postoperative serum AMH levels were significantly decreased in the endometrioma group, but not in the non-endometrioma group. CONCLUSION: Serum AMH levels were significantly decreased after laparoscopic cystectomy without any changes of other ovarian reserve tests.

Arteriovenous malformation in uterine cervix during pregnancy.

As the development of Doppler ultrasonography, many cases of uterine arteriovenous malformation (AVM) have beed diagnosed. But there is no case of cervical AVM in pregnant uterus. We present a 33-year-old pregnant woman who was diagnosed with AVM of the uterine cervix during the midtrimester. Color Doppler sonography and magnetic resonance image were used for diagnosis. We performed Cesarean section because of the risk of massive bleeding from the cervical AVM at 34 weeks' gestation. This is the first case of cervical AVM during pregnancy with a successful outcome and an uneventful postpartum course.

Obstetrical outcome of anti-inflammatory and anticoagulation therapy in women with recurrent pregnancy loss or unexplained infertility.

PROBLEM: Women with a history of recurrent pregnancy losses (RPL) and unexplained infertility (UI) have a high incidence of preeclampsia (PE) and other obstetrical complications. We aimed to investigate the incidence of PE and other obstetrical complications in women with RPL or UI who were treated with anti-inflammatory and anticoagulant treatment. METHODS: The medical records of 72 women who delivered a live born infant from January 2008 to December 2009 with anti-inflammatory (prednisone and/or intravenous immunoglobulin G) and anticoagulant (low-molecular-weight heparin and low-dose aspirin) treatment were reviewed retrospectively. A total of 41 women with a history of RPL and 31 with UI were enrolled as a study group. RESULTS: All patients had at least one or more positive test results for autoantibodies, thrombophilic gene mutations, elevated proportion of peripheral blood CD56(+) NK cells or NK cell cytotoxicities, or high T helper 1 to T helper 2 cytokine-producing CD3(+) /CD4(+) cell ratios. The incidence of PE was 5.6% (n = 4), which was comparable to that of general population (2009 CDC data) (P > 0.05); one of them developed HELLP syndrome and none exacerbated to eclampsia. Preterm birth was more frequent in study group than general population (21.7 versus 10.4%, P < 0.028); however, early preterm birth (<34 weeks of gestation, 1.72%), small or large for gestation (SGA or LGA) (10.6 and 4.3%, each), gestational diabetes (GDM) (4.2%), and abruptio placentae (0 of 72) were not increased in study group as compared to general population data. CONCLUSION: The incidences of PE, GDM, SGA, LGA, early preterm birth, and abruptio placentae are not increased in women with RPL or UI who were administered anti-inflammatory and anticoagulation treatment compared to general population. The potential role of anti-inflammatory and anticoagulation treatment in prevention of obstetrical complications in women with immune abnormalities and thrombophilia is suggested.

Plasma components affect accuracy of circulating cancer-related microRNA quantitation.

Circulating microRNAs (miRNAs) have emerged as candidate biomarkers of various diseases and conditions including malignancy and pregnancy. This approach requires sensitive and accurate quantitation of miRNA concentrations in body fluids. Herein we report that enzyme-based miRNA quantitation, which is currently the mainstream approach for identifying differences in miRNA abundance among samples, is skewed by endogenous serum factors that co-purify with miRNAs and anticoagulant agents used during collection. Of importance, different miRNAs were affected to varying extent among patient samples. By developing measures to overcome these interfering activities, we increased the accuracy, and improved the sensitivity of miRNA detection up to 30-fold. Overall, the present study outlines key factors that prevent accurate miRNA quantitation in body fluids and provides approaches that enable faithful quantitation of miRNA abundance in body fluids.

Upregulated amniotic fluid cytokines and chemokines in emergency cerclage with protruding membranes.

PROBLEM To identify the prognostic factors for pregnancy outcome in women who received emergency cerclage for dilated cervix with protruding membranes. METHOD OF STUDY A prospective cohort study was performed, and a total of 14 women who received emergency cerclage were included. Clinical features and laboratory findings including amniotic fluid cytokines and chemokines were compared between women who had successful pregnancy (survival group, n = 6) and those who had perinatal death (non-survival group, n = 8). Five healthy pregnant women served for normal controls for amniotic fluid study. RESULTS The overall neonatal survival was 42.9% in women with emergency cerclage. Serum C-reactive protein levels on postoperative day 3 and 7 were significantly higher in non-survival group when compared with those in survival group (P = 0.002, P = 0.01). Amniotic fluid levels of interleukin (IL)-1α, IL-1ß, IL-6, IL-8, IL-10, tumor necrosis factor-α, and monocyte chemoattractant protein-1 levels of the patients were significantly higher than those of normal controls. Amniotic fluid levels of IL-1α, IL-1ß, and IL-8 were significantly increased in the non-survival group when compared with those of the survival group. CONCLUSION Systemic and local inflammatory markers including proinflammatory cytokines and chemokines may predict pregnancy outcome in women with emergency cerclage for dilated cervix with protruding membranes.

Endometrial histology and predictable clinical factors for endometrial disease in women with polycystic ovary syndrome.

OBJECTIVE: This study was aimed to investigate endometrial histology and to find predictable clinical factors for endometrial disease (hyperplasia or cancer) in women with polycystic ovary syndrome (PCOS). METHODS: We investigated the endometrial histology and analyzed the relationship between endometrial histology and clinical parameters, such as LH, FSH, estradiol, testosterone, fasting and 2 hours postprandial glucose and insulin, insulin resistance, body mass index, endometrial thickness, menstrual status from 117 women with PCOS. Statistical analysis was performed with chi square and t-test, p-value<0.05 was considered as statistically significant. And receiver operating characteristic curve was used to find predictable clinical factors for endometrial disease and to decide the cuff off values. RESULTS: In 117 women with PCOS, endometrial histologic profiles are as follows: proliferative phase in 90 women (76.9%), endometrial hyperplasia in 25 women (21.4%), and endometrial cancer in 2 women (1.7%). Of 25 women with endometrial hyperplasia, simple hyperplasia without atypia, complex hyperplasia without atypia and complex hyperplasia with atypia were diagnosed in 15 (12.8%), 6 (5.1%), 4 (3.4%) women, respectively. Age and endometrial thickness were significantly related with endometrial disease, p=0.013 and p=0.001, respectively. At the cut off level of 25.5 years in age, sensitivity and specificity predicting for endometrial disease were 70.4% and 55.6%, respectively (p=0.023). At the cut off level of 8.5 mm in endometrial thickness, sensitivity and specificity were 77.8% and 56.7%, respectively (p=0.000). CONCLUSION: In women with PCOS, the incidence of endometrial hyperplasia and cancer were 21.4% and 1.7%. The age and endometrial thickness may be used as clinical determining factors for endometrial biopsy.

Pulmonary and retroperitoneal benign metastasizing leiomyoma.

Benign metastasizing leiomyoma (BML) is a rare disease, which usually occurs in women with a history of a prior hysterectomy or myomectomy for benign uterine leiomyoma, and has the potential to metastasize to distant sites, such as the lung, lymph nodes, muscular tissue, heart, or retroperitoneum. These lesions are slow-growing, asymptomatic, and usually found incidentally. The prognosis of BML is also excellent. However, there has been debate on the origin and the correct classification of BML, and there are no guidelines for the treatment of BML. We report here on a rare case of BML in both the retroperitoneal cavity and lung in a 48-year-old woman with a history of hysterectomy due to histologically benign uterine leiomyoma. The patient underwent retroperitoneal mass excision and bilateral salpingo-oophorectomy, and then wedge biopsy of two pulmonary nodules was performed additionally 9 days later. Until now, there has been no sign of recurrence and the patient remains asymptomatic. To our knowledge, pulmonary BML is rare and the co-existence of the retroperitoneal metastases after previous hysterectomy is even rarer.

Thyroid autoimmunity and its association with cellular and humoral immunity in women with reproductive failures.

PROBLEM: thyroid autoimmunity (TAI), which is T helper (Th)1-cell-mediated autoimmunity to thyrocytes, is associated with increased risk of miscarriages and highly prevalent in women with infertility. We aim at investigating the prevalence of TAI in women with recurrent spontaneous abortions (RSA) or unexplained infertility (UI) and its relationship with cellular and humoral immune abnormalities. METHOD OF STUDY: prevalence of antiphospholipid antibodies, anti-nuclear antibody, other non-organ-specific antibodies (NOSAs; anti-dsDNA, anti-ssDNA, anti-histone, anti-Scl70), peripheral blood natural killer (NK) cell levels (%) and cytotoxicity, and CD3(+) /CD4(+) Th1/Th2 cell ratios were compared in women with and without TAI. Thyroid functional tests (TFT) were analyzed in both groups before and after pregnancy. RESULTS: tumor necrosis factor-α/IL-10 expressing CD3(+) /CD4(+) cell ratios (P < 0.05), CD56(+) NK cell levels (P < 0.05), the prevalence of anticardiolipin antibodies (P < 0.05) and other NOSAs (P < 0.005) were significantly higher in women with TAI when compared to women without TAI. Changes in thyroid-stimulating hormone levels between before and after pregnancy in women with TAI were significantly higher when compared to those of women without TAI (P < 0.05). CONCLUSION: TAI is associated with impaired cellular and humoral immune responses in women with RSA or UI. In women with TAI, serial TFT is recommended when pregnancy is established.

Immunological modes of pregnancy loss.

During the implantation period, a significant portion of embryos are lost and eventually less than half of clinically established pregnancies end as full-term pregnancies without obstetrical complications. A significant portion of these pregnancy losses is associated with immune etiologies, including autoimmune and cellular immune abnormalities. Although an autoimmune etiology such as anti-phospholipid antibodies (APAs) has been reported to induce placental infarct and thrombosis at maternal-fetal interface, APAs induce inflammatory immune responses as well. Inflammatory immune responses, such as increased proportions of NK cells and Th1/Th2 cell ratios in peripheral blood are related to recurrent pregnancy losses and multiple implantation failures. Systemic and local inflammatory immune responses seem to be induced by activation of Toll-like receptors with infectious agents, fetal cell debris, or gonadotropin-releasing hormone agonist, etc. Cellular activation of T and NK cells leads to pro-inflammatory cytokine storm and consequently, placental infarction and thrombosis. Potential application of anti-inflammatory therapeutic agents for the prevention of pregnancy losses should be explored further.

Loss of cyclin g1 expression in human uterine leiomyoma cells induces apoptosis.

Observations from the authors' laboratory suggest a physiological role for increased cyclin G1 protein levels in human uterine leiomyoma. The hypothesis of the present study is that the strategic modulation of cyclin G1 by antisense technology will inhibit the survival of in vitro-grown uterine leiomyoma cells. Cultured uterine leiomyoma cells were transfected with cyclin G1 ribbon-type antisense oligonucleotide (cyclin G1 RiAS) to effectively reduce cyclin G1 expression. Cell viability, in situ terminal deoxyuridine nick end-labeling (TUNEL) assay, flow cytometry, DNA fragmentation, and expression of cell cycle regulatory-related proteins were evaluated by Western blot. Antisense oligonucleotides compromised uterine leiomyoma cell viability and inducted apoptosis in a caspase-independent mechanism. In situ TUNEL and DNA fragmentation revealed apoptosis induction, and fluorescent-activated cell sorting analysis showed increased sub-G1-phase cells. Furthermore, abrogation of cyclin G1 enhanced p53 accumulation, phosphorylation of p53 at Ser-15 residue, and increased expression of cyclin-dependent kinase inhibitors p21 and p27. These data imply that cyclin G1 expression is associated with growth promotion and the potential utility and novelty of using ribbon-type antisense oligonucleotides as a gene therapy strategy to treat human uterine leiomyoma.

A successful live birth through in vitro fertilization program after conservative treatment of FIGO grade I endometrial cancer.

Infertile women with chronic anovulation are prone to be exposed to unopposed estrogen stimulation and have the high risk of being suffering from endometrial hyperplasia or even endometrial carcinoma. A few reports have suggested that nulliparous young women (under 40 yr of age) with endometrial carcinoma could be treated conservatively to preserve fertility and succeed the live birth. We report on a 36-yr-old woman who received conservative treatment of endometrial carcinoma (stage I, grade 1) by curettage and progestin. After megestrol medication of total 71,680 mg during 24 weeks, we found the regression of endometrial lesion by curettage and hysteroscopic examination. Then we decided to perform in vitro fertilization program. Two embryos were transferred and heterotypic pregnancy was diagnosed 27 days after embryo transfer. After right salpingectomy, she received routine obstetrical care and delivered by cesarean section at 38 weeks in gestational periods. Two years after delivery, she is healthy without any evidence of recurrent disease. The fertility preserving treatment is an option in endometrial cancer patients if carefully selected, and assisted reproductive technologies would be helpful.