Gestational Diabetes Risk and Low Birth Weight After Metabolic Bariatric Surgery: a Complex Interplay to be Balanced.

INTRODUCTION: Metabolic bariatric surgery (MBS) is known to improve the obstetric outcomes of women with obesity and to prevent gestational diabetes (GD). To what extent does MBS decreases GD, without incurring at additional risks is a matter of concern. METHODS: A retrospective case-control study to compare the pregnancy outcomes of women previously submitted to MBS to those of age and preconception body mass index (PC BMI) matched non-operated controls. RESULTS: Pregnancies of women after MBS (n = 79) and matched controls (n = 79) were included. GD was significantly less frequent after MBS (7.6% vs. 19%; p = 0.03). Fasting blood glucose (76.90 ± 0.77 vs 80.37 ± 1.15 mg/dl, p < 0.05; 70.08 ± 1.34 vs. 76.35 ± 0.95 mg/dl; p < 0.05, first and second trimesters respectively) and birth weight (2953.67 ± 489.51 g vs. 3229.11 ± 476.21 g; p < 0.01) were significantly lower after MBS when compared to controls. The occurrence of small-for-gestational-age (SGA) was more frequent after MBS (22.8% vs. 6.3%; p < 0.01), but no longer significant after controlling for smoking habits (15.5% vs. 6%, p = 0.14). There were no significant differences in gestational weight gain, prematurity rate nor mode of delivery between groups. CONCLUSION: MBS was associated with a lower prevalence of GD than observed in non-operated women with the same age and BMI. After controlling for smoking, this occurred at the expense of a lower birth weight. Our data reinforces the hypothesis that MBS has body weight independent effects on glucose kinetics during pregnancy with distinctive impacts for mother and offspring, which need to be balanced.

Influence of preconception body mass index on perinatal outcomes after metabolic and bariatric surgery.

INTRODUCTION: Metabolic and bariatric surgery (MBS) is a very effective weight loss intervention, although does not invariably reverses the obesity status. Our aim was to evaluate whether despite successful weight loss after MBS, persistence of obesity at time of conception still carries additional risks of adverse perinatal pregnancy outcomes. METHODS: Retrospective study comparing pregnancy outcomes of women previously submitted to MBS with a preconception (PC) body mass index BMI < 30 kg/m2 or PC BMI ≥ 30 kg/m2. RESULTS: Eighty pregnancies (n = 80) were included, 49 from women with a PC BMI < 30 kg/m2 and 31 with a PC BMI ≥ 30 kg/m2. Gestational weight gain was significantly lower (9.72 ± 7.10 vs. 13.81 ± 7.16 respectively; p = 0.01) and neonatal intensive care unit admissions were significantly higher (5% vs. 0% respectively; p = 0.02) in women with PC BMI ≥ 30 kg/m2 as compared to those with PC BMI < 30 kg/m2. There were no statistically significant differences in gestational diabetes, anemia, fetal growth restriction, prematurity rate, mode of delivery or birth weight between groups. CONCLUSION: Perinatal outcomes of pregnancies after MBS may be significantly influenced by PC BMI. The benefits of MBS induced weight loss on obesity-associated adverse pregnancy outcomes can be maximized if the obesity status can be reverted before pregnancy.

Management of Buerger's disease during pregnancy.

Buerger's disease (BD), also known as thromboangiitis obliterans, is a non-atherosclerotic inflammatory disorder of unknown aetiology that affects small-sized and medium-sized vessels of the extremities. It is usually observed in middle-aged adults, especially those who smoke or use tobacco products. This condition is more frequently observed in men, although recent findings indicate an increasing prevalence among women, potentially due to increased cigarette use. The association between pregnancy and BD is rare, with only a few published cases. Previous reports have indicated that BD may worsen during gestation due to the characteristic hypercoagulable state of pregnancy. In addition, it seems to be associated with intrauterine growth restriction secondary to infarction of placental vessels. Careful obstetric management of maternal and fetal status is mandatory in pregnancies complicated with BD. We report a successful case of a pregnancy in a patient with BD treated with low-molecular-weight heparin.

Th17 / Treg ratio: A prospective study in a group of pregnant women with preeclampsia and fetal growth restriction.

INTRODUCTION: During pregnancy, the maternal immune system is challenged to tolerate a semi-allogenic fetus. A proinflammatory profile has been linked to adverse pregnancy outcomes and poor placental development. In this study, the authors evaluated the number of circulating Tregs and Th17 cells in a group of patients diagnosed with preeclampsia(PE) and fetal growth restriction(FGR). METHODS: Prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed in a cohort of pregnant patients with PE, FGR, and a control group of healthy pregnant women. RESULTS: The diagnosis of PE was associated with a significative higher number of circulating Th17 cells and a significative relative reduction in the Treg cell count. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4+CD25highFOXP3+ Treg ratio. In the FGR group, the Th17 cell count was significantly higher during the third trimester of pregnancy. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4+CD25highFOXP3+ Treg ratio. When we compare the immunological profiles of patients with PE and FGR we observed a higher number of proinflammatory Th17 cells and a significative lower number of Treg cells in PE patients. This is particularly expressed in the differences found between the Th17/ CD4+CD25highFOXP3+ Treg ratios of these two groups. Discussion/Conclusion Our data showed a that a proinflammatory profile and a relative excess of Th17 cells was associated with the diagnosis of PE and FGR. A more exuberant systemic proinflammatory profile present in the PE patients is absent in patients with FGR without preeclampsia.

Perinatal depression and mental health uptake referral rate in an obstetric service.

Perinatal depression is an important indicator of mothers' mental health. Studies have been carried out to identify and characterize women at risk of such affective disorder. The aim of this study is to assess mothers' adherence to our perinatal depression screening and eventual follow-up by a multidisciplinary team, including mental health and obstetrics professionals. Ultimately, a risk profile for the uptake rate of referral was described to psychological support. Pregnant women from a maternity of a tertiary center with on-site assessment and treatment (n = 2163) were included in this study. The identification of women at risk for depression was based on a two-question screening and the EPDS scale. Demographic and obstetric data were obtained from medical records. The number of screening evaluations, the uptake referral rate and the compliance to treatment were analyzed. Logistic regression was used to predict a risk profile for adherence. Among 2163 enrolled in the protocol, 10.2% screened positive for depression. Of these, 51.8% accepted referral for mental health assistance. 74.9% were compliant to Psychology appointments and 74.1% to Psychiatry appointments. Women who had a previous history of depression were more likely to accept referral for mental health support. With this study, we were able to understand the behaviour of this population towards the screening protocol we offer. Women with a previous history of depression are more likely to accept mental health assistance.

The endocannabinoidome in human placenta: Possible contribution to the pathogenesis of preeclampsia.

Preeclampsia (PE) was first reported thousands of years ago, yet there is still a shortage of biomarkers to determine the severity and type of PE. The importance of the expanded endocannabinoid system, or endocannabinoidome (eCBome), has emerged recently in placental physiology and pathology, though the potential alterations of the eCBome in PE have not been fully explored. Analysis by qRT-PCR using placental samples of normotensive and PE women demonstrate for the first time the presence of ABHD4, GDE1, and DAGLß in both normotensive and PE placental tissues. Interestingly, NAPE-PLD, FAAH-1, DAGLα, MAGL, and ABHD6 mRNA levels were increased in the placental tissues of PE patients. Quantification in plasma and placental tissues showed a decrease for anandamide (AEA), N-oleoylethanolamine (OEA), and N-docosahexaenoylethanolamine (DHEA) in the placenta, accompanied only by a decrease in plasma levels of AEA. In addition, a strong negative correlation was obtained between OEA and the biomarker of PE, soluble fms-like tyrosine kinase-1. Given the inflammatory nature of PE and the anti-inflammatory role of OEA and DHEA, the decrease in the local levels of these mediators may underlie the inflammatory component of this pathology. Additionally, lower AEA levels in both placenta and plasma may contribute to the atypical alterations of the spiral arteries in PE due to the vasorelaxation effects of AEA. These results add new information to the role of the eCBome members in placental development, while also pointing to a potential role as biomarkers of PE.

Sjögren's syndrome and pregnancy: a Portuguese case-control study.

Introduction: Pregnancy in patients with autoimmune disorders is associated with an increased risk of adverse outcomes. Sjögren's syndrome (SS) is one of the most common among autoimmune diseases. Presently data regarding the impact of SS on obstetric outcomes are scarce and inconclusive. This study aims to evaluate the impact of SS on maternal-fetal and neonatal outcomes compared with pregnancy outcomes in the general population. Material and methods: A retrospective case-control study included 26 pregnancies in SS patients and a healthy control group (CG), followed in a Portuguese tertiary center, between 2015 and 2020. Baseline maternal data were collected, and maternal-fetal and neonatal outcomes were evaluated. Statistical analysis used SPSS 25.0, and a p-value of 0.05 was considered statistically significant. Results: All pregnancies occurred after the diagnosis of SS, with a mean exposure time between diagnosis and pregnancy of 4.92 ±2.78 years. In the SS group, the incidence of ANA, anti-Ro/SSA, and anti-La/SSB antibodies positivity was 80.8%, 61.5%, and 46.2%, respectively. Hydroxychloroquine (HCQ) was used in 57.7%.Miscarriage was significantly higher in the SS group (19.2% vs. 1.8%, p < 0.01). There was a higher prevalence of fetal growth restriction (OR 11.16, 95% CI: 0.96-129.26). Preterm delivery (9.5% vs. 5.6%, p = 0.503) and mean birth weight (2998.16 g vs. 3155.79 g, p = 0.178) did not differ significantly between the groups. In the SS group, admission to the neonatal intensive care unit (NICU) rate was increased (OR 71.67, 95% CI: 3.78-1357.16). Three pregnancies were complicated by congenital heart block (CHB) (14.3% vs. 0%, p = 0.015). In all cases, the diagnosis was performed during second trimester of pregnancy, and betamethasone was administered. Conclusions: Women with SS had a significantly higher incidence of miscarriage, admission to NICU, and CHB than controls. Congenital heart block was the most critical condition that affects the offspring of mothers with SS. Successful pregnancy in the study group was possible with prenatal monitoring and a multidisciplinary approach.

Pregnancy in kidney transplantation women: perinatal outcomes and impact on kidney function.

OBJECTIVES: This study aimed to evaluate maternal and perinatal outcomes in pregnancies after kidney transplant (KT) and the impact of pregnancy on graft function. METHODS: A descriptive and retrospective case-control study included 43 pregnancies in women after KT, followed in our institution, from January 1991 to December 2019. The control group included 200 non-transplanted pregnant women. Statistical analysis used SPSS 25.0 (SPSS Inc., Chicago, IL), and a p value of .05 was considered statistically significant. RESULTS: We studied 43 pregnancies in 37 KT women. The live birth rate of KT pregnant was 81.4%. The mean interval between transplantation and pregnancy was 4.6 years (range 1-16). We found a higher rate of obstetric complications in pregnancies after KT: miscarriage (14.0%, OR 6.7 (2.0-22.1), p < .001), preeclampsia (31.4%, OR 25.7 (7.7-85.3), p < .001), and fetal growth restriction (37.1%, OR 37.6 (9.9-142.3), p < .001). The rate of urogenital infections and anemia during pregnancy was higher in the KT group (p < .001). The gestational age at delivery was 35.0 ± 2.8 weeks and premature delivery was observed in 24 (68.6%) cases. The cesarean rate was higher in the KT group (p < .001). In the KT group, there were two neonatal deaths due to prematurity complications. Renal function deterioration, measured by serum creatinine levels, was observed in two pregnancies. Immunosuppressive therapy was used in all pregnancies after KT, and dosage escalation of immunosuppressive therapy was necessary for 69.8%. CONCLUSIONS: A higher rate of adverse obstetric outcomes was found in KT pregnant. Kidney function remained stable in most pregnancies. An antenatal and postpartum multidisciplinary approach is essential to improve outcomes and minimization of complications.

The dynamics of Th17 / Treg ratio in SLE patients during pregnancy.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder that affects women at childbearing age. During pregnancy, maternal immune system is challenged to tolerate a semi-allogenic fetus and a shift toward a tolerogenic profile is essential. Failure to develop this tolerogenic profile seems to be associated with the development of adverse obstetric outcomes. We conducted a prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed during pregnancy in a group of SLE patients and compared with healthy gestations. We observed a reduction in peripheric Treg cell count throughout all pregnancy in control patients, which was not observed in SLE patients. In contrast, the Th17 cell count remained stable in both groups. In the control group, the Treg/Th17 ratio decreased throughout pregnancy to the postpartum, which was not observed in the study group. These changes may be justified by the migration of the immunotolerant Treg cells to the maternal decidua and may lead to the establishment of a pro-inflammatory profile by the end of pregnancy in healthy pregnancies, which was not observed in the SLE pregnant patients. This pro-inflammatory state at the end of a healthy pregnancy may be necessary for the spontaneous beginning of labor and help to explain why systemic syndromes like preeclampsia develop during the second half of pregnancy. The lack of these findings in SLE patients may express a pro-inflammatory state from the beginning of pregnancy, the influence of immunomodulatory medication or an intrinsic deregulation of immune function, which is a characteristic of these patients.

Symptomatic haemophilia A: management during pregnancy and the postpartum period.

As an X linked disorder, the presence of severe symptomatic haemophilia A is an extremely rare disorder in women. Therefore there are no high-level evidence-based guidelines when it comes to pregnancy. Although there have been advances in the fields of prenatal counselling and maternal-fetal care, the management of these gestations continues to embody a challenge for any medical team. We report the successful management of a pregnant woman with symptomatic haemophilia A, from pregnancy to the postpartum period. Our aim is to enhance knowledge on this topic, and further improve outcomes for these mothers and their offspring.

Uterine Compression Sutures in Controlling Postpartum Haemorrhage: A Narrative Review.

INTRODUCTION: Postpartum haemorrhage is still the main cause of maternal morbidity and mortality. Many treatments are available, but they may threaten fertility potential. As a uterine sparing procedure, we aimed to review uterine compression sutures in order to better understand when they should represent an appropriate option. MATERIAL AND METHODS: A comprehensive search in MEDLINE and PubMed databases including the terms 'postpartum haemorrhage' and 'uterine compression sutures' was performed. Results were revised and articles reviewing or presenting case reports of uterine compression sutures to treat postpartum haemorrhage were included. RESULTS: The first description of uterine compression sutures to control postpartum haemorrhage was published in 1997, by B-Lynch et al. After this publication, many others have reported successful management of postpartum haemorrhage with different suturing techniques. Most of them describe success rates above 75% and the possibility of fertility preservation, with cases of uneventful pregnancy after uterine compression sutures already published. Complications associated with each technique are rare. DISCUSSION: Reports of use of uterine compression sutures include small series of cases or even single case reports which limits the quality of existing evidence to support one technique over another. Nevertheless, uterine compression sutures are recognized as an effective surgical conservative strategy to control postpartum haemorrhage due to uterine atony and its use is recommended, if possible, prior to hysterectomy. CONCLUSION: Uterine compression sutures are effective, safe and simple to perform in an emergent situation and preserve fertility potential in cases of postpartum haemorrhage.

Introdução: A hemorragia pós-parto é a principal causa de morbimortalidade materna. Apesar dos tratamentos disponíveis, o potencial fértil da mulher pode ser colocado em causa. As suturas uterinas de compressão representam uma terapêutica conservadora do útero. Assim, revimos os tipos de suturas uterinas de compressão para compreender quando devem ser uma opção terapêutica. Material e Métodos: Foi realizada pesquisa na MEDLINE e PubMed com os termos 'postpartum haemorrhage' e 'uterine compression sutures' separados e em conjunto. Os resultados foram revistos e os artigos de revisão ou descrevendo casos clínicos de suturas uterinas de compressão foram selecionados. Resultados: Em 1997, B-Lynch et al descreveu pela primeira vez as suturas uterinas de compressão para tratamento da hemorragia pós-parto. Desde aí, publicações de diferentes tipos de suturas uterinas de compressão, com registo de casos bem-sucedidos, têm sido publicadas. A maioria reporta taxas de sucesso acima de 75%, com preservação da fertilidade, existindo vários casos de bom desfecho obstétrico posteriormente descritos. As complicações associadas são raras. Discussão: A evidência acerca do uso de suturas uterinas de compressão é limitada pela qualidade dos artigos existentes que incluem apenas pequenas séries de casos ou descrições de casos isolados. Apesar disso, tem sido reconhecido o seu potencial enquanto estratégia conservadora no controlo da hemorragia pós-parto devido a atonia uterina, sendo recomendado o seu uso, se possível, antes de realizar histerectomia. Conclusão: Em situações de hemorragia pós-parto, as suturas uterinas de compressão são eficazes, seguras e simples de realizar, preservando o potencial reprodutivo.

Systemic Lupus Erythematosus and Pregnancy: a Portuguese Case-Control Study.

Pregnancy in systemic lupus erythematosus (SLE) patients is associated with an increased risk of adverse outcomes. During pregnancy, SLE patients have a higher rate of miscarriage, stillbirth, preterm delivery, fetal growth restriction, or hypertensive disorders of pregnancy. To date, only a few case-control studies were published with the purpose to evaluate the magnitude of risk associated with pregnancy in lupus patients. The aim of our study was to evaluate the maternal and fetal outcomes in a cohort of Portuguese SLE patients and to compare it with a group of healthy pregnant women. We conducted a retrospective case-control study that included all pregnant women with SLE managed at a Portuguese tertiary center, between 2010 and 2019. Pregnancy outcomes were compared between SLE patients and a group of matched healthy pregnant women. Baseline maternal data was collected, and maternal-fetal and neonatal outcomes were evaluated. One hundred twenty-four SLE pregnancies were included. Of the patients, 95.2% were in remission at conception. In 13.7% of cases, a lupus flare was diagnosed during gestation and in 17.9% in the postpartum period. The live birth rate was 84.6%, and the incidence of adverse outcomes was 40.3% (OR 2.64, 95% CI 1.67-4.18). Considering only patients in remission at conception, the presence of adverse outcomes remained significantly higher (36.8% vs. 20.3%, P < 0.01). Miscarriage rate was 15.3% (OR 5.85, 95% CI 2.57-13.34) and preterm delivery occurred in 12.4% of the patients (OR 1.72, 95% CI 0.83-3.57). Preeclampsia prevalence was higher in SLE patients (OR 3.92, 95% CI 1.32-11.57). In the SLE group, the newborn admission to an intensive care unit rate was increased (OR 4.99, 95% CI 1.47-16.90). No neonatal or maternal deaths were reported. In our study, pregnancy with SLE was associated with an increased incidence of adverse outcomes, even in a population of SLE patients with well-controlled disease.

Behçet's Disease and Pregnancy: A Retrospective Case-control Study.

Background: Behçet's disease (BD) is a rare chronic multisystemic vasculitis of unknown etiology. It is usually diagnosed between the 2nd and 4th decades of life, so its association with pregnancy is not unusual. This study aims to characterize the evolution of pregnancy in a group of pregnant women with BD and the impact of this pathology in embryo-fetal morbidity. Methods: A retrospective case-control study included 49 pregnancies in women suffering from BD, followed in our institution. Pregnancy outcomes were compared with a control group of healthy pregnant women. Two controls per case were randomly selected. Statistical analysis used SPSS 25.0, and a p-value of 0.05 was considered statistically significant. Results: Forty-nine pregnancies were included in 27 patients with BD. BD exacerbation occurred in 32.6% of the pregnancies. There were no significant statistical differences between the two groups regarding the rate of preterm delivery, gestational diabetes, and preeclampsia (p>0.05). In the BD group, we found a higher rate of miscarriage (24.5%) and fetal growth restriction (FGR, 13.3%, p<0.05). In the study group, 13 (32.5%) of the pregnant patients did not need treatment. The cesarean rate was significantly higher in the BD group (43.2% vs 20.4% in the control group, p<0.05), and there were no significant differences in median gestational age at the time of delivery (p>0.05). The birth weight of newborns did not differ significantly between the groups. There was no association of BD with maternal morbidity and neonatal complications. Conclusion: In this study, the majority of pregnant with BD did not present clinical exacerbation of their pathology. However, BD may have an adverse influence on pregnancy outcomes. FGR and miscarriage rates were significantly higher in the study group.

Systemic lupus erythematosus and pregnancy: A retrospective single-center study of 215 pregnancies from Portugal.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a life-threatening disorder that affects women at reproductive age. We evaluate the clinical impact of pregnancy in a cohort of Portuguese SLE patients and the risk factors associated with maternal and fetal adverse outcomes. METHODS: A retrospective observational study that included all pregnant women with SLE managed at a Portuguese tertiary hospital, between January 1993 and December 2019. Baseline maternal information was collected, and maternal-fetal and neonatal outcomes were evaluated. Disease activity before and during pregnancy was assessed. RESULTS: We included 215 pregnancies from 143 patients. Lupus nephritis was present in 20.0% and antiphospholipid syndrome (APS) in 21.9% of the cases. Preconception consultation was performed in 86.9% of the pregnancies, and 92.5% of the patients had no or low disease activity at conception. During gestation, 79.6% of the patients were under treatment, and hydroxychloroquine (HCQ) was the most commonly used drug (63.7%). Low-dose acetylsalicylic acid (ASA) was prescribed at conception in 87.9% of the patients. The live birth rate was 84.2%. An adverse pregnancy outcome (APO) occurred in 41.4% of the pregnancies. A miscarriage rate of 15.3% and a preterm delivery rate of 15.4% were found. Preeclampsia and fetal growth restriction complicated 13.1% and 14.0% of the gestations, respectively. Neonatal lupus occurred in 7.1% of the newborns, and there were 2 cases of congenital heart block. Significant risk factors for the development of AOP were disease activity at conception, lupus flare, hypocomplementemia, positivity for lupus anticoagulant, and APS. The use of ASA was significantly associated with a reduced incidence of miscarriage. An SLE flare was diagnosed in 16.3% of the cases. We identified as risk factors for lupus flares the presence of active disease at conception, a previous history of lupus nephritis, and the use of chronic medication. HCQ use during pregnancy was associated with a significant reduction of flare incidence during pregnancy and postpartum. CONCLUSIONS: Pregnancy in an SLE patient is associated with an increased incidence of adverse obstetric outcomes. Good disease control before pregnancy and adequate treatment, especially with HCQ, is crucial to achieving the best obstetric results.

Severe polyhydramnios as neonatal presentation of Bartter's syndrome type IV / Polihidrâmnios grave como manifestação neonatal da síndrome de Bartter tipo IV

Abstract Introduction: Bartter's syndrome comprises a heterogeneous group of inherited salt-losing tubulopathies. There are two forms of clinical presentation: classical and neonatal, the most severe type. Types I and II account for most of the neonatal cases. Types III and V are usually less severe. Characteristically Bartter's syndrome type IV is a saltlosing nephropathy with mild to severe neonatal symptoms, with a specific feature - sensorineural deafness. Bartter's syndrome type IV is the least common of all recessive types of the disease. Description: the first reported case of a Portuguese child with neurosensorial deafness, polyuria, polydipsia and failure to thrive, born prematurely due to severe polyhydramnios, with the G47R mutation in the BSND gene that causes Bartter's syndrome type IV. Discussion: there are few published cases of BS type IV due to this mutation and those reported mostly have moderate clinical manifestations which begin later in life. The poor phenotype-genotype relationship combined with the rarity of this syndrome usually precludes an antenatal diagnosis. In the presence of a severe polyhydramnios case, with no fetal malformation detected, normal karyotype and after maternal disease exclusion, autosomal recessive diseases, including tubulopathies, should always be suspected.

Resumo Introdução: a síndrome de Bartter inclui um grupo heterogéneo de tubulopatias hereditárias perdedoras de sal. Existem duas formas de apresentação clínica: clássica e neonatal, a forma mais grave. Os tipo I e II representam a maioria dos casos neonatais. Os tipos III e V são geralmente menos graves. Caracteristicamente, a síndrome de Bartter tipo IV é uma nefropatia perdedora de sal com sintomas neonatais ligeiros a graves, com um aspeto especí- fico - surdez neurossensorial. A síndrome de Bartter tipo IV é o tipo menos comum das formas recessivas da doença. Descrição: relatamos o primeiro caso de uma criança portuguesa, com surdez neurossensorial, poliúria, polidipsia e restrição de crescimento, nascida prematuramente devido a polihidrâmnios grave, homozigótica para a mutação G47R do gene BSND, responsável pela síndrome de Bartter tipo IV. Discussão: são raros os casos publicados sobre síndrome de Bartter tipo IV atribuída a esta mutação, e a maioria referem-se a diagnósticos mais tardios, com manifestações clínicas ligeiras. A fraca correlação fenótipo-genótipo combinada com a raridade desta síndrome tornam o diagnóstico pré-natal desafiante. Perante um caso de polihidrâmnios grave em um feto sem malformações aparentes, cariótipo normal e após exclusão de patologia materna, as doenças autossómicas recessivas, incluindo as tubulopatias, devem ser sempre consideradas.

Impact of tetrahydrocannabinol on the endocannabinoid 2-arachidonoylglycerol metabolism: ABHD6 and ABHD12 as novel players in human placenta.

Cannabis use has been increasing worldwide for recreational and medical purposes. Consumption by pregnant women is associated with disturbances in pregnancy outcome, such as low birth weight, prematurity and intrauterine growth retardation, though the underlying biochemical mechanisms are unknown. The endocannabinoid system is involved in several reproductive events and the disruption of its homeostasis by ∆9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid, may lead to a negative gestational outcome. In human placenta, THC impairs the levels of the endocannabinoid anandamide (AEA). The other major endocannabinoid, 2-arachidonoylglycerol (2-AG) also plays an important role on proper placentation and pregnancy success. However, THC impact on 2-AG homeostasis has never been addressed. Hence, the effects of THC in 2-AG levels and metabolic enzymes expression were explored. Long-term treatment impairs the expression of the main 2-AG synthetic and degradative enzymes. Curiously, with the highest concentration, despite the maintenance of diacylglycerol lipase alpha (DAGLα) and the decrease in monoacylglycerol lipase (MAGL) expression, 2-AG levels remain constant. Given the endocannabinoid signalling local tight regulation, we hypothesize the involvement of other 2-AG degradative enzymes. Indeed, THC increases the expression of the hydrolyzing enzymes alpha beta hydrolase domain-6 (ABHD6) and -12 (ABHD12), that we firstly describe in human placental tissues. The results show that THC, depending on time of exposure, induces alterations in 2-AG metabolic enzymes expression in placental explants, highlighting the importance of 2-AG regulation and endocannabinoid signalling in placental development. Alterations in this homeostasis may explain the negative pregnancy outcome related to cannabis consumption.

The Cannabinoid Delta-9-tetrahydrocannabinol Disrupts Estrogen Signaling in Human Placenta.

Cannabis consumption is increasing worldwide either for recreational or medical purposes. Its use during gestation is associated with negative pregnancy outcomes such as, intrauterine growth restriction, preterm birth, low birth weight, and increased risk of miscarriage, though the underlying molecular mechanisms are unknown. Cannabis sativa main psychoactive compound, Δ9-tetrahydrocannabinol (THC) is highly lipophilic, and as such, readily crosses the placenta. Consequently, THC may alter normal placental development and function. Here, we hypothesize alterations of placental steroidogenesis caused by THC exposure. The impact on placental estrogenic signaling was examined by studying THC effects upon the enzyme involved in estrogens production, aromatase and on estrogen receptor α (ERα), using placental explants, and the cytotrophoblast cell model BeWo. Aromatase expression was upregulated by THC, being this effect potentiated by estradiol. THC also increased ERα expression. Actions on aromatase were ERα-mediated, as were abolished by the selective ER downregulator ICI-182780 and dependent on the cannabinoid receptor CB1 activation. Furthermore, the presence of the aromatase inhibitor Exemestane did not affect THC-induced increase in ERα expression. However, THC effects on ERα levels were reversed by the antagonists of CB1 and CB2 receptors AM281 and AM630, respectively. Thus, we demonstrate major alterations in estrogen signaling caused by THC, providing new insight on how cannabis consumption leads to negative pregnancy outcomes, likely through placental endocrine alterations. Data presented in this study, together with our recently reported evidence on THC disruption of placental endocannabinoid homeostasis, represent a step forward into a deeper comprehension of the puzzling actions of THC.

The endocannabinoid 2-arachidonoylglycerol promotes endoplasmic reticulum stress in placental cells.

Proliferation, differentiation and apoptosis of trophoblast cells are required for normal placental development. Impairment of those processes may lead to pregnancy-related diseases. Disruption of endoplasmic reticulum (ER) homeostasis has been associated with several reproductive pathologies including recurrent pregnancy loss and preeclampsia. In the unfolded protein response (UPR), specific ER-stress signalling pathways are activated to restore ER homeostasis, but if the adaptive response fails, apoptosis is triggered. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and Activating transcription factor 6 (ATF6) are central players in UPR and in ER-stress-induced apoptosis, as well as downstream transcription factors, as C/EBP homologous protein (CHOP). Our previous studies have shown that the endocannabinoid 2-arachidonoylglycerol (2-AG) modulates trophoblast cell turnover. Nevertheless, the role of ER-stress on 2-AG induced apoptosis and cannabinoid signalling in trophoblast has never been addressed. In this work, we used BeWo cells and human primary cytotrophoblasts isolated from term-placenta. The expression of ER-stress markers was analysed by qRT-PCR and Western blotting. ROS generation was assessed by fluorometric methods, while apoptosis was detected by the evaluation of caspase -3/-7 activities and Poly (ADP-ribose) polymerase (PARP) cleavage. Our findings indicate that 2-AG is able to induce ER-stress and apoptosis. Moreover, the eukaryotic initiation factor 2 (eIF2α)/CHOP pathway involved in ER-stress-induced apoptosis is triggered through a mechanism dependent on cannabinoid receptor CB2 activation. The results bring novel insights on the importance of ER-stress and cannabinoid signalling on 2-AG mechanisms of action in placenta.

Association between contraceptive method chosen after induced abortion and incidence of repeat abortion in Northern Portugal.

OBJECTIVES: In Portugal, a country with strong Catholic roots, elective termination of pregnancy at women's request is still stigmatised, especially if it is a repeat abortion. The objectives of this study were to determine the incidence of repeat abortion, taking into account the contraceptive method chosen after the index abortion event, and characterise the risk factors for repeat abortion. METHODS: This was a retrospective cohort study of 988 women who requested termination of pregnancy during 2015 in a Portuguese tertiary care public hospital. Contraception was given free of charge after the index event. The occurrence of a repeat induced abortion was evaluated during a 24 month follow-up period. RESULTS: Forty-nine (5.0%) of the 988 women had a repeat abortion. Users of long-acting reversible contraception (LARC) had fewer repeat abortions compared with users of non-LARC methods. Overall repeat abortion was 0.8% in subcutaneous contraceptive implant users, 1.5% in intrauterine contraceptive device (IUCD) users, 2.8% in vaginal ring users and 5.8% in oral contraceptives users (p < 0.05). Cox hazards ratio (HR) analysis showed that method choice after abortion correlated significantly with the probability of repeat abortion (p < 0.05). Using women choosing oral contraception as the reference group, the HRs (95% CIs) for repeat abortion were as follows: IUCD 0.282 (0.084, 0.942), contraceptive implant 0.142 (0.019, 1.050), vaginal ring 0.508 (0.175, 1.477). CONCLUSION: Even though highly effective contraceptive methods are freely accessible in Portugal, other challenges must be managed to improve outcomes, such as a timely, patient-centred counselling approach.