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..

Can the First Fasting Plasma Glucose Test in Pregnancy Predict Subsequent Gestational Complications?

Objective: To determine the best cut-off level of pregnant women's first fasting plasma glucose (FFPG) test results for the prediction of subsequent onset of gestational diabetes mellitus (GDM) and to examine the association between FFPG and maternal and neonatal outcomes in a large Caucasian population. Methods: 1437 medical records of women with singleton pregnancies followed up between 2015 and 2018 were retrospectively analyzed. Data on FFPG tested in the first trimester and 75 g oral glucose tolerance test (OGTT) findings performed according to IADPSG criteria and Italian guidelines were collected and evaluated. The women's clinical and metabolic characteristics (age, prepregnancy body mass index (BMI), previous pregnancies complicated by GDM, timing of delivery, and gestational hypertension) were also recorded. The fetal variables considered were being large for gestational age (LGA) or small for gestational age (SGA), macrosomia, and hypoglycemia. Results: Among the 1437 pregnant women studied, 684 had a normal glucose tolerance (NGT) and 753 developed GDM. In a univariate analysis FFPG ≥92 mg/dl predicts the risk of GDM with an OR = 2.36 (95% CI 1.930-3.186; p < 0.001). In multivariate analysis, after adjusting for principal risk factors of GDM (BMI, previous GDM, age >35 years, family history of diabetes) FFPG ≥92 mg/dl was associated with the risk of GDM (OR = 1.92; 95% CI 1.488-2.492; p < 0.001). In univariate analysis, FFPG ≥92 mg/dl predict the risk of insulin therapy in GDM women with a OR = 1.88 (95% CI 1.230-2.066; p < 0.001). As regards LGA, in a multivariate analysis, after adjusting for BMI, FFPG ≥92 mg/dl was associated with the risk of LGA only in NGT women (OR = 2.34; 95% CI 1.173-4.574; p=0.014), but not in GDM women. FFPG was not associated with other maternal or neonatal outcomes. Conclusions: FFPG ≥92 mg/dl is related to GDM diagnosis and to the need of insulin therapy if GDM is diagnosed. An early diagnosis and a prompt start of insulin therapy are essential to prevent maternal and fetal complications.

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.

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.

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.

Different Gestational Diabetes Phenotypes: Which Insulin Regimen Fits Better?

Objective: Maternal characteristics and OGTT values of pregnancies complicated by gestational diabetes mellitus (GDM) were evaluated according to treatment strategies. The goal was to identify different maternal phenotypes in order to predict the appropriate treatment strategy. Methods: We conducted a retrospective study among 1,974 pregnant women followed up for GDM in a tertiary referral hospital for high-risk pregnancies (Careggi University Hospital, Florence, Italy) from 2013 to 2018. We compared nutritional therapy (NT) alone (n = 962) versus NT and insulin analogues (n = 1,012) group. Then, we focused on different insulin analogues groups: long acting (D), rapid acting (R), both D and R. We compared maternal characteristics of the three groups, detecting which factors may predict the use of rapid or long-acting insulin analogue alone versus combined therapy. Results: Among women included in the analysis, 51.3% of them needed insulin therapy for glycemic control: 61.8% D, 28.3% combined D and R, and 9.9% R alone. Age >35 years, pre-pregnancy BMI >30, family history of diabetes, previous GDM, altered fasting plasma glucose (FPG), hypothyroidism, and assisted reproductive technologies (ART) were identified as maternal variables significantly associated with the need of insulin therapy. Altered 1-h and 2-h glucose plasma glucose level at OGTT, age >35 years, and previous GDM were found as independent predicting factors for the use of combined therapy with rapid and long acting analogues for glycemic control. On the contrary, pre-pregnancy BMI <25 and normal fasting plasma glucose values at OGTT were found to be significantly associated to the use of rapid insulin analogue only. Conclusion: A number of maternal and metabolic variables may be identified at the diagnosis of GDM, in order to identify different GDM phenotypes requiring a personalized treatment for glycemic control.

Postpartum hemorrhage: not only hypertensive disorders in oocyte donation pregnancies.

BACKGROUND: The aim of the study is to compare the obstetric outcome between single pregnancies obtained by medically-assisted procreation using oocyte donors (MAP-E) versus homologous gametes (MAP-O) and single spontaneous conception pregnancies (SC). METHODS: This is a retrospective case-control study on pregnancy outcome of consecutive singleton live birth pregnancies from MAP-E between January 2011 and August 2017 referred to Careggi University Hospital, Florence. The control group includes singleton pregnancies from MAP-O and pregnancies from spontaneous conceptions in the same period. The pregnancy outcomes considered were: postpartum hemorrhage (PPH), cesarean section (CS), gestational diabetes mellitus (GDM), hypertensive disorders including preeclampsia (HDP), preterm birth ≤34 weeks (PTB), and small-for-gestational-age (SGA) fetuses. RESULTS: The study group included 290 MAP-E pregnancies that were compared with 290 MAP-O and 870 singleton spontaneous conception pregnancies. The three groups did not show significant differences in maternal traits except for mean age (43.4±2.9 vs. 37.7±2.4 vs. 33.6±5.5, P<0.001), including a higher percentage of patients over 45 years (41.3% vs. 5% vs. 0.8%, P<0.001) and higher incidence of obesity (7.2% vs. 1.7%, P=0.02) in MAP-E than in MAP-O. The risk of HDP is increased in singleton pregnancies by oocyte donation with a significantly increased risk if compared to MAP-O (12% vs. 1%, P<0.001, OR=12.6). The risk of PPH in singleton pregnancies from oocyte donation is higher than in MAP-O (22% vs. 9% P<0.0001, OR=2.87). When we considered severe PPH (blood loss >1000 mL) the risk for MAP-E was higher if compared to MAP-O (OR=2.1, P=0.2) and mostly to SC (OR=14, P<0.005). Compared to SC, MAP-E pregnancies showed increased OR for all the outcomes: CS (78% vs. 30.8%, P<0.001, OR=7.91); GDM (26.1% vs. 10.8%, P<0.001, OR=2.92); HDP (12% vs. 2.2%, P<0.001, OR=5.99); PPH (22% vs. 8.5%, P<0.0001, OR=3.0); SGA (16% vs. 11%, P<0.05, OR=1.16); PTB ≤34 weeks (9.4% vs. 1%, P<0.001, OR=7.94). CONCLUSIONS: Most women who undergo MAP-E are in advanced age, representing a high-risk population for obstetric complications, like HPD and PPH, which stands as the main worldwide cause of maternal mortality.

Human leukocyte antigen DQ2/DQ8 positivity in women with history of stillbirth.

PROBLEM: The aim of this study was to investigate the prevalence of human leukocyte antigens (HLA) DQ2 and DQ8 haplotypes, two common polymorphisms associate with celiac disease (CD), in women with previous stillbirth, but not affected by CD. METHOD OF STUDY: Women with history of unexplained term stillbirth referred to our Center for High-Risk Pregnancies for a preconception counseling, and women with previous uncomplicated pregnancies, were enrolled as cases and controls. Celiac women were excluded from the study. Genetic tests for HLA DQ2/DQ8 were performed, and patients' data were compared. RESULTS: The population included 56 women with a previous term stillbirth and 379 women with history of uncomplicated pregnancies. The prevalence of HLA-DQ2 or DQ8 positivity was significantly higher in cases than in controls (50% vs 29.5%) (P = 0.0031). Women with HLA DQ8 genotype have a significantly higher risk of stillbirth (OR: 2.84 CI: 1.1840-6.817) and in case of DQ2 genotype the OR for stillbirth was even higher (OR: 4.46 CI: 2.408-8.270). In the stillbirth group, SGA neonates were significantly more frequent in those with HLA-DQ2/DQ8 haplotypes than in those resulted negative to genetic testing (85.7% vs 42 .8%, P = 0.004). CONCLUSION: In women with history of term stillbirth, a significantly higher prevalence of HLA DQ2/DQ8 haplotypes has been found compared to women with previous uneventful pregnancies. In addition, HLA DQ2/DQ8 positivity was significantly associated with suboptimal fetal growth in intrauterine fetal death cases, as shown by an increased prevalence of SGA babies.

Mothers with HIP - The short term and long-term impact, what is new?

Hyperglycemia is one of the most common medical conditions that women encounter during pregnancy and it is due to gestational diabetes (GDM) in the majority of cases (International Diabetes Federation, 2015) [1]. GDM is associated with a higher incidence of maternal morbidity in pregnancy in term of hypertensive disorders/preclampsia and higher rate of cesarean delivery but also with long-term risk of type 2 diabetes and cardiovascular disease. Pregnancy can therefore be considered a stress test; diagnosis of HIP can unmask a preexisting susceptibility and consequently a future risk for type 2 diabetes and can be a useful marker of future cardiovascular risk. Postpartum follow up provides an excellent opportunity to implement healthy lifestyle behaviors to prevent or delay the development of diabetes or cardiovascular disease. The aim of the current review is to focus on short and long term maternal morbidity of HIP.

Prescribing exercise for prevention and treatment of gestational diabetes: review of suggested recommendations.

Exercise has been proved to be safe during pregnancy and to offer benefits for both mother and fetus; moreover, physical activity may represent a useful tool for gestational diabetes prevention and treatment. Therefore, all women in uncomplicated pregnancy should be encouraged to engage in physical activity as part of a healthy lifestyle. However, exercise in pregnancy needs a careful medical evaluation to exclude medical or obstetric contraindications to exercise, and an appropriate prescription considering frequency, intensity, type and duration of exercise, to carefully balance between potential benefits and potential harmful effects. Moreover, some precautions related to anatomical and functional adaptations observed during pregnancy should be taken into consideration. This review summarized the suggested recommendations for physical activity among pregnant women with focus on gestational diabetes.

Continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI) of rapid-acting insulin analogues and detemir in type 1 diabetic (T1D) pregnant women.

OBJECTIVE: To compare glycemic control, maternal-neonatal outcomes and fetal fat body mass growth of type 1 diabetic pregnant women treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) with the long-acting insulin analogue detemir as basal insulin. METHODS: Retrospective study of 53 women, attending the Unit of Prenatal Medicine of Careggi University Hospital, Florence, from 2009 to 2012: 35 treated with CSII, 18 with MDI-detemir. Each woman performed daily blood glucose self-monitoring, had an individualized nutritional therapy, weekly prenatal visits and ultrasound scans (US) according to the Tuscan guidelines. US were also performed every two weeks from 28 to 38 weeks of gestation to assess fetal fat body mass growth. Student's t-test and Chi-square test were performed to compare the groups' results. RESULTS: No significant differences were observed in metabolic control, in any maternal and neonatal outcome nor fetal fat body mass growth for either group. The MDI group needed higher daily doses of insulin (MDI: 1.00 ± 0.32 UI/kg versus CSII: 0.75 ± 0.29 UI/kg, p = 0.007) to reach results comparable to the CSII group. CONCLUSIONS: MDI therapy with detemir is a safe and effective alternative, with a good benefit-cost ratio compared to insulin pumps.

Metabolomic profile of term infants of gestational diabetic mothers.

OBJECTIVE: Maternal diabetes increases the risk of perinatal mortality and morbidity, but the maintenance of antenatal normal glucose serum prevents the majority of neonatal complications. The aim of our study is to compare the metabolomic profile of infants of gestational diabetic mothers (IGDMs) to that of infants of healthy mothers to evaluate if differences remain despite a strict control of gestational diabetes. METHODS: We performed the metabolomics study in cord serum sampled from 30 term IGDMs and 40 controls recording the occurrence of the most frequent complications in IGDMs. RESULTS: We demonstrated that IGDMs have lower level of glucose and higher level of pyruvate, histidine, alanine, valine, methionine, arginine, lysine, hypoxanthine, lipoprotein and lipid than controls, but we did not find any clinical differences. CONCLUSIONS: Our results suggest that prolonged fetal exposure to hyperglycemia during pregnancy can change neonatal metabolomic profile at birth without affecting the clinical course.

Glucose variability in diabetic pregnancy.

BACKGROUND: Fetal overgrowth is the most important complication of gestational (GDM) and pregestational diabetes mellitus. METHODS: We correlated maternal glucose profiles, as detected by continuous glucose monitoring (CGM), with fetal growth parameters for 80 pregnant women (32 with type 1 diabetes, 31 with GDM, and 17 healthy controls). Glucose profiles were monitored in the first, second, and third trimesters of pregnancy for type 1 diabetes women and in the second and third trimesters for GDM women and controls. To analyze glycemic variability, we considered the mean amplitude of glycemic excursion, mean glycemia, the continuous overlapping net glycemic action (CONGA), the SD, the High Blood Glucose Index (HBGI), the Low Blood Glucose Index, and the interquartile range (IQR). RESULTS: Mean age was the same for the three groups. Prepregnancy body mass index was higher for the women with diabetes (GDM and type 1) than for controls. The newborn's mean birth weight and ponderal index were higher, although not significantly so, for the women with diabetes than for controls. For the type 1 diabetes patients, ponderal index correlated with the HBGI in the first trimester, CONGA1 and IQR in the second, and mean glycemia and SD in the third. For GDM patients, ponderal index correlated with mean glycemia and the HBGI in the second trimester. CONCLUSIONS: Fetal exposure to glycemic variability and hyperglycemia seems to be important in determining fetal overgrowth in pregnant women with diabetes. Optimal glucose control and less glucose variability are needed as early as possible in both type 1 diabetes and GDM patients to ensure normal fetal growth.

Ethical issue and consent form in the management of high-risk pregnancy.

Through the description of two high risk unplanned pregnancy cases and the subsequent interview of the patients, a few years after delivery, this article focuses on the following issues: 1. The importance of a planned pregnancy in a woman with diabetes or other chronic disease; 2. The ethical role of counselling and how it should not be influenced by the ethical belief of the obstetrician; 3. The legal aspect related to the knowledge and qualifications of the obstetrician in the management of a high-risk pregnancy to improve both maternal and fetal outcomes. Here, two cases of complicated type 1 diabetes in women with unplanned pregnancies and the importance of counselling in high-risk pregnancy are presented.