Corrigendum: Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy.

[This corrects the article DOI: 10.3389/fphar.2022.854562.].

Ritodrine in external cephalic version: is it effective and safe?

OBJECTIVE: The external cephalic version (ECV) has been shown to lower the likelihood of cesarean section requirements among pregnant women with breech presentations. In the current study, we investigated the effectiveness and safety of ritodrine as a tocolytic for ECV. METHODS: A total of 407 pregnant women with breech presentations, who had no contraindications for ECV, were enrolled in this study. Multivariable logistic regression analyses were used to assess the impact of ritodrine use on the safety and efficacy of ECV. RESULTS: The overall success rate was 67.6%, and ritodrine use was associated with significantly higher odds of successful ECV after adjusting for confounders. Moreover, using ritodrine did not increase the risk of adverse effects, including temporary changes in fetal heart rate, need for elective or emergency cesarean section due to fetal distress during ECV, low Apgar scores, and perinatal mortality. CONCLUSION: Our results suggest that using ritodrine as a tocolytic during ECV may increase the likelihood of ECV success and may not increase adverse perinatal outcomes.

Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy.

Alprazolam is a commonly prescribed benzodiazepine for anxiety or panic disorder, even in pregnant women. Information on the safety of alprazolam during pregnancy is insufficient. We aimed to evaluate pregnancy and neonatal outcomes after exposure to alprazolam during pregnancy. A prospective study was conducted on 725 pregnancies from January 2000 to December 2019. Participants were recruited through the Korean Mother-Safe Program, a service providing information on drug-induced teratogenic risk during pregnancy and breastfeeding. Exposed (N = 96) and non-exposed (N = 629) women to alprazolam during pregnancy were selected and followed-up until delivery. Pregnancy outcomes, including spontaneous abortion, still birth, low birth weight (LBW), preterm birth, Apgar score (at 1 and 5 min), and malformations were measured and compared. Multivariable logistic regression was performed to examine the association between alprazolam exposure and outcomes. The mean age was 32.9 (SD 4.0) years in the alprazolam-exposed group and 31.8 (SD 3.8) years in the unexposed group (p = 0.008). The alprazolam exposure group demonstrated a significantly higher likelihood of pregnancy and neonatal outcomes: spontaneous abortion (OR = 2.38; 95% CI 1.20-4.69), LBW (OR = 3.65; 95% CI 1.22-11.00), and Apgar score at 1 min ≤ 7 (OR = 2.19; 95% CI 1.02-4.67). There was no significant difference in congenital abnormalities between the exposure and non-exposure groups. Our findings confirmed that alprazolam exposure during pregnancy was significantly associated with adverse pregnancy and neonatal outcomes, including spontaneous abortion, low birth weight, and Apgar score at 1 min ≤ 7. Alprazolam during pregnancy should be appropriately regulated and monitored.

Pregnancy and neonatal outcomes after periconceptional exposure to isotretinoin in Koreans.

OBJECTIVE: Isotretinoin should not be used during pregnancy because of the risk of birth defects. Most pregnant women exposed to isotretinoin choose voluntary pregnancy termination due to concerns about birth defects. However, birth outcome data supporting the termination of pregnancy are lacking. This study aimed to evaluate pregnancy and neonatal outcomes after periconception exposure to isotretinoin. METHODS: This was a prospective cohort study. We evaluated pregnancy and neonatal outcomes after exposure to isotretinoin in 151 pregnant women. Among 1,026 callers at the Korean Teratology Information Service from 2001 to 2017 exposed to isotretinoin during the periconception period, 151 pregnant women who received counseling on teratogenic risk after visiting the clinic were included. RESULTS: Among the 151 participants who visited the clinic, only 42 were evaluated using ultrasonography until approximately 20 weeks of gestation. Ultimately, 23 patients were included in the study. The average gestation period during the last exposure to the drug was 2 weeks, and the average daily exposure dose was 12 mg. There were two cases of major birth defects in the exposure group. Spontaneous abortion rates were 17.7% and 8.7% in the exposure and nonexposure groups, respectively (P=0.035). There was no significant difference between the exposure and non-exposure groups in terms of pregnancy and neonatal outcomes. CONCLUSION: There was no significant difference in pregnancy and neonatal outcomes, including birth defects, between the exposure and non-exposure groups. Further studies with larger sample sizes are required to validate our findings.

The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis.

OBJECTIVE: Isotretinoin is among the most notorious human teratogens, documented originally as causing up to 30% of malformations. This systematic review and meta-analysis aimed to evaluate the rates of major malformation (MM) among isotretinoin-exposed pregnant women over the years through a systematic review and meta-analysis. METHODS: Eligible studies were searched and identified using various databases. Single-arm meta-analysis and meta-analysis of odd ratios among controlled studies were performed using Review Manager version 5.3. RESULTS: Ten eligible studies that combined 2,783 isotretinoin-exposed women were included in our study. The rate of MM weighted for the sample size was 15%. Three studies that included an unexposed comparison group were eligible for the meta-analysis. The pooled odds ratio of MM for isotretinoin-exposed women was 3.76. After 2006, the pooled odds ratio of MM for isotretinoin exposure was significantly lower at 1.04. CONCLUSION: The current rate of MM in isotretinoin-exposed women was substantially lower after 2006.

How to approach the rupture of tubo-ovarian abscess during pregnancy: A case report and literature review.

We present the case of a 26-year-old multiparous woman who experienced rupture of a tubo-ovarian abscess during the second trimester of pregnancy. She presented with epigastric and right lower quadrant pain at 12 + 0 weeks' gestation. There were no other specific findings on the magnetic resonance imaging images. We recommended hospitalization to observe the changes in pain, but she refused confinement. About 3 weeks later, she revisited our emergency room at 15 + 4 weeks' gestation. She complained of worsening abdominal pain with fever. She underwent right salpingo-oophorectomy and appendectomy due to uncontrollable, severe abdominal pain without any obstetric abnormal condition. There was a rupture site in the right adnexa, which was covered with pus. The rupture of tubo-ovarian abscess during pregnancy is very rare. Therefore, obstetricians should carefully monitor the adnexal masses observed during pregnancy, which should be treated with caution, whether or not the patient is symptomatic.

Delayed intestinal perforation and vertebral osteomyelitis after high-intensity focused ultrasound treatment for uterine leiomyoma.

High-intensity focused ultrasound (HIFU) is a non-invasive uterine fibroid treatment option for patients who want to preserve fertility. However, according to several reports regarding ablation of solid tumors by HIFU, there are rare complications in patients with uterine leiomyomas, and overall data are still insufficient. Here, we report rare and major complications of HIFU, such as delayed intestinal perforation, uterine perforation with recto-uterine fistula, and osteomyelitis 29 days after the HIFU procedure to treat multiple myomas. Thus, we present a very serious case resulting from HIFU treatment of uterine fibroids and a review of the literature.

Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case-Control Study.

We assessed the urinary concentration of 16 phthalate metabolites in 57 women with and without uterine leiomyoma (n = 30 and 27; respectively) to determine the association between phthalate exposure and uterine leiomyoma. To evaluate exposure to di-(2-ethylhexyl) phthalate (DEHP); we calculated the molar sum of DEHP metabolites; ∑3-DEHP (combining mono-(2-ethylhexyl) phthalate (MEHP); mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); and mono-(2-ethyl-5-oxohexyl) phthalate); ∑4-DEHP (∑3-DEHP plus mono-(2-ethyl-5-carboxypentyl) phthalate); and ∑5-DEHP (∑4-DEHP plus mono (2-(carboxylmethyl)hexyl) phthalate (2cx-MMHP)). The log transformed urinary levels of MEHP; MEHHP; 2cx-MMHP; ∑3-DEHP; ∑4-DEHP; and ∑5-DEHP in the leiomyoma group were significantly higher than those of controls. When we adjusted for age; waist circumference; and parity using multiple logistic regression analyses; we found log ∑3-DEHP (OR = 10.82; 95% CI = 1.25; 93.46) and ∑4-DEHP (OR = 8.78; 95% CI = 1.03; 75.29) were significantly associated with uterine leiomyoma. Our findings suggest an association between phthalate exposure and uterine leiomyoma. However; larger studies are needed to investigate potential interactions between phthalate exposure and uterine leiomyoma.

Innervation in women with uterine myoma and adenomyosis.

OBJECTIVE: To determine if neurofilament (NF) is expressed in the endometrium and the lesions of myomas and adenomyosis, and to determine their correlation. METHODS: Histologic sections were prepared from hysterectomies performed on women with adenomyosis (n=21), uterine myoma (n=31), and carcinoma in situ of the uterine cervix. Full-thickness uterine paraffin blocks, which included the endometrium and myometrium histologic sections, were stained immunohistochemically using the antibodies for monoclonal mouse antihuman NF protein. RESULTS: NF-positive cells were found in the endometrium and myometrium in 11 women with myoma and in 7 with adenomyosis, but not in patients with carcinoma in situ of uterine cervix, although the difference was statistically not significant. There was no significant difference between the existence of NF-positive cells and menstrual pain or phases. The NF-positive nerve fibers were in direct contact with the lesions in nine cases (29.0%) of myoma and in five cases (23.8%) of adenomyosis. It was analyzed if there was a statistical significance between the existence of NF positive cells in the endometrium and the expression of NF-positive cells in the uterine myoma/adenomyosis lesions. When NF-positive cell were detected in the myoma lesions, the incidence of NF-positive nerve cells in the eutopic endometrium was significantly high. When NF-positive cell were detected in the basal layer, the incidence of NF-positive nerve cells in the myoma lesions and adenomyosis lesions was significantly high. CONCLUSION: We assume that NF-positive cells in the endometrium and the myoma and adenomyosis lesions might play a role in pathogenesis. Therefore, more studies may be needed on the mechanisms of nerve fiber growth in estrogen-dependent diseases.

Progesterone reduces neurofilament (NF)--positive nerve fibers in eutopic endometrium of patients with endometriosis and myomata.

OBJECTIVE: To evaluate whether there are neurofilament (NF)-positive nerve fibers in the eutopic endometrium of patients with myoma and endometriosis by using stromal cell culture and to verify whether progesterone has an effect on the NF-positive nerve fiber by using stromal cell culture. STUDY DESIGN: Patients with uterine myoma (N = 11), ovarian and pelvic endometriosis (N = 10), and without myoma and endometriosis (N = 10) were included in the study. Human endometrial tissues were obtained from hysterectomy and curettage. The stromal cells were cultured and immunostaining was performed before and after treatment with progesterone by using NF. RESULTS: Before progesterone treatment the percentage of NF-positive nerve fibers between the uterine myoma group (4.91 +/- 2.05) and the endometriosis group (2.22 +/- 0.92) was statistically significant, and there was a significantly different percentage of NF-positive nerve fibers between the uterine myoma group (4.91 +/- 2.05) and the levonorgestrel intrauterine device-inserted group (1.50 +/- 0.25). After progesterone treatment the percentage of NF-positive nerve fibers was significantly decreased in the uterine myoma (2.09 +/- 1.73) and the endometriosis (1.48 +/- 0.80) groups. CONCLUSION: We showed that the NF-positive nerve fibers were reduced after progesterone treatment by using stromal cell culture and suggest that progesterone could have a role in the decrease of endometriosis/myoma-associated pain.

Vero cell co-culture counteracts the detrimental effects of hydrosalpinx fluid on the development of mouse embryos in vitro.

Recent studies have suggested that the hydrosalpinx has a negative effect on pregnancy outcome, with markedly diminished implantation and increased early pregnancy loss. Fluid from the hydrosalpinx may leak into and accumulate in the uterine cavity. It is not clear, however if this creates a hostile local environment in the uterus for embryo implantation or exerts a direct embryotoxic effect. This study was conducted to investigate the detrimental effects of hydrosalpinx fluid (HSF) on the development of mouse embryos in vitro and to demonstrate whether Vero cells overcome these adverse effects. HSF was collected from three women with bilateral hydrosalpinx at the time of laparoscopic surgery. Collected fluid was centrifuged and the supernatant was frozen at -20 degrees C. For co-culture, Vero cells were commercially obtained in a frozen state and cultured using Ham's F10 medium. Single-cell mouse embryos (B6CBAF1) were cultured for 5 days in 0, 0.4, 0.8, and 1.2% of HSF in media with and without Vero cells and examined daily to record the number of embryos reaching expanded blastocyst and hatching stage. Co-culture of mouse embryos with Vero cells at 0.8% HSF concentration significantly enhanced embryo development, but not at 1.2% hydrosalpinx fluid concentration. These results suggest that HSF is highly embryotoxic and Vero cells are likely to overcome these detrimental effects to some degree.