Delivery mode after cervical ripening among patients with no prior vaginal births.

PURPOSE: To compare mode of delivery and maternal and neonatal outcomes using cervical ripening balloon (CRB) for induction of labor (IOL) in nulliparous patients vs. those undergoing first trial of labor after cesarean (TOLAC). METHODS: Retrospective cohort study including data from two tertiary medical centers. Included were all patients with a singleton pregnancy and a gestational age > 37+0 weeks and no prior vaginal birth undergoing IOL with CRB. Nulliparous patients (nulliparous group) were compared to patients with one prior cesarean delivery (CD) and no prior vaginal delivery (TOLAC group). Patients who withdrew consent for trial of labor at any time in both groups were excluded. The primary outcome was mode of delivery. RESULTS: Overall, 161 patients were included in the TOLAC group and 1577 in the nulliparous group. The rate of CD was similar in both groups and remained similar after adjusting for confounders (29.8 % vs. 28.9 %, p = 0.86, OR 1.1, 95 %, CI 0.76-1.58). CD due to fetal distress was more common in the TOLAC group (75 % vs. 56 %, p = 0.014). Other maternal outcomes and neonatal outcomes were similar in the two groups. CONCLUSION: Comparable vaginal delivery rates may be achieved in patients with or without a previous CD attempting their first trial of labor, with a cervical ripening balloon for labor induction, without increasing adverse maternal or neonatal outcomes.

Hypoxia leads to diminished ovarian reserve in an age dependent manner.

OBJECTIVES: Perinatal hypoxia causes premature activation and initiation of growth in dormant follicles, leading to diminished ovarian reserve. An indirect mechanism such as the release of stress-related hormones, may influence ovarian follicle recruitment under hypoxic conditions. We wanted to determine whether hypoxic ovarian damage results from increased follicle growth and "burnout" or from increased apoptosis, and whether this damage is age-dependent. DESIGN: Animal study Participants/Materials, Setting, Methods: Using adult 6-week-old (n=8) and one-day-old newborn (n=20) ICR (CD-1) female mice, ovarian follicular counts were conducted on H&E-stained sections. METHODS: Immunohistochemistry was performed on sections stained with Ki-67, anti-Caspase 3 and anti-FOXO3A. RESULTS: Exposure to hypoxia resulted in significantly reduced proportion of primordial follicles vs normoxia in both adult dams and newborn pups (3.17±2.75% vs. 17.89±4.4%; p=0.004; 40.59±14.88% vs. 81.92±31.56%, p=0.001, respectively), concomitant with increased growing- primary and secondary follicles, and more pronounced in adult dams vs newborn pups (6-fold vs. 2-fold, respectively). Ki67 staining revealed higher scores of cell proliferation in follicular granulosa cells after exposure to hypoxia than normoxia. However, Caspase 3 and Foxo3A staining did not show any differences in these markers of apoptosis in oocytes, granulosa cells, theca cells, or stromal cells when exposed to hypoxia versus normoxia. LIMITATIONS: The current study has several limitations; first, the sample size for each group is relatively small, which could limit the generalizability of the findings. Second, the study uses an ex vivo culture system, which may not fully capture the complex interactions that occur in the whole animal. Third, the exposure to hypoxia only lasted for 3 hours, which may not be long enough to observe all the potential effects. In addition, the study only analyzed specific markers of apoptosis in a few cell types, and other cell types or apoptotic pathways might be involved. Lastly, the study provides evidence for accelerated follicular activation and decreased ovarian reserve, but the underlying mechanisms are not fully explored. Conclusions Direct tissue hypoxia led to premature activation and initiation of growth in dormant follicles leading to diminished ovarian reserve. Hypoxic damage is age-dependent, with adult ovaries more susceptible than newborn ovaries. These findings support the possibility of follicular "burn out" as a potential mechanism responsible for hypoxia-induced loss of ovarian reserve.

Intestine and brain TLR-4 modulation following N-acetyl-cysteine treatment in NEC rodent model.

Necrotizing enterocolitis (NEC) brain injury is mediated through Toll-like receptor 4 (TLR4) on the intestinal epithelium and brain microglia. Our aim was to determine whether postnatal and/or prenatal NAC can modify NEC associated intestinal and brain TLR4 expression and brain glutathione levels in a rat model of NEC. Newborn Sprague-Dawley rats were randomized into three groups: Control (n = 33); NEC (n = 32)-hypoxia and formula feeding; and NEC-NAC (n = 34)-received NAC (300 mg/kg IP) in addition to NEC conditions. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg IV) for the last 3 days of pregnancy: NAC-NEC (n = 33) or NAC-NEC-NAC (n = 36) with additional postnatal NAC. Pups were sacrificed on the fifth day, and ileum and brains harvested for TLR-4 and glutathione protein levels. Brain and ileum TLR-4 protein levels were significantly increased in NEC offspring as compared to control (brain 2.5 ± 0.6 vs. 0.88 ± 0.12 U and ileum 0.24 ± 0.04 vs. 0.09 ± 0.01, p < 0.05). When NAC was administered only to dams (NAC-NEC) a significant decrease in TLR-4 levels was demonstrated in both offspring brain (1.53 ± 0.41 vs. 2.5 ± 0.6 U, p < 0.05) and ileum (0.12 ± 0.03 vs. 0.24 ± 0.04 U, p < 0.05) as compared to NEC. The same pattern was demonstrated when NAC was administered only or postnatally. The decrease in brain and ileum glutathione levels observed in NEC offspring was reversed with all NAC treatment groups. NAC reverses the increase in ileum and brain TLR-4 levels and the decrease in brain and ileum glutathione levels associated with NEC in a rat model, and thus may protect from NEC associated brain injury.

Intrapartum Atosiban Treatment During Tachysystole and Non-reassuring Fetal Monitoring: A Retrospective Cohort Study.

BACKGROUND: Uterine tachysystole during labor can lead to a decrease in fetal oxygen saturation and intracerebral oxygen saturation. Acute tocolysis using atosiban can inhibit uterine smooth muscle activity, potentially improving fetal status and facilitating vaginal delivery or allowing time to prepare for operative delivery. OBJECTIVES: To compare maternal and neonatal outcomes in cesarean and vaginal deliveries following atosiban administration during fetal prolonged deceleration and tachysystole at gestational age 37 0/7 to 43 0/7 weeks. METHODS: We conducted a single-center, descriptive retrospective cohort study at a large tertiary referral center. RESULTS: Of the 275 patients treated with atosiban, 186 (68%) delivered vaginally (either spontaneous delivery or instrumental delivery) and 89 (32%) underwent a cesarean delivery. In a univariate analysis, cesarean delivery was associated with higher body mass index (27.9 ± 4.3 vs. 30.2 ± 4.8, P = 0.003). Second stage atosiban administration was associated with vaginal delivery (89.3% vs. 10.7%, P = 0.01). Cesarean delivery was associated with lower Apgar at 1 and 5 minutes and a higher rate of neonatal intensive care unit admissions. The incidence of PPH among women treated with atosiban in our study (2.3-4.3%) was higher than the incidence reported in the literature (1-3%). CONCLUSIONS: Atosiban may be an effective acute intervention for non-reassuring fetal heart rate during tachysystole, increasing the rate of vaginal delivery and potentially reducing the need for cesarean delivery. However, the potential risk of postpartum hemorrhage should be taken into consideration.

COVID-19 Quarantine and Sexual Function after First Vaginal Delivery.

OBJECTIVES: Sexual function is an important part of quality of life at all ages. Childbirth brings many changes that may affect sexual function. During COVID-19 global pandemic, nuclear families were forced to stay home. The goal of this study was to evaluate sexual function during the COVID-19 quarantine, in postpartum couples in the first months following their first vaginal childbirth. DESIGN: This is a single-center, prospective study of females following their first vaginal delivery and their male partners. Participants were recruited in the maternity ward after their first delivery at Rambam Medical Center. Both spouses signed a consent form for answering the sexual function questionnaires. PARTICIPANTS: Participants were interviewed by telephone during the last week of the first COVID-19 quarantine, according to Arizona Sexual Experience Scale (ASEX). MAIN OUTCOME MEASURES: pre- and post-quarantine sexual function according to ASEX scores. ASEX is a survey that assesses sexual drive, arousal, vaginal lubrication, the ability to reach orgasm, and satisfaction from orgasm. Responses are scored on a 1-6 Likert scale with a potential range of 5-30, where the highest scores indicate worse sexual function. RESULTS: The participants were 38 women and 29 men. The average time from delivery to the interviews was 182.8 ± 84.7 days; 56% of the spouses were under quarantine. The median baseline total ASEX score was 13 (sexual drive 3, arousal 2.5, vaginal lubrication 2.5, ability to reach orgasm 2, orgasm satisfaction 2) for women and 11 (sexual drive 3, arousal 2, penile erection 1, ability to reach orgasm 2, orgasm satisfaction 2) for men. Sixteen percent of the women and none of the men had a baseline sexual dysfunction (ASEX score >19). Significant differences were not observed in total ASEX scores before and during the quarantine. LIMITATIONS: Sexual function at the end of the quarantine was evaluated prospectively and pre-quarantine sexual function was evaluated retrospectively, with the limitation of recall bias. CONCLUSIONS: COVID-19 quarantine did not seem to have a significant effect on female or male sexual function, three to 9 months after the first vaginal delivery. The current study is the first to describe primiparous postpartum sexual function as median ASEX score.

Late preterm delivery has a distinctive second-stage duration and characteristics.

BACKGROUND: Late preterm neonates born between 34.0 and 36.6 weeks' gestation are at increased risk for short- and long-term morbidity and mortality when compared with their term counterparts. Currently, no separate labor curve is available for late preterm births, and this group's optimal duration of the second stage of labor has never been defined separately. OBJECTIVE: This study aimed to compare the second stage duration between late preterm and term births. STUDY DESIGN: This was a retrospective study from May 2014 until May 2021. Eligible were women with a singleton pregnancy, vertex presentation, spontaneous or induced onset of labor, and those who delivered vaginally beyond 34.0 weeks of gestation. The primary outcome of our study was to compare and characterize the second stage of labor duration between late preterm and term births. RESULTS: We analyzed 962 late preterm and 9476 term vaginal deliveries. Women who delivered during the late preterm period were more likely to be multiparous (52.4% vs 45.2%; P<.001) and fewer required oxytocin during labor (41.2% vs 54.4%; P<.001) or used epidural analgesia (75.2% vs 83.6%; P<.001). The overall mean duration of the second stage of labor was significantly shorter in the late preterm period than at term (1.08±1.09 hours vs 1.49±1.22 hours; P<.001). This was even more pronounced for nulliparous women (1.05±1.00 hours vs 2.10±1.17 hours; P<.001). Among multiparous women, epidural use significantly affected the duration of the second stage of labor, and the second stage was relatively longer during the late preterm period than at term in this subgroup (1.16 vs 0.5 hours; P<.001). Using a multivariate Cox regression, variables such as maternal age (hazard ratio, 1.02; 95% confidence interval, 1.01-1.04), parity (hazard ratio, 4.11; 95% confidence interval, 3.65-4.63), preterm birth (hazard ratio, 2.08; 95% confidence interval, 1.4-3.10), and birthweight at delivery (hazard ratio, 1.15; 95% confidence interval, 1.01-1.30) shortened the second stage, whereas induction of labor (hazard ratio, 0.75; 95% confidence interval, 0.66-0.86) and epidural use (hazard ratio, 0.68; 95% confidence interval, 0.64-0.86) extended its total duration. Regardless of parity, lower rates of operative vaginal deliveries were observed in the late preterm period than at term (3.7% vs 15.5%; P<.001). This period was also associated with lower rates of third- and fourth-degree perineal lacerations (0.2% vs 2.2%; P<.001) but higher rates of chorioamnionitis (1.7% vs 0.1%; P<.001), Apgar score at 5 minutes <7 (1.0% vs 0.2%; P<.001), and admission to the neonatal intensive care unit (19.3% vs 1.0%; P<.001). CONCLUSION: Women who delivered vaginally during the late preterm period had a distinctive second-stage duration. Primarily, it was shown to be significantly shorter for nulliparous and multiparous women. Future studies should further clarify the optimal duration of this stage in relation to neonatal outcomes at such a vulnerable period.

Optimizing cervical ripening in women presenting with decreased fetal movements.

OBJECTIVE: To determine the optimal method for cervical ripening in women presenting with decreased fetal movements at term. We hypothesized that women who undergo induction of labor for decreased fetal movements represent a higher risk group, and will benefit from mechanical intervention with cervical ripening balloon rather than with pharmacological prostaglandin E2 vaginal insert. STUDY DESIGN: Retrospective cohort study from January 2014 and January 2019. We recommended induction of labor to every woman ≥39 weeks' gestation with complaints of persistent decreased fetal movements. We excluded women with major fetal anomalies, Bishop score of ≥6 on admission, and cases with contraindications to prostaglandins. Women were allocated into one of two groups based on the cervical ripening agent used. In group 1 we introduced the prostaglandin E2 vaginal insert (10 mg dinoprostone in a timed-release formulation). In group 2 we placed the mechanical cervical ripening balloon. The primary outcome of the study, analyzed separately to nulliparous and multiparous women, was the rate of cesarean delivery in each of the groups. RESULTS: During the 5-years study, 294 women were included in the final analysis, of which 201 were in the prostaglandin E2 vaginal insert group and 93 were in the cervical ripening balloon group. The rate of cesarean delivery was comparable between the groups (nulliparous: 20.8%, 16/77 versus 21.3%, 10/47. multiparous: 16.9%, 21/124 versus 7%, 3/46, respectively). Other maternal and neonatal secondary outcomes, including the induction-to-delivery time (nulliparous: 32.5 ± 25.3 h versus 26.5 ± 12.2 h. multiparous: 24.6 ± 17.2 h versus 21.25 ± 12.3 h, respectively), were also not different between the two induction methods used. A longer induction-to-delivery time was observed in nulliparous women who had repeat prostaglandin E2 vaginal insert compared with the cervical ripening balloon group (74.6 ± 27.3 h versus 26.5 ± 12.2 h, p < .01). CONCLUSION: Both pharmacological and mechanical methods can safely and efficiently be used for cervical ripening in women presenting with decreased fetal movements at term. With repeat prostaglandin E2 use, nulliparous women may experience a prolong labor compared with the cervical ripening balloon group, but maternal or fetal safety are not compromised.

Perinatal hypoxia leads to primordial follicle activation and premature depletion of ovarian reserve.

BACKGROUND: The human ovary contains 6-million follicles during the 20th week of embryonic development and 1 million at birth. Girls born at small for gestational age weight demonstrate higher FSH levels during infancy, an earlier onset of puberty, and menarche. In light of these observations, we hypothesized that exposure to hypoxia at the early neonatal period might impact the primordial follicular pool and lead to premature depletion of ovarian reserve. METHODS: Ovarian development in the rat model at days 1-5 postpartum reflects its human counterpart in the late perinatal period. We exposed newborn rat pups (n = 5) to controlled hypoxia, (5% oxygen/95% nitrogen) for 10 min three times daily for days 1-5 postpartum. On day 5, ovaries were harvested, H&E, Ki-67, and TUNEL staining were performed. RESULTS: The percentage of primordial follicles out of total follicles in ovaries of pups exposed to hypoxia was lower compared to control (76 ± 8.2% and 90.33 ± 6.3% respectively, p < .05). Correspondingly the percentage of primary and secondary follicles was higher than in control. The mean stromal Ki67 staining score was significantly lower in the study group (1.67 ± 0.58 and 2.5 ± 0.55 respectively, p < .05). TUNEL staining demonstrated no difference in stromal apoptosis rates between both groups. CONCLUSIONS: We provide evidence for the first time that perinatal hypoxia causes premature activation and growth initiation of dormant follicles. These changes were associated with decreased stromal cell proliferation, suggesting hypoxia-induced impairment of the support cell pool as a possible mechanism for accelerated follicular activation.

The influence of lifestyle of OB/GYN female residents on gynecological and obstetrical outcomes: A cross-sectional study.

OBJECTIVE: To learn the influence of obstetrics and gynecology (OB/GYN) female residents' lifestyle on obstetric and gynecological characteristics compared to women matched by age from the general population. STUDY DESIGN: A cross-sectional multicenter study including OB/GYN female residents from ten different hospitals in Israel, who completed an internet questionnaire published during 2017-2018, that were compared to women matched by age from the general population. Questions dealt with lifestyle habits, obstetrical and gynecological outcomes. Data are presented as median and inter-quartile range. RESULTS: During the study period 97 women completed the questionnaire, of them 56 (57.7%) OB/GYN female residents and 41(42.3%) controls. No statistically significant differences were found between the groups regarding age, marital status, gravidity and parity. However, lifestyle characteristics reported by OB/GYN female residents differed compared to controls: OB/GYN female residents found their work more stressogenic [53 (94.6%) vs. 20 (48.8%); p = 0.001], suffered from deprived sleep [42(75.6%) vs. 13(31.8%); p = 0.001], were less punctilious on dental hygiene [13(23.2%) vs. 27(65.8%); p = 0.001] and reported maintaining a less healthy diet [35(62.5%) vs. 15(36.6%); p = 0.003]. Despite these differences, general happiness reported by both groups was comparable (35(62.5%) vs. 27(65.9%) for OB/GYN and control women respectively; p = 0.73). Pregnancy rate was found to be more than double in the resident's group [30 (53.6%) vs. 9 (22%); p = 0.002], with no differences in the rates of: complications during pregnancy [51(91.1%) vs. 38(92.7%); p = 0.78]; abortions [10 (17.9%) vs. 8 (19.5%); p = 0.84]; augmentation of labor [5 (9%) vs. 7 (17.1%); p = 0.18]; or cesarean deliveries [7(12.5%) vs. 7(17%); p = 0.48]. Logistic regression analysis found both parity and residency as independent variables significantly associated with pregnancy rate [(B = 0.69, p = 0.047), (B = 1.95, p = 0.016), respectively]. CONCLUSION: Although resident women in OB/GYN reported on more adverse lifestyle parameters, comparable obstetric and gynecological outcomes were seen, with residency and parity being independently associated with higher pregnancy rate.

In Vitro Fertilization Entails a High Prevalence of Erectile and Male Sexual Dysfunction: A Prospective Case-Control Study.

PURPOSE: We evaluated the effect of in vitro fertilization (IVF) on sexual function in men, particularly for erectile dysfunction. MATERIALS AND METHODS: A prospective case-control study at a tertiary medical center. The study group comprised men of infertile couples that required IVF to conceive. The control group comprised men of couples who conceived spontaneously. The effects of IVF on sexual and erectile function were assessed based on the International Index of Erectile Function (IIEF-15) and the Self-Esteem and Relationship (SEAR) questionnaires. Participants were followed up to 1 year postpartum. RESULTS: Compared to the control group (378), for the IVF group (356), mean IIEF-15 scores were significantly lower: prior to pregnancy (31.7±4.5 vs 64.4±7.2, p <0.0001), at mid-pregnancy (37.3±5.1 vs 66.4±5.5, p <0.0001) and up to one year postpartum (42.3±4.9 vs 68.6±4.3, p <0.0001). Compared to the control group, in the IVF group, mean SEAR scores were significantly lower at these 3 respective time points (29.9±6.3 vs 66.5±8.3; 34.1±5.8 vs 66.9±7.2; and 40.9±6.7 vs 67.3±5.6; p <0.0001). At the 3 time points, for the IVF compared to the control group, the median monthly sexual intercourse rate was lower; and both the use of phosphodiesterase-5 inhibitor and psychologist/sexologist care were higher. CONCLUSIONS: The prevalence of erectile dysfunction among men participating in IVF in order to conceive is significantly higher compared to couples that conceived spontaneously, thus leading to an extremely high rate of phosphodiesterase-5 inhibitor use.

Vaginal Fractional Carbon Dioxide Laser Treatment and Changes in Vaginal Biomechanical Parameters.

BACKGROUND AND OBJECTIVES: Vaginal fractional carbon dioxide (CO2 ) laser treatment has emerged in the past two decades as a non-surgical option for vaginal tightening. Mounting evidence supports the effectiveness and safety of this treatment for female sexual dysfunction. A newly developed vaginal tactile imaging (VTI) technique accurately evaluates the biomechanical parameters of the female pelvic floor and vagina, including tissue elasticity, pelvic support, and pelvic muscle function in high definition. In the current study, we evaluated changes in objective biomechanical parameters using VTI, following vaginal CO2 laser treatment for vaginal tightening and sexual dysfunction. STUDY DESIGN/MATERIALS AND METHODS: We conducted a prospective cohort between June 2018 and January 2020. Inclusion criteria were vaginal looseness, decreased local sensation during sexual intercourse, and sexual dysfunction. All the participants were treated with a vaginal carbon dioxide laser. They underwent a gynecological evaluation based on the Vaginal Health Index (VHI) and sexual function assessment according to the Female Sexual Function Index (FSFI). Vaginal biomechanical parameters were assessed by VTI. Initial evaluations were performed at the pre-treatment consult visit, 1 week prior to the first treatment and at a 6-month post-treatment follow-up visit. RESULTS: Twenty-five women were included in the final analysis. Compared with baseline, the post-treatment mean scores for vaginal elasticity and tightening were higher (54.8 ± 5.2 vs. 41.5 ± 6.3, P = 0.0027 and 1.97 ± 0.25 vs. 1.32 ± 0.31, P = 0.0014, respectively). Post-treatment increases were demonstrated in pelvic muscle contraction strength (25.9 ± 3.5 vs. 16.5 ± 4.2, P = 0.0011) and in reflex pelvic muscle contraction (2.93 ± 0.44 vs. 2.12 ± 0.47, P = 0.0022); the mean FSFI and VHI scores were higher following treatment (28.47 ± 1.73 vs. 21.12 ± 1.58, P = 0.036 and 19.15 ± 1.27 vs. 11.6 ± 0.97, P = 0.0032). CONCLUSIONS: The quantification of vaginal biomechanical parameters using VTI technology offers objective evidence of the beneficial effect of vaginal CO2 laser treatment. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Low-Intensity Shockwave for Treatment of Vestibulodynia: A Randomized Controlled Therapy Trial.

BACKGROUND: Provoked vestibulodynia (PVD) is an exhausting pain syndrome that immensely affects quality of sexual life and consequently negatively affects quality of life. Low-intensity shock wave therapy produces physical forces that lead to pain relief. AIM: The aim of this study was to evaluate the feasibility, safety, and efficacy of low-intensity shockwave therapy in patients with provoked vestibulodynia. METHODS: This is a double-blinded, randomized, sham-controlled, prospective study of 32 women. The treatment protocol included a series of treatments, performed twice a week for 6 weeks. Each treatment consisted of 500 pulses of low intensity shockwaves (0.09 mJmm2) using the Medispec, ED-1000 shockwave generator or sham. Participants were assessed at the baseline, and at 1 and 3 months after completing all treatments. OUTCOMES: Pain was assessed by both subjective and objective measures. The primary outcome was a change in dyspareunia, as assessed by scores on the 10-point visual analog scale. Secondary outcome measures were changes in pain threshold and tolerance, assessed by a quantitative validated algometer test, the Wong-Baker pain FACES scale, the Female Sexual Function Index and the Patients' Global Impression of Change scale. RESULTS: From the baseline to 1 month and 3 months after completion of treatment, visual analog scale scores for dyspareunia decreased (8.0 ± 1.4, 5.7 ± 2.3, and 4.4 ± 2.5, respectively, P < .005). For these respective time points, Wong-Baker scores decreased (4.0 ± 0.6, 2.9 ± 1.2, 2.5 ± 1.3, respectively, P < .05); and total Female Sexual Function Index increased (17.9 ± 6.3, 20.9 ± 6.2, 22.5 ± 8, respectively, P < .002). Pain threshold and tolerance measured by the algometer were increased 3 months after completion of the treatment compared with the baseline (69.8 mmHg ± 11.8 vs 22.9 mmHg ± 9.0, P < .01 and 87.7 mmHg ± 35.7 vs 43.3 mmHg ± 14.7, P < .0001, respectively). No changes were observed in any of the measures assessed in the sham group. CLINICAL IMPLICATIONS: We found a new effective treatment for alleviating the most bothersome symptom in PVD, pain during penetration and intercourse. This resulted in improved sexual function. STRENGTHS & LIMITATIONS: The strengths of this study are the randomized controlled design, the correlated subjective questionnaires, and the use of semiquantitative algometer methodology. The limitations are the relative low number of participants in a single center. CONCLUSION: For women with PVD, low-intensity shockwave therapy applied at the introitus is a feasible, safe, and effective treatment option that may have a beneficial effect in pain relief and in sexual function. Gruenwald I, Gutzeit O, Petruseva A, et al. Low-Intensity Shockwave for Treatment of Vestibulodynia: A Randomized Controlled Therapy Trial. J Sex Med 2021;18:347-352.

Progesterone Attenuates Brain Inflammatory Response and Inflammation-Induced Increase in Immature Myeloid Cells in a Mouse Model.

Progesterone has been shown to regulate immunity during pregnancy, and progesterone administration may reduce inflammation-induced preterm labor. We sought to determine the maternal brain immune response to LPS-induced inflammation in pregnant and non-pregnant mice and whether additional progesterone supplementation attenuates this response. Pregnant (P: n = 9) and non-pregnant mice (NP: n = 9) were randomized to pretreatment with vaginal progesterone/carrier (Replens), daily from days 13 to 16. On days 15 and 16, LPS/saline was administered by intraperitoneal injection (Replens + saline n = 3; Replens + LPS n = 3; progesterone + LPS n = 3). Mice were sacrificed on day 16 and maternal serum analyzed for IL-6 levels and brains analyzed for nNOS, NF-kB, IL-6 protein levels and for immature myeloid cells (IMCs) and microglial activity. LPS significantly increased brain nNOS, NF-kB, and IL-6 in both NP and P mice, with significantly greater responses in P mice. In both NP and P groups, progesterone significantly attenuated LPS-induced increase of nNOS and NF-kB, however with no effect on serum IL-6. In the NP brains, LPS significantly increased IMC population and progesterone reduced the IMC phenotype to levels similar to controls. In P mice, neither LPS nor LPS + progesterone altered the brain IMC population. LPS significantly increased the microglial activity in both NP and P groups, which was attenuated by progesterone. Progesterone attenuates brain inflammatory response to LPS in both NP and P mice although it has no effect on systemic inflammation. In NP mice, progesterone attenuated the increase in brain IMC following LPS administration. Our results suggest that endogenous progesterone during pregnancy may protect the brain from LPS-induced inflammation.

Maternal Progesterone Treatment Reduces Maternal Inflammation-Induced Fetal Brain Injury in a Mouse Model of Preterm Birth.

Maternal natural vaginal progesterone (nVP) administration has been shown to reduce the risk of preterm birth (PTB). The largest randomized trial of nVP for PTB (OPPTIMUM) noted a sonographic reduction in neonatal brain injury following nVP treatment. We investigated the neuroinflammatory protective effect of maternal nVP in a mouse model for maternal inflammation. Pregnant mice (n = 24) were randomized to nVP (1 mg/day) or vehicle from days 13-16 of gestation. At days 15 and 16, lipopolysaccharide (30 µg) or saline were administered. Mice were sacrificed 4 h following the last injection. Fetal brains and placentas were collected. Levels of NF-κB, nNOS, IL-6, and TNFα were determined by Western blot. Maternal lipopolysaccharide significantly increased fetal brain levels of IL-6 (0.33 ± 0.02 vs. 0.11 ± 0.01 u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01 u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01 u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01 u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001 pmol/µl; p < 0.01) compared with control. Maternal nVP significantly reduced fetal brain levels of IL-6 (0.14 ± 0.01 vs. 0.33 ± 0.02 u), TNFα (0.2 ± 0.06 vs. 0.3 ± 0.02 u), NF-κB (0.16 ± 0.01 vs 0.32 ± 0.01 u), and nNOS (0.14 ± 0.01 vs 0.24 ± 0.04 u), and prevented the reduction of fetal brain total glutathione levels (0.022 ± 0.001 vs. 0.014 ± 0.001 pmol/µl; p < 0.01) to levels similar to controls. A similar pattern was demonstrated in the placenta. Maternal nVP for PTB may protect the fetal brain from inflammation-induced brain injury by inhibiting specific inflammatory and oxidative pathways in both brain and placenta.

Maternal N-acetyl-cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model.

INTRODUCTION: Preterm infants with necrotizing enterocolitis (NEC) are at increased risk of cerebral injury and neurodevelopmental dysfunction. N-acetyl-cysteine (NAC) is a known anti-inflammatory and antioxidant agent. Currently, there is no prophylactic treatment in clinical use to prevent NEC and its neurodevelopmental sequelae. We sought to determine whether brain inflammation/apoptosis accompanies NEC systemic inflammation, and whether it can be attenuated by maternal NAC treatment during pregnancy and/or in the neonatal period in a rat model. MATERIAL AND METHODS: An established NEC newborn model (hypoxia 5% O2 for 10 min and formula feeding thrice daily, beginning on day 1 for 4 days) was used in Sprague-Dawley rat pups (n = 32). An additional group of pups (n = 33) received NAC (300 mg/kg intraperitoneal thrice daily) in addition to NEC conditions (NEC-NAC). Control pups (n = 33) were nursed and remained with the dam in room air. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg intravenous) in the last 3 days of pregnancy. After birth, pups were randomized into NAC-NEC (n = 33) with NEC conditions and NAC-NEC-NAC (n = 36) with additional postnatal NAC treatment. Pups were sacrificed on the fifth day of life. Pup serum interleukin (IL)-6 protein levels, and brain nuclear factor kappa B (NF-κB) p65, neuronal nitric oxide synthase (nNOS), Caspase 3, tumor necrosis factor alpha (TNF-α), IL-6 and IL-1ß protein levels were determined by ELISA, western blot and TUNEL staining, and the groups were compared using analysis of variance (ANOVA). RESULTS: NEC pups had significantly increased serum IL-6 levels compared with the control group as well as increased neuronal apoptosis and brain protein levels of NF-κB, nNOS, Caspase 3, TNF-α, IL-6 and IL-1ß compared with control. In all NAC treatment groups, levels of serum IL-6, neuronal apoptosis and brain NF-κB, nNOS, Caspase 3, TNF-α, IL-6 and IL-1ß protein levels were significantly reduced compared with the NEC group. The most pronounced decrease was demonstrated within the NAC-NEC-NAC group. CONCLUSIONS: NAC treatment can attenuate newborn inflammatory response syndrome and decrease offspring brain neuroapoptosis and inflammation in a rat model of NEC by inhibition of NF-κB, nNOS and Caspase 3 pathways.

Lockdown with a Price: The impact of the COVID-19 Pandemic on Prenatal Care and Perinatal Outcomes in a Tertiary Care Center.

BACKGROUND: The World Health Organization classified coronavirus disease-19 (COVID-19) as a pandemic and recommends strict restrictions regarding most aspects of daily activities. OBJECTIVES: To evaluate whether the pandemic has changed the prenatal care and pregnancy outcome in pregnant women without COVID-19. METHODS: The authors conducted a cross-sectional study to describe changes in outpatient clinic visits and to compare the rates of cesarean and instrumental deliveries between two periods of time: March-April 2020 (during the COVID-19 outbreak) with March-April of the preceding year, 2019. RESULTS: During the COVID-19 outbreak, visits to obstetric triage, gynecologic triage, high-risk clinic, and ultrasound units decreased by 36.4%, 34.7%, 32.8%, and 18.1%, respectively. The medical center experienced a 17.8% drop in the total number of births (610 births) compared with March and April 2019 (742 births). During the outbreak women were more likely to be nulliparous (33.3% vs. 27.6%, P = 0.02) and present with hypertensive disorders during pregnancy (7.5% vs. 4%, P = 0.005) or gestational diabetes (13% vs. 10%, P = 0.03). More epidural analgesia was used (83.1% vs. 77.1%, P = 0.006). There were more operative vaginal deliveries during the outbreak (16.7% vs. 6.8%, P = 0.01). All other maternal and neonatal outcomes were comparable between the two periods. CONCLUSIONS: The medical facility experienced a major decline in all aspects of the routine obstetrics activities during the time of the pandemic. The higher rate of operative vaginal deliveries among nulliparous may be associated with the pandemic effect on the rate of high-risk patients.

Prophylactic antenatal N-Acetyl Cysteine administration combined with postnatal administration can decrease mortality and injury markers associated with necrotizing enterocolitis in a rat model.

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of neonates, especially premature neonates. To date, there is no prophylactic treatment against NEC, except breast milk and slow increase in enteral feeding, and there is no antenatal prophylaxis. AIMS: To assess possible protective effects of antenatal N-Acetyl Cysteine (NAC) against the intestinal pathophysiological changes associated with NEC in a rat model of NEC and against its associated mortality. METHODS: Newborn Sprague-Dawley rats were divided into 5 groups: control (n = 33); NEC (n = 32)-subjected to hypoxia and formula feeding for 4 days to induce NEC; NEC-NAC (n = 34)-with induced NEC and concomitant postnatal NAC administration; NAC-NEC (n = 33)-born to dams treated with NAC for the last 3 days of pregnancy starting at gestational age of 18 days, and then subjected to induced NEC after birth; NAC-NEC-NAC (n = 36)-subjected to induced NEC with both prenatal and postnatal NAC treatment. At day of life 5, weight and survival of pups in the different groups were examined, and pups were euthanized. Ileal TNF-α, IL-6, IL-1ß, IL-10, NFkB p65, iNOS and cleaved caspase 3 protein levels (western blot) and mRNA expression (RT-PCR) were compared between groups. RESULTS: Pup mortality was significantly reduced in the NAC-NEC-NAC group compared to NEC (11% vs. 34%, P<0.05). Ileal protein levels and mRNA expression of all injury markers tested except IL-10 were significantly increased in NEC compared to control. These markers were significantly reduced in all NAC treatment groups (NEC-NAC, NAC-NEC, and NAC-NEC-NAC) compared to NEC. The most pronounced decrease was observed in the NAC-NEC NAC group. CONCLUSIONS: Antenatal NAC decreases injury markers and mortality associated with NEC in a rat model. Antenatal administration of NAC may present a novel approach for NEC prophylaxis in pregnancies with risk for preterm birth.