Maternal Hemodynamics from Preconception to Delivery: Research and Potential Diagnostic and Therapeutic Implications: Position Statement by Italian Association of Pre-Eclampsia and Italian Society of Perinatal Medicine.

OBJECTIVE: The Italian Association of Preeclampsia (AIPE) and the Italian Society of Perinatal Medicine (SIMP) developed clinical questions on maternal hemodynamics state of the art. STUDY DESIGN: AIPE and SIMP experts were divided in small groups and were invited to propose an overview of the existing literature on specific topics related to the clinical questions proposed, developing, wherever possible, clinical and/or research recommendations based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale were submitted to 8th AIPE and SIMP Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. RESULTS: More and more evidence in literature underlines the relationship between maternal and fetal hemodynamics, as well as the relationship between maternal cardiovascular profile and fetal-maternal adverse outcomes such as fetal growth restriction and hypertensive disorders of pregnancy. Experts agreed on proposing a classification of pregnancy hypertension, complications, and cardiovascular states based on three different hemodynamic profiles depending on total peripheral vascular resistance values: hypodynamic (>1,300 dynes·s·cm-5), normo-dynamic, and hyperdynamic (<800 dynes·s·cm-5) circulation. This differentiation implies different therapeutical strategies, based drugs' characteristics, and maternal cardiovascular profile. Finally, the cardiovascular characteristics of the women may be useful for a rational approach to an appropriate follow-up, due to the increased cardiovascular risk later in life. CONCLUSION: Although the evidence might not be conclusive, given the lack of large randomized trials, maternal hemodynamics might have great importance in helping clinicians in understanding the pathophysiology and chose a rational treatment of patients with or at risk for pregnancy complications. KEY POINTS: · Altered maternal hemodynamics is associated to fetal growth restriction.. · Altered maternal hemodynamics is associated to complicated hypertensive disorders of pregnancy.. · Maternal hemodynamics might help choosing a rational treatment during hypertensive disorders..

Early Fetal Growth Restriction with or Without Hypertensive Disorders: a Clinical Overview.

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR.

Progesterone receptor ligands for the treatment of endometriosis.

Estrogen dependence and progesterone resistance play a crucial role in the origin and development of endometriosis. Therefore, hormonal therapies are currently the most effective treatment. Progestins are considered the first-line approach, especially for a long-term management. Progestins are synthetic compounds that mimic the effects of progesterone by binding progesterone receptors. Continuous use of progestins leads to the suppression of ovarian steroidogenesis with anovulation and low serum levels of ovarian steroids, causing endometrial pseudodecidualization. Moreover, they act by interfering on several endometriosis pathogenetic pathways, decreasing inflammation, provoking apoptosis in endometriotic cells, stimulating atrophy or regression of endometrial lesions, inhibiting angiogenesis, and decreasing expression of metalloproteinases, thus diminishing the invasiveness of endometriotic implants. Progestins are effective for pain relief and improvement of the quality of life (QoL). The side effects are limited, and the compounds are available in different formulations and routes of administration and represent, in most cases, an inexpensive treatment option. Dienogest, Medroxyprogesterone acetate and Norethisterone acetate are the labeled progestins for endometriosis, but other progestins, such as Dyhidrogesterone, Levonorgestrel and Desogestrel, have been shown to be effective in the treatment of endometriosis-associated pain. The present review aims to describe the available and emerging evidences on progestins used for the treatment of endometriosis.

Uterine Fibroids, Perceived Stress, and Menstrual Distress: a Key Role of Heavy Menstrual Bleeding.

Uterine fibroids (UFs) are the most common benign tumors in women of reproductive age, frequently associated with pain symptoms and heavy menstrual bleeding (HMB), leading to impaired quality of life. Thus, the aim of the study was to evaluate the global perception of stress and the menstrual distress in patients with UFs. A cross-sectional observational study was conducted on a group (n = 69) of fertile age women with UFs compared to age-matched controls, by administering two questionnaires: the perceived stress scale (PSS) and the Menstrual Distress Questionnaire (MEDI-Q). The PSS, MEDI-Q Total Score and 3 subscales-menstrual symptoms (MS), menstrual symptoms distress (MSD), and menstrual specificity index (MESI)-were evaluated. Patients with UFs showed higher PSS than controls (18.5 ± 5.0 vs. 13.8 ± 5.0, p < 0.001) and PSS values were very high in those with HMB, severe dysmenorrhea, and impaired social and working life. Patients with UFs also showed significantly higher score for MEDI-Q Total Score (16.51 ± 12.99 vs. 10.86 ± 12.36) (p < 0.01) as well as for the subscales MSD (2.54 ± 1.07 vs. 1.57 ± 0.98) (p < 0.001) and MESI (0.76 ± 0.30 vs 0.60 ± 0.39) (p < 0.05). The menstrual distress was associated to being uncomfortable about uterine bleeding; in fact, MEDI-Q Total Score was significantly higher in women with HMB compared to those with moderate/normal bleeding. UF characteristics (number, type, and size) did not correlate with perceived stress or menstrual distress. In conclusion, women with UFs have significantly higher levels of perceived stress and menstrual distress than controls and HMB plays a major role in determining such conditions.

Advances in targeting estrogen synthesis and receptors in patients with endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease on the background of progesterone resistance. Increased estrogen production, low estrogen metabolization, and altered estrogen receptors (ERs) expression contribute to the hyperestrogenic milieu within endometriotic lesions. Since estrogens play a crucial role in the pathogenesis of the disease, inhibition of estrogen production is one of the main targets of available and emerging drugs. AREAS COVERED: Firstly, we described the molecular alterations responsible for estrogen dependence. Secondly, we reviewed available and emerging treatments that interfere, through central (gonadotropin-releasing hormone analogs (GnRH-a), GnRH antagonists) or local mechanisms (aromatase inhibitors (AIs), inhibitors of steroid sulfatase (STS) and hydroxysteroid dehydrogenase type 1 (17ß-HSD1)), with estrogen dependence. Finally, we focused on emerging treatments targeting ERs (selective estrogen receptor modulators (SERMs), estrogen receptors agonists, and antagonists). EXPERT OPINION: Available treatments interfering with estrogen pathways exert a contraceptive effect, have hypoestrogenic side effects, and cannot prevent or definitively treat the disease. Preclinical and animal studies are focusing on emerging drugs targeting ERs in order to overcome limitations of available treatments. These treatments may represent a promising option, as they may produce a more specific inhibition of disease activity within endometriotic implants, avoiding prolonged hypoestrogenic status and limiting systemic side effects.

Perinatal outcomes of pregnant women with severe COVID-19 requiring extracorporeal membrane oxygenation (ECMO): a case series and literature review.

PURPOSE: Pregnant women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have a higher risk of hospitalization, admission to intensive care unit (ICU) and invasive ventilation, and of acute respiratory distress syndrome (ARDS). In case of ARDS and critical severe coronavirus disease 2019 (COVID-19), the use of extracorporeal membrane oxygenation (ECMO) is recommended when other respiratory support strategies (oxygen insufflation, non-invasive ventilation [NIV], invasive ventilation through an endotracheal tube) are insufficient. However, available data on ECMO in pregnant and postpartum women with critical COVID-19 are very limited. METHODS: A case series of three critically ill pregnant women who required ECMO support for COVID-19 in pregnancy and/or in the postpartum period. RESULTS: The first patient tested positive for COVID-19 during the second trimester, she developed ARDS and required ECMO for 38 days. She was discharged in good general conditions and a cesarean-section [CS] at term was performed for obstetric indication. The second patient developed COVID-19-related ARDS at 28 weeks of gestation. During ECMO, she experienced a precipitous vaginal delivery at 31 weeks and 6 days of gestation. She was discharged 1 month later in good general conditions. The third patient, an obese 43-year-old woman, tested positive at 38 weeks and 2 days of gestation. Because of the worsening of clinical condition, a CS was performed, and she underwent ECMO. 143 days after the CS, she died because of sepsis and multiple organ failure (MOF). Thrombosis, hemorrhage and infections were the main complications among our patients. Neonatal outcomes have been positive. CONCLUSION: ECMO should be considered a life-saving therapy for pregnant women with severe COVID-19.

Long-term treatment of endometriosis-related pain among women seeking hormonal contraception.

OBJECTIVE: To evaluate the different effects of a progestin-only contraceptive with desogestrel (DSG) vs combined oral contraceptives (COCs) for a first line long-term treatment of endometriosis-related pain among patients seeking hormonal contraception. METHODS: An observational retrospective cohort study was conducted in collaboration with a local outpatient clinic for endometriosis among a group of nulliparous young women (n = 216) with endometriosis-related pain and seeking contraception. The cohort was subdivided into a group (n = 73) treated as first line by DSG and another group (n = 75) treated by a COC. During the study, clinical symptoms, side effects and possible changes in OC type use were recorded. RESULTS: No significant difference was found between the two groups in terms of clinical characteristics and pain scores before treatment. After 6 months both treatments were effective in reducing endometriosis-related pain, and those treated with DSG showed lower levels of dysmenorrhea, dyspareunia and nonmenstrual pelvic pain than COCs group (p < .01). After 12 months, in DSG Group some patients (15%) switched from DSG to a COC for breakthrough bleeding, whereas in COC Group 48% of patients switched to another type of COC for reduced efficacy on pain and/or for side effects. After 3 years of OC treatment, in DSG Group 79% of patients maintained the same therapy, whereas in COC Group only 14% continued the same COC type, 37% switched to another COC and 47% to DSG. CONCLUSIONS: A progestin-only contraceptive with DSG is a valid option for long term management of endometriosis-related pain in patients seeking hormonal contraception.

Undifferentiated Connective Tissue Disease in Pregnancy: A Topic Yet to be Explored.

Undifferentiated connective tissue disease (UCTD) is characterized by signs and symptoms suggestive of a connective tissue disease (CTD), but not fulfilling criteria for a specific CTD. Although UCTD is probably the most common rheumatic disease diagnosed in pregnant women, data about disease course during pregnancy and perinatal outcomes are very limited. Compared to other CTDs, UCTD seems to have milder clinical manifestations in pregnancy. Its natural history is related to disease activity at conception. In fact, if the disease is in a state of remission or minimal activity at conception, pregnancy outcomes are generally good. On the contrary, patients who become pregnant in a moment of high disease activity and/or who have multiple antibodies positivity show an increased risk of disease flares, evolution to a definite CTD and obstetric complications, such as fetal growth restriction, preeclampsia and preterm birth. Therefore, a preconception assessment is essential in women with UCTD to evaluate maternal and fetal risks, to initiate interventions to optimize disease activity, and to adjust medications to those that are least harmful to the fetus. The aim of the present study was to review the available literature about pregnancy course, maternal and fetal outcomes and therapeutic approaches of pregnant women with UCTD.

Maternal hemodynamic changes in gestational diabetes: a prospective case-control study.

PURPOSE: The aim of the study is to compare maternal hemodynamic adaptations in gestational diabetes (GDM) versus healthy pregnancies. METHODS: A prospective case-control study was conducted, comparing 69 singleton pregnancies with GDM and 128 controls, recruited between September 2018 and April 2019 in Maternal-Fetal Medicine Unit, Careggi University Hospital, Florence, Italy. Hemodynamic assessment by UltraSonic Cardiac Output Monitor (USCOM) was performed in both groups in four gestational age intervals: 17-20 weeks (only in early GDM cases), 26-30 weeks, 32-35 weeks and 36-39 weeks. We evaluated six hemodynamic parameters comparing GDM cases versus controls: cardiac output (CO), cardiac index (CI), stroke volume (SV), total vascular resistance (TVR), inotropy index (INO) and potential to kinetic energy ratio (PKR). RESULTS: GDM group had significantly lower values of CO and SV than controls from the early third trimester (26-30 weeks) until term (p < 0.001). CI is significantly lower in GDM women already at the first evaluation (p = 0.002), whereas TVR and PKR were significantly higher in GDM (p < 0.001). GDM women showed also lower INO values than controls in all assessments. CONCLUSIONS: A hemodynamic maternal maladaptation to pregnancy can be detected in GDM women. The effect of hyperglycemia on vascular system or a poor pre-pregnancy cardiovascular (CV) reserve could explain this hemodynamic maladaptation. The abnormal CV response to pregnancy in GDM women may reveal a predisposition to develop CV disease later in life and might help in identifying patients who need a CV follow-up.

Hormonal treatments for endometriosis: The endocrine background.

Endometriosis is a benign uterine disorder characterized by menstrual pain and infertility, deeply affecting women's health. It is a chronic disease and requires a long term management. Hormonal drugs are currently the most used for the medical treatment and are based on the endocrine pathogenetic aspects. Estrogen-dependency and progesterone-resistance are the key events which cause the ectopic implantation of endometrial cells, decreasing apoptosis and increasing oxidative stress, inflammation and neuroangiogenesis. Endometriotic cells express AMH, TGF-related growth factors (inhibin, activin, follistatin) CRH and stress related peptides. Endocrine and inflammatory changes explain pain and infertility, and the systemic comorbidities described in these patients, such as autoimmune (thyroiditis, arthritis, allergies), inflammatory (gastrointestinal/urinary diseases) and mental health disorders.The hormonal treatment of endometriosis aims to block of menstruation through an inhibition of hypothalamus-pituitary-ovary axis or by causing a pseudodecidualization with consequent amenorrhea, impairing the progression of endometriotic implants. GnRH agonists and antagonists are effective on endometriosis by acting on pituitary-ovarian function. Progestins are mostly used for long term treatments (dienogest, NETA, MPA) and act on multiple sites of action. Combined oral contraceptives are also used for reducing endometriosis symptoms by inhibiting ovarian function. Clinical trials are currently going on selective progesterone receptor modulators, selective estrogen receptor modulators and aromatase inhibitors. Nowadays, all these hormonal drugs are considered the first-line treatment for women with endometriosis to improve their symptoms, to postpone surgery or to prevent post-surgical disease recurrence. This review aims to provide a comprehensive state-of-the-art on the current and future hormonal treatments for endometriosis, exploring the endocrine background of the disease.

Low Molecular Weight Heparins (LMWH) and Implications along Pregnancy: a Focus on the Placenta.

Low molecular weight heparins (LMWH) have been largely studied for their use during pregnancy. The biology and the pharmacology of these molecules are well known and may be summarized in three main mechanisms of action: anti-coagulant, anti-inflammatory, and immunomodulant. The clinical implications of these drugs during pregnancy are mainly related to their action on the placenta, because of the presence of specific molecular and cellular targets, particularly at the trophoblast-endometrial interface. As well as for the prevention and treatment of thromboembolism, LMWH have been largely investigated for the improvement of embryo implantation and for the prevention of placenta-related complications such as preeclampsia, fetal growth restriction, and intrauterine fetal death. However, data on this topic are still unclear. The present review discusses the biological features, the mechanisms of action, and the possible contribution of LMWH to the success of placentation along pregnancy, pointing out the need for future basic science and clinical researches in this important field with the final aim to improve clinical practice in high-risk pregnancies.

Fetal nondiabetic-macrosomia: risk factors for pregnancy adverse outcome and comparison of two growth curves in the prediction of cesarean section.

BACKGROUND: Randomized trials reported no difference whether induction or expectant management is performed in non-diabetic women with large for gestational age babies but no tool has been validated for the prediction of high risk cases. AIM: Assessing the performance of different growth curves in the prediction of complications. METHODS: Data from 1066 consecutive non-diabetic women who delivered babies ≥4000 g were collected. Logistic regression analysis was used to analyze the impact of the maternal variables on: instrumental delivery, shoulder dystocia (SD), perineal tears, cesarean section (CS), and postpartum hemorrhage. Intergrowth21 curves and customized Gardosi's curves were compared in terms of prediction of adverse outcomes. FINDINGS: Induction of labor was performed in 23.1% cases. The rate of CS was 17%. Hemorrhage, fetal distress, and SD occurred in 2%, 1.3%, and 2.7% of cases, respectively. Induction was significantly associated with instrumental delivery (p < .001), CS (p = .001), third and fourth degree perineal tears (p = .031), and post-partum hemorrhage (p = .02). The cutoff of 90th percentile according to Intergrowth21 did not show significant performance in predicting CS, while the same cutoff according to the Gardosi curves showed an OR 1.92 (CI 1.30-2.84) (p = .0009). DISCUSSION: Gardosi curves showed a better performance in predicting the risk of CS versus Intergrowth curves. Induction is significantly associated with adverse outcome in non-diabetic women with LGA babies.

Non-invasive Maternal Hemodynamic Assessment to Classify High-Risk Pregnancies Complicated by Fetal Growth Restriction.

Objectives: To verify whether the use of the temporal criterion of 32 weeks' gestation is effective in identifying maternal hemodynamic differences between early- and late-onset fetal growth restriction (FGR), and to test the statistical performance of a classificatory algorithm for FGR. Materials and methods: A prospective multicenter study conducted at three centers over 17 months. Singleton pregnant women with a diagnosis of FGR based on the international Delphi survey consensus at ≥ 20 weeks of gestation were included. FGR was classified as early-onset if diagnosed <32 weeks' gestation and as late-onset if ≥32 weeks. Hemodynamic assessment was performed by USCOM-1A at the time of FGR diagnosis. Comparisons between early- and late-onset FGR among the entire study cohort, FGR associated with hypertensive disorders of pregnancy (HDP-FGR), and isolated FGR (i-FGR) were performed. In addition, HDP-FGR cases were compared to i-FGR, regardless of the temporal cut-off of 32 weeks' gestation. Finally, a classificatory analysis based on the Random Forest model was performed to identify significant variables with the ability to differentiate FGR phenotypes. Results: During the study period, 146 pregnant women fulfilled the inclusion criteria. In 44 cases, FGR was not confirmed at birth, thus limiting the final study population to 102 patients. In 49 (48.1%) women, FGR was associated to HDP. Fifty-nine (57.8%) cases were classified as early-onset. Comparison of the maternal hemodynamics between early- and late-onset FGR did not show any difference. Similarly, non-significant findings were observed in sensitivity analyses performed for HDP-FGR and for i-FGR. In turn, comparison between pregnant women with FGR and hypertension and women with i-FGR, independently of the gestational age at FGR diagnosis, revealed substantial differences, with the former showing higher vascular peripheral resistances and lower cardiac output, among other significant parameters. The classificatory analysis identified both phenotypic and hemodynamic variables as relevant in distinguishing HDP-FGR from i-FGR (p=0.009). Conclusions: Our data show that HDP, rather than gestational age at FGR diagnosis, allows to appreciate specific maternal hemodynamic patterns and to accurately distinguish two different FGR phenotypes. In addition, maternal hemodynamics, alongside phenotypic characteristics, play a central role in classifying these high-risk pregnancies.

Is primary dysmenorrhea a precursor of future endometriosis development?

Primary dysmenorrhea (PD) is the most common gynecologic disorder during adolescence and it is characterized by crampy lower abdominal pain that occurs during menstruation. Secondary dysmenorrhea, in contrast, has the same clinical features but occurs in women with a disease that could account for their symptoms (endometriosis, adenomyosis, uterine fibroids, pelvic inflammatory disease). Endometriosis is the most common cause of secondary dysmenorrhea and it should be considered in patients with persistent and clinically significant dysmenorrhea despite treatment. It is often diagnosed after a long delay, increasing the likelihood of pain chronicity and fertility problems at a later age. Women who suffer from dysmenorrhea in adolescence have higher risk of endometriosis in future. The open question is if endometriosis was already present at the onset of dysmenorrhea but undiagnosed or if PD favors subsequent development of endometriosis-associated pain. Since PD is associated with higher risk for developing chronic pain state and shares some of the same pain pathways of endometriosis (prostaglandins overproduction, inflammation, peripheral sensitization, central sensitization and abnormal stress responses), a correlation between PD and endometriosis is suggested. To know whether it is a risk factor for the development of endometriosis-associated pain may provide an opportunity for early intervention and prevention. The present review aims to investigate the clinical and pathogenetic features of PD and endometriosis in order to identify a possible association between the two conditions.

Dysmenorrhea and Heavy Menstrual Bleeding in Elite Female Athletes: Quality of Life and Perceived Stress.

In female athletes, the incidence of menstrual disorders is variable, and their impact on perceived stress and quality of life (QoL) is poorly known.The aim of the present study was to investigate the menstrual cycle characteristics and disorders in athletes performing different sports, also evaluating perceived stress and QoL according to their menstrual cycle features. A cross-sectional survey was conducted in nulliparous elite athletes of reproductive age, and the study population included 112 cases. Three questionnaires were administered on (1) gynecological health, (2) perceived stress scale (PSS), and (3) short form QoL (SF-12). A group of women not practising regular sport activities (n = 103) was used as control. Data obtained in elite athletes were also analyzed according to the static and dynamic component percentage of practised sports in 3 sub-groups. Athletes had a significantly higher incidence of irregular periods and heavy menstrual bleeding (HMB) (p < 0.01) and a lower incidence of dysmenorrhea (p < 0.01) than controls. Furthermore, athletes had a better physical QoL (53.9 ± 5.9 vs 51.2 ± 6.0) (p < 0.05) but higher PPS level (17.3 ± 4.8 vs 13.8 ± 4.8) and a worse mental QoL (44.9 ± 9.9 vs 47.6 ± 9.0) (p < 0.05) than controls. HMB was associated with lower mental scores (39.7 ± .8.9 vs 45.6 ± 9.9) and higher PSS scores (19.8 ± .3.2 vs 17.0 ± .4.9) than those observed in athletes with normal bleeding. No difference was found in different sports regarding gynecological health, PSS level, and QoL. An increased incidence of HMB should be considered in elite athletes with increased PSS and impaired QoL.

From pathogenesis to clinical practice: Emerging medical treatments for endometriosis.

Endometriosis is a chronic disease, and a lifelong management plan should be developed by using pharmacological treatment and surgical procedures. The pathogenesis of endometriosis is complicated and has not been definitively established. The mechanisms involved are numerous, and their understanding is constantly evolving. Currently, the first-line drugs act by blocking ovarian function, creating an hypoestrogenic environment. The blockade of estrogen secretion and receptor activity and the activation of progesteron receptors are the main target of several current drugs, as well as those under development. The oral GnRH antogonists, the aromatase inhibitors, SERMs, and SPRMs are the hormonal drugs currently studied for treating endometriosis. The increasing knowledge of the pathogenesis has allowed the development of new treatments. The most studied are the anti-inflammatory drugs, starting from the new NSAIDs to the monoclonal antibodies and the statins. Among the antiangiogenic compounds, a role is suggested for Icon, PPARs, and HDACIs. A new class of drugs is the cannabinoids. The aim of this review was to investigate the new therapeutic hormonal and non-hormonal alternatives to standard treatments.

Epidemiology and Risk Factors of Uterine Fibroids.

Risk factors, both modifiable and non-modifiable, are associated with the development of fibroids. These include age, race, endogenous and exogenous hormonal factors, obesity, uterine infection, and lifestyle (diet, caffeine and alcohol consumption, physical activity, stress, and smoking). Some of the epidemiological data were conflicting; consequently, further studies are needed to better understand the factors that influence fibroid prevalence.