Mode of birth in women with low-lying placenta: protocol for a prospective multicentre 1:3 matched case-control study in Italy (the MODEL-PLACENTA study).

INTRODUCTION: The term placenta praevia defines a placenta that lies over the internal os, whereas the term low-lying placenta identifies a placenta that is partially implanted in the lower uterine segment with the inferior placental edge located at 1-20 mm from the internal cervical os (internal-os-distance). The most appropriate mode of birth in women with low-lying placenta is still controversial, with the majority of them undergoing caesarean section. The current project aims to evaluate the rate of vaginal birth and caesarean section in labour due to bleeding by offering a trial of labour to all women with an internal-os-distance >5 mm as assessed by transvaginal sonography in the late third trimester. METHODS AND ANALYSIS: The MODEL-PLACENTA is a prospective, multicentre, 1:3 matched case-control study involving 17 Maternity Units across Lombardy and Emilia-Romagna regions, Italy. The study includes women with a placenta located in the lower uterine segment at the second trimester scan. Women with a normally located placenta will be enrolled as controls. A sample size of 30 women with an internal-os-distance >5 mm at the late third trimester scan is needed at each participating Unit. Since the incidence of low-lying placenta decreases from 2% in the second trimester to 0.4% at the end of pregnancy, 150 women should be recruited at each centre at the second trimester scan. A vaginal birth rate ≥60% in women with an internal-os-distance >5 mm will be considered appropriate to start routinely admitting to labour these women. ETHICS AND DISSEMINATION: Ethical approval for the study was given by the Brianza Ethics Committee (No 3157, 2019). Written informed consent will be obtained from study participants. Results will be disseminated by publication in peer-reviewed journals and presentation in international conferences. TRIAL REGISTRATION NUMBER: NCT04827433 (pre-results stage).

Effect of L-arginine supplementation in pregnant women with chronic hypertension and previous placenta vascular disorders receiving Aspirin prophylaxis: a randomized control trial.

BACKGROUND: The aim of the study is to evaluate the effects of supplementation with Arginine (L-Arg) 3g, (together with Magnesium (Mg) 350 mg and Salicilate (Sal) 100 mg) on maternal blood pressure (BP), uterine artery doppler PI and neonatal outcomes in women with high-risk pregnancy for chronic hypertension (CH) and other previous placenta vascular disorders (PVD) already treated with low dose of aspirin (LDA), as recommended by guidelines. METHODS: We enrolled women affected by CH and other previous PVD referred to the High-Risk Clinic of the Department of Maternal and Child's Health at the University Hospital of Modena and Reggio Emilia from September 2017 to June 2019. The study design was a controlled, randomized trial of oral supplementation of L-Arg 3g (together with Mg 350 mg and Sal extract 100 mg) + LDA 100 mg/day versus only LDA 100 mg/day. Inclusion criteria were: singleton pregnancy; diagnosis of chronic hypertension, previous preeclampsia <34 weeks, previous intrauterine growth restriction (IUGR) <10th centile or previous stillbirth (SB) related to placenta vascular disorders; gestational age <14 weeks. Each woman was enrolled between 12-14 weeks gestation and underwent 24-hour ambulatory BP monitoring with an automatic device (SpaceLab 92710, Critikon, WA), repeated at 18-20th and 24-26th weeks. Moreover Uterine artery Doppler ultrasound evaluation including PI were performed at 18-20 weeks gestation and repeated at 24-26th weeks. Pregnancy outcomes data were collected in a password protected database. RESULTS: Seventy-nine women agreed to participate in the study. No significant differences between the demographic characteristics in the two groups were found at enrolment (Group LDA + L-Arg: 30 patients versus Group LDA: 49 patients). In the LDA-L-Arg group there is no significant increase in both systolic (127.22±12.02 and 132.75±7.51 mmHg, P=0.002) and diastolic (75.85±8.53 and 83.63±6.05 mmHg, P=0.0000) BP values at 24-26 weeks reveled in the LDA group. The value of the uterine artery Doppler median PI>95th centile at 24-26 weeks show a significant reduction in the LDA+L-Arg group respect the LDA group (seven women, 23.3% vs. 21 women, 42.9%; P=0.04). A significantly lower percentage of women received new antihypertensive drugs in the LDA+ L-Arg group than the LDA group (6.7% vs. 24.5%) (P=0.02). There was neither statistically significant difference in perinatal outcomes between the two groups, except for trend of significance. CONCLUSIONS: Although we found only trends of improvements of perinatal outcomes in LDA+L-Arg group, considering the promising results on BP values, uterine artery PI and the low need to start a new antihypertensive treatment, thus the resulting impact in reducing pregnancy medicalization, number of maternal-fetal well-being monitoring visits and the need of induction of labor, we believe that further studies should be performed to enlarge our observation and clarify the role of L-Arg 3g supplementation as a protective integration in high-risk pregnancies already in prophylaxis with LDA.

Estimation of fetal weight near term: comparison between ultrasound and symphysis-fundus evaluation by Johnson's rule.

INTRODUCTION: The fetal weight estimation is commonly performed by ultrasound but the manual method is also applied in developing countries due to the lack of scan availability and in western countries for the management of low-risk pregnancy managed autonomously by the midwives. The most applied method to estimate fetal weight measures the longitudinal diameter of the symphysis-fundus according to Johnson's rule. The aim of the present study is to evaluate the reliability of the symphysis-fundus method with respect to the ultrasound to estimate fetal weight in low risk pregnancies according to the classification of adequate, small and large for gestational age. MATERIALS AND METHODS: Two hundred twenty low-risk women referred to the clinic for the management of term pregnancy were enrolled for the study. The following data were collected: age, body mass index, parity, values of symphysis-fundus evaluation according to Johnson's rule, ultrasound fetal weight estimation values, and birthweight. RESULTS: Considering the whole sample, fetal weight was estimated similarly by the manual method and with the ultrasound (79.5 versus 85% of the cases; n.s.). However, in overweight women, the ultrasound better estimates fetal weight in respect to manual method (94.4 versus 80.3% of the cases; p < .02) and similarly in obese women also ultrasound performed better in comparison to manual method (91.8 versus 71.4% of the cases; p < .01). CONCLUSIONS: The manual evaluation could be considered a reliable method to assess fetal weight for the management of low-risk pregnancies near term to optimize the resources and also offer a safe nonmedical approach. Further studies should clarify the accuracy of the manual method to estimate fetal weight in overweight and obese women, also considering the great increase of the obesity incidence in the obstetric population.

Effectiveness of Progestogens as Maintenance Tocolysis and Urogenital Cultures: Secondary Analysis of the PROTECT Trial.

Background In a recently published multicenter randomized controlled trial, we demonstrated that progestogens are not effective as maintenance tocolysis. Objective This study was aimed to evaluate if previous finding may be affected by positive urine culture and/or vaginal swab. Study Design We performed a secondary analysis of the PROTECT trial (NCT01178788). Women with singleton pregnancy between 22 and 31 6/7 weeks' gestation, admitted for threatened preterm labor were considered. At admission, we collected urine culture and vaginal swabs. At discharge, women with a cervical length ≤25 mm were randomized to vaginal progesterone or 17α-hydroxyprogesterone caproate or observation group. We used Chi-square statistics, considering 97.5% CI (confidence interval) and p -value less than 0.025 for significance. Results Urine culture and vaginal swabs were collected in 232 out of 235 patients included in the primary analysis. Overall, 31 out of 232 women (13.4%) had positive urine culture and 60 out of 232 (25.9%) had positive vaginal swab. In women with negative urine culture, a higher rate of preterm birth was found in vaginal progesterone group (27/69, 39.7%) respect with controls (14/68, 20.6%; relative risk [RR] = 1.90; 97.5% CI: 1.01-3.57; p = 0.018). Conclusion Among women with negative urine culture, the rate of preterm birth <37 weeks' gestation was significantly increased in those receiving vaginal progesterone, reinforcing our previous findings in symptomatic women.

Food glycemic index changes in overweight/obese pregnant women enrolled in a lifestyle program: a randomized controlled trial.

BACKGROUND: The calculation of the glycemic index of food mirrors a rise in blood sugar levels. A low-glycemic index carbohydrate diet in pregnancy has been associated with normal infant birthweight. Thus, strategies to lower the food glycemic index could be successful in improving pregnancy outcomes. OBJECTIVE: The purpose of this study was to compare different prescribed diets on food glycemic index intake and its relationship with rate of large-for-gestational-age infants. STUDY DESIGN: At the 9th-12th week of gestation (with a gynecologist and a dietitian both present), 273 Italian women with a body mass index of ≥25 kg/m2 were assigned randomly either to a customized low-glycemic index diet that was detailed by a dietitian (customized intervention; n=139 women; 1800 kcal/d+30 minutes walking 4 times/wk) or to generic lifestyle advice (standard care; n=134 women) with counseling about a prudent diet and physical activity, according to Italian guidelines. At enrollment and at the 36th week of gestation, the food frequency questionnaire was completed. In 73 Italian foods, the glycemic index was assessed with the use of a classic formula (available carbohydrate×glycemic index prescribed/total carb content of the meal) then was subdivided according to meal pattern. The main outcome was the change in food- glycemic index. RESULTS: Sociodemographic features were similar between the groups. One hundred fifty-six women completed the study (customized intervention=81; standard care=75). The mean daily glycemic index decreased from 58.4±19 to 52.5±11.2 (P=.008) in the customized intervention group although it remained unchanged in the standard care group. After the intervention, women in the customized intervention group reported a significant decrease in the diet glycemic index at dinner compared with both lunch and breakfast values (P<.02). Lower birthweight and fewer large-for-gestational-age infants were observed in the customized intervention group. CONCLUSION: A customized low-glycemic index, calorie-restricted diet that was associated with constant physical activity effectively reduced the food glycemic index. This reduced food glycemic index is associated with lower rate of large-for-gestational-age newborn infants.

Acupuncture in Postdate Pregnancy Management.

OBJECTIVES: Pharmacological labor induction is obtained through prostaglandins application and/or oxytocin infusion; however, the use seems to be related to fetal and maternal side effects. Traditional Chinese Medicine advocates the use of acupuncture to soften the cervix and induce uterine contractions. at which presented for The primary outcome was the rate of women admitted for labour induction in case of prolonged pregnancy at 41 + 5 weeks, and the secondary outcome was the rate of induction planning for other indications. METHODS: After obtaining informed consent, 375 undelivered women after 40 + 2 gestational age were enrolled for the study: 112 women received acupuncture and 263, routine care. Acupuncture was applied every odd day starting from 40 + 2 weeks up to 41 + 4 weeks. Women allocated to the control group received standard care. At 41 + 5 weeks, a pharmacological induction was planned. RESULTS: The rate of labor induction significantly differed between acupuncture and observation groups (19.6% vs. 38%; p < 0.01); in particular, women receiving acupuncture showed a lower rate of induction, indicating prolonged pregnancy (5.3% vs. 10.1%; p < 0.01). As far as the pharmacological device is concerned, no differences were observed with regard to the prostaglandins use, whereas oxytocin infusion rate was lower in the acupuncture group than in the observation group. CONCLUSIONS: The present study suggested that acupuncture applied at term of pregnancy seems to be effective in reducing the rate of labor induction which is performed for prolonged pregnancy at 41 + 5 weeks. Moreover, acupuncture also seems to be able to reduce oxytocin use; such a "saving" effect could play a role in childhood, considering that a recent study underlined the adverse effect of oxytocin on birth outcomes.

Castor oil for induction of labour: a retrospective study.

PURPOSE: The aim of this study is to investigate the safety and efficacy of castor oil to induce labour. MATERIALS AND METHODS: A retrospective observational case control study was conducted over five years. Castor oil was proposed to women referred to the Birth Centre (Castor Oil group (COG)). They were compared to women who chose to be followed by the traditional doctor-led unit (control group (CG)). Castor oil was administered in a 60 ml single dose in 200 ml of warm water. Inclusion criteria were gestational age between 40 and 41 weeks plus premature rupture of membranes between 12 and 18 hours or amniotic fluid index ≤4 or Bishop Score of ≤4 or absence of spontaneous labour over 41 + 4 weeks. RESULTS: Pharmacological induction of labour was required for 18 women in the COG (45%) and 36 in the CG (90%) (p < .001). The mode of delivery differed significantly between groups: women assuming castor oil showed a higher incidence of vaginal delivery, whereas the incidence of caesarean section was lower in the COG, but no statistical significance was reached. CONCLUSIONS: The use of castor oil is related to a higher probability of labour initiation within 24 hours. Castor oil can be considered a safe non-pharmacological method for labour induction.

Progestogens for Maintenance Tocolysis in Women With a Short Cervix: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy of progestogens for maintenance tocolysis in women undelivered after their first preterm labor episode. METHODS: Women with singleton pregnancies between 22 0/7 and 31 6/7 weeks of gestation with arrested preterm labor and a cervical length 25 mm or less at hospital discharge were eligible. Patients with a previous preterm birth were excluded. In a randomized controlled trial conducted in five university hospitals, women were randomized to receive vaginal progesterone (200 mg per day) or intramuscular 17α-hydroxyprogesterone caproate (341 mg per week) or to an observation groups (control group). The primary outcome was the proportion of women with preterm birth at less than 37 weeks of gestation. A sample size of 160 per group (n=480) was planned to compare vaginal progesterone and 17α-hydroxyprogesterone caproate groups with those in the control group. The sample size estimation was based on the hypothesis that the risk of experiencing preterm birth in the control group would be 30% and that 17α-hydroxyprogesterone caproate or progesterone would decrease this risk to 15%. A P value of <.025 was defined as statistically significant. At planned interim analysis (n=254), the trial was stopped for futility. RESULTS: Between July 2010 and June 2015, 257 women were eligible and 254 were subsequently randomly assigned to vaginal progesterone (n=86), 17α-hydroxyprogesterone caproate (n=87), or observation (n=81). Nineteen (8%) were excluded from the analysis because they either dropped out or information was missing, leaving 235 women available for analysis. Demographic characteristics were similar across groups. The preterm birth rate did not differ significantly between groups: 23% in the 17α-hydroxyprogesterone caproate group, 39% in the vaginal progesterone group, and 22% in the women in the control group (P=.949 for 17α-hydroxyprogesterone caproate compared with the women in the control group and P=.027 for vaginal progesterone compared with women in the control group). CONCLUSION: The use of progestogens for maintenance tocolysis in women with a short cervix did not reduce the rate of preterm birth. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01178788.

Vaginal alpha-lipoic acid shows an anti-inflammatory effect on the cervix, preventing its shortening after primary tocolysis. A pilot, randomized, placebo-controlled study.

INTRODUCTION: Inflammation might be an important underlying cause of preterm birth. Our aim is to explore whether vaginal administration α-lipoic acid reduces cervical inflammation and shortening after primary tocolysis. MATERIALS AND METHODS: Singleton pregnancies between 24-30 weeks remaining undelivered after hospitalization for preterm labor were randomly allocated to placebo (20 women, 15 analyzed) or vaginal ALA 400 mg (active ingredient 10 mg) daily (20 women, 17 analyzed) for 30 days. A cervical swab to quantify pro-inflammatory (IL1, IL2, IL6, IL8, TNFα) and anti-inflammatory (IL4, IL10) cytokines as well as transvaginal ultrasound cervical length measurement (CL) were performed before and after treatment. RESULTS: The % changes of pro-inflammatory cytokines do not differ between treatment groups, while IL4 significantly increases by vaginal ALA in comparison to placebo (118.0 ± 364.3% versus 29.9 ± 103.5%, p = 0.012). Combined anti-inflammatory cytokines show same trend (292.5 ± 208.5% versus 64.5 ± 107.4, p = 0.03). CL remains similar in vaginal ALA group (from 23.1 ± 6.6 to 20.80 ± 7.9 mm), while it significantly decreased in placebo group (from 20.4 ± 6.5 to 13.8 ± 7.5 mm, p < 0.001 versus Baseline; p = 0.003 versus vaginal ALA). CONCLUSION: Vaginal ALA significantly stimulates anti-inflammatory ILs in the cervix of undelivered women after a preterm labor episode. This effect is associated with a stabilization of the CL.

The l-arginine/nitric oxide pathway is impaired in overweight/obese pregnant women.

OBJECTIVE: To evaluate the l-arginine/NO system and its role in insulin signaling and endothelial function during the pregnancy of women of different BMI categories. STUDY DESIGN: Twelve women with BMI⩾25 were compared with 10 normal-weight women in a fasting condition after the infusion of l-arginine (20g in 3h) and after the evaluation of the flow-mediated vasodilation (FMD) of the brachial artery between the 9th-12th and 24th-27th weeks. Blood samples for insulin and nitrite/nitrate (NOx) were collected at baseline and after 1, 2 and 3h after initiating the infusion. RESULTS: In both trimesters, the baseline NOx levels were similar among groups. In the 1st trimester of the lean women, there was a NOx increase in response to l-Arg (AUC: 1328; 3, 3173), which had increased by the 2nd trimester (AUC: 3884; 1905, 7686); in overweight/obese women, no responses to l-Arg were found in the 1st or 2nd trimesters. In the 1st trimester, the insulin levels were significantly reduced in both groups after l-Arg infusion. Although the insulin levels in all BMI categories were higher in the 2nd trimester, such levels during weeks 24-27 were suppressed only in normal-weight women after l-Arg infusion. The FMD was higher during both trimesters in the lean controls and was impaired in the overweight/obese subjects. CONCLUSIONS: NO availability is impaired in overweight/obese women during pregnancy, which affects endothelial functioning and interferes with insulin regulation. These mechanisms could be involved in the development of hypertensive disorders and glucose intolerance in this population.