Secular Trends in Preterm Birth Rates: Uncovering the Primary Challenge for Perinatal Medicine in Greece.

INTRODUCTION: Preterm labour is a serious pregnancy complication that is the primary cause of infant mortality, with detrimental impacts on the offspring and the mother in the short as well as the long term. This study aims to comprehensively present the time trends of national preterm birth rates (PBRs) in Greece. METHODS: Official national data regarding live births in Greece were acquired from the Hellenic Statistical Authority, and the annual total PBR and rates for gestational age groups were computed per 100 total live births spanning from 1980 to 2022. Time trends were analyzed through joinpoint regression analysis, and annual percent changes (APC) and average annual percent change (AAPC) were calculated with a 95% confidence interval (95% CI). RESULTS: Following a steady decline from 4.66% in 1980 to a historic low of 2.77% in 1991 with an APC of -5.1 (-6.2 to -4.2), the PBR exhibited a dramatic increase during 1991-2011 with an APC of 7.3 (6.9 to 7.8). Subsequently, between 2011 and 2022, the rise in PBR was attenuated, showing a slight statistically non-significant upward trend (APC = 0.5, 95% CI: -0.6 to 1.5). This led to a historical high of 12.07% in 2018, 4.4 times higher than that in 1991, and eventually, the PBR reached 11.90% in 2022. From 1991 to 2022, there were sharper increases in the rates of moderate (32-33 weeks) and late (34-36 weeks) preterm births, with AAPCs of 4.9 (3.5-6.4) and 5.8 (5.3-6.3), respectively. In contrast, the rates of extremely (<28 weeks) and very (28-31 weeks) preterm births saw slower growth, with AAPCs of 2.2 (1.7-2.7) and 0.7 (0.5-1.0), respectively. CONCLUSION: The PBR in Greece more than quadrupled during 1991-2022, mainly due to increases in moderate and late preterm births. Although its rise has markedly decelerated since 2011, amidst the country's economic recession, the PBR is alarmingly higher than those in all other European and developed nations. More than one in nine neonates is born prematurely in the Greek population, posing challenges in implementing evidence-based prevention strategies and perinatal care.

ENhancinG vAGinal dElivery in Greece through educational and behavioral interventions among maternity care providers regarding labor management: the ENGAGE stepped-wedge randomized prospective trial protocol.

BACKGROUND: There is an emerging need to systematically investigate the causes for the increased cesarean section rates in Greece and undertake interventions so as to substantially reduce its rates. To this end, the ability of the participating Greek obstetricians to follow evidence-based guidelines and respond to other educational and behavioral interventions while managing labor will be explored, along with barriers and enablers. Herein discussed is the protocol of a stepped-wedge designed intervention trial in Greek maternity units with the aforementioned goals in mind, named ENGAGE (ENhancinG vAGinal dElivery in Greece). METHODS: Twenty-two selected maternity units in Greece will participate in a multicenter stepped-wedge randomized prospective trial involving 20,000 to 25,000 births, with two of them entering the intervention period of the study each month (stepped randomization). The maternity care units entering the study will apply the suggested interventions for a period of 8-18 months depending on the time they enter the intervention stage of the study. There will also be an initial phase of the study lasting from 8 to 18 months including observation and recording of the routine practice (cesarean section, vaginal birth, and maternal and perinatal morbidity and mortality) in the participating units. The second phase, the intervention period, will include such interventions as the application of the HSOG (the Hellenic Society of Obstetrics and Gynecology) Guidelines on labor management, training on the correct interpretation of cardiotocography, and dealing with emergencies in vaginal deliveries, while the steering committee members will be available to discuss and implement organizational and behavioral changes, answer questions, clarify relevant issues, and provide practical instructions to the participating healthcare professionals during regular visits or video conferences. Furthermore, during the study, the results will be available for the participating units in order for them to monitor their own performance while also receiving feedback regarding their rates. Τhe final 2-month phase of the study will be devoted to completing follow-up questionnaires with data concerning maternal and neonatal morbidities that occurred after the completion of the intervention period. The total duration of the study is estimated at 28 months. The primary outcome assessed will be the cesarean section rate change and the secondary outcomes will be maternal and neonatal morbidity and mortality. DISCUSSION: The study is expected to yield new information on the effects, advantages, possibilities, and challenges of consistent clinical engagement and implementation of behavioral, educational, and organizational interventions described in detail in the protocol on cesarean section practice in Greece. The results may lead to new insights into means of improving the quality of maternal and neonatal care, particularly since this represents a shared effort to reduce the high cesarean section rates in Greece and, moreover, points the way to their reduction in other countries. TRIAL REGISTRATION: NCT04504500 (ClinicalTrials.gov). The trial was prospectively registered. Ethics Reference No: 320/23.6.2020, Bioethics and Conduct Committee, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Bridging the Gap between Galectin-3 Expression and Hypertensive Pregnancy Disorders: A Narrative Review.

Galectin-3 belongs to a family of soluble glycan-binding proteins, which are increasingly recognized as modulators of pregnancy-associated processes, including proper placental development. Gestational hypertension and preeclampsia are significant complications of pregnancy, affecting millions of women annually. Despite their prevalence, the underlying pathophysiological mechanisms remain poorly understood. Several theories have been proposed, including inflammation, placental insufficiency, disturbed placental invasion, and angiogenesis. The Scopus and PubMed/MEDLINE databases were utilized until the end of May 2024. In total, 11 articles with 1011 patients, with 558 in the control group and 453 in the preeclampsia group, were included. Seven articles investigated the expression of galectin-3 (Gal-3) in placental tissue samples, eight studies calculated the serum levels of Gal-3 in maternal blood samples, while one study referred to the possible correlation of galectin-3 levels in umbilical cord blood. The results were inconsistent in both the placental tissue and maternal serum; Gal-3 placental expression was found to be statistically increased in five studies compared to that in women without gestational hypertensive disorders, while two studies either mentioned decreased expression or no difference. Similarly, the Gal-3 maternal serum levels, compared to those in women without gestational hypertensive disorders, were found to be statistically increased in five studies, while three studies did not find any statistical difference. Gal-3 can play a crucial role in the pathogenesis of preeclampsia, and its expression is influenced by gestational age and placental insufficiency. A further investigation ought to be conducted to enlighten the correlation of Gal-3 with gestational hypertension and preeclampsia development.

Ectopic pregnancy with full implantation of the gestational sac in the caesarean section scar managed successfully with laparotomy.

Caesarean scar pregnancy represents one of the rarest locations of ectopic pregnancies. It occurs when the blastocyst is implanted in a scar from a previous caesarean section. A dramatic increase of its prevalence has been observed for the last decades, reaching about 21% globally. Early diagnosis and treatment are crucial to avoid maternal morbidity and mortality. Our case presents the characteristic appearance of a caesarean scar pregnancy with full implantation of the gestational sac in the scar, which was managed successfully with laparotomy.

The Contribution of Multiple Pregnancies in Stillbirths in Greece: A Time-Trend Analysis.

Introduction Multiple pregnancy is an established risk factor for fetal death. This study aimed to examine the impact of multifetal pregnancies on stillbirth rates (SBRs) in the Greek population. Methods Data on live births and stillbirths by multiplicity were derived from the Hellenic Statistical Authority, covering a 65-year period from 1957 to 2021. The SBR for multiple and single gestations, and the population attributable risk (%) (PAR (%)) stillbirth attributable to multifetal gestations were calculated, and temporal trends were assessed using joinpoint regression analysis, with annual percentage changes (APC) and 95% confidence interval (95% CI). Results In the period 1957-2021, multiple pregnancies accounted for 9.4% of total stillbirths in Greece and the overall relative risk of fetal death among multifetal gestations was 3.34, in comparison with singletons. The SBR in multiple births remained unchanged from 1957 to 1976 and showed downward trends from 1976 to 2021 (APC = -3.0, 95% CI: -3.4 to -2.7, p < 0.001). PAR (%), after two decades of stability, showed an increasing trend over the period 1975-2011 (APC = 3.4, 95% CI: 2.8 to 4.0, p < 0.001), which was reversed in the more recent decade 2011-2021 (APC = -6.1, 95% CI: -9.6 to -2.5, p = 0.001), with PAR (%) decreasing from a historical high of 19.3% in 2012 to 8.6% in 2021. Conclusion The high incidence of multiple births has a considerable impact on stillbirth rates in the Greek population. The recent downward trends of SBR and PAR (%) of multiple gestations are encouraging, however more measures and targeted interventions are needed to improve perinatal outcomes in multifetal gestation.

Measurement of Calprotectin and PTH in the Amniotic Fluid of Early Second Trimester Pregnancies and Their Impact on Fetuses with Growth Disorders: Are Their Levels Related to Oxidative Stress?

Background: During the early stages of human fetal development, the fetal skeleton system is chiefly made up of cartilage, which is gradually replaced by bone. Fetal bone development is mainly regulated by the parathyroid hormone parathormone (PTH) and PTH-related protein, with specific calprotectin playing a substantial role in cell adhesion and chemotaxis while exhibiting antimicrobial activity during the inflammatory osteogenesis process. The aim of our study was to measure the levels of PTH and calprotectin in early second trimester amniotic fluid and to carry out a comparison between the levels observed among normal full-term pregnancies (control group) and those of the groups of embryos exhibiting impaired or enhanced growth. Methods: For the present prospective study, we collected amniotic fluid samples from pregnancies that underwent amniocentesis at 15 to 22 weeks of gestational age during the period 2021-2023. Subsequently, we followed up on all pregnancies closely until delivery. Having recorded fetal birthweights, we then divided the neonates into three groups: small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Results: In total, 64 pregnancies, including 14 SGA, 10 LGA, and 40 AGA fetuses, were included in our study. Both substances were detected in early second trimester amniotic fluid in both groups. Concentrations of calprotectin differed significantly among the three groups (p = 0.033). AGA fetuses had a lower mean value of 4.195 (2.415-6.425) IU/mL, whereas LGA fetuses had a higher mean value of 6.055 (4.887-13.950) IU/mL, while SGA fetuses had a mean value of 5.475 (3.400-9.177) IU/mL. Further analysis revealed that only LGA fetuses had significantly higher calprotectin concentrations compared to AGA fetuses (p = 0.018). PTH concentration was similar between the groups, with LGA fetuses having a mean value of 13.18 (9.51-15.52) IU/mL, while SGA fetuses had a mean value of 14.18 (9.02-16.00) IU/mL, and AGA fetuses had similar concentrations of 13.35 (9.05-15.81) IU/mL. The differences in PTH concentration among the three groups were not statistically significant (p = 0.513). Conclusions: Calprotectin values in the amniotic fluid in the early second trimester were higher in LGA fetuses compared to those in the SGA and AGA categories. LGA fetuses can possibly be in a state of low-grade chronic inflammation due to excessive fat deposition, causing oxidative stress in LGA fetuses and, eventually, the release of calprotectin. Moreover, PTH concentrations in the amniotic fluid of early second trimester pregnancies were not found to be statistically correlated with fetal growth abnormalities in either LGA or SGA fetuses. However, the early time of collection and the small number of patients in our study should be taken into account.

Second Trimester Amniotic Fluid Angiotensinogen Levels Linked to Increased Fetal Birth Weight and Shorter Gestational Age in Term Pregnancies.

BACKGROUND: Despite the considerable progress made in recent years in fetal assessment, the etiology of fetal growth disturbances is not as yet well understood. In an effort to enhance our knowledge in this area, we investigated the associations of the amniotic fluid angiotensinogen of the renin-angiotensin system with fetal growth abnormalities. METHODS: We collected amniotic fluid samples from 70 pregnant women who underwent amniocentesis during their early second trimester. Birth weight was documented upon delivery, after which the embryos corresponding to the respective amniotic fluid samples were categorized into three groups as follows: small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Amniotic fluid angiotensinogen levels were determined by using ELISA kits. RESULTS: Mean angiotensinogen values were 3885 ng/mL (range: 1625-5375 ng/mL), 4885 ng/mL (range: 1580-8460 ng/mL), and 4670 ng/mL (range: 1995-7250 ng/mL) in the SGA, LGA, and AGA fetuses, respectively. The concentrations in the three groups were not statistically significantly different. Although there were wide discrepancies between the mean values of the subgroups, the large confidence intervals in the three groups negatively affected the statistical analysis. However, multiple regression analysis revealed a statistically significant negative correlation between the angiotensinogen levels and gestational age and a statistically significant positive correlation between the birth weight and angiotensinogen levels. DISCUSSION: Our findings suggest that fetal growth abnormalities did not correlate with differences in the amniotic fluid levels of angiotensinogen in early second trimester pregnancies. However, increased angiotensinogen levels were found to be consistent with a smaller gestational age at birth and increased BMI of neonates.

Robotic-assisted fertility sparing surgery in gynecological oncology.

While gynecological malignancies are more commonly diagnosed in elderly women, a substantial proportion of women will still be diagnosed with some type of gynecologic cancer during their reproductive age. Over 10% of newly diagnosed ovarian cancers and over one third of newly diagnosed cervical cancers involve women who are under the age of 45. This, coupled with the rising trend of women having their first child after the age of 35, has led to a concerning prevalence of complex fertility issues among women who have been diagnosed with cancer. Since the advent of robotic-assisted surgeries in gynecology, there has been a rise in the occurrence of these procedures. Fertility preserving gynecological surgeries require precise management in order to avoid fertility disorders. Therefore, we conducted a narrative review of robotic assisted fertility sparing surgery in gynecologic malignancies in order to highlight the role of this approach in preserving fertility.

Inguinal Lymph Node Metastasis as Sole Manifestation of Ovarian / Fallopian Tube Cancer: a Review of the Literature.

Background: Ovarian/fallopian tube cancer is the deadliest gynecological malignancy. Most cases are diagnosed at an advanced stage, typically after the cancer has spread to the peritoneal cavity, or via lymphatic drainage. The presence of distant lymph node metastasis in the inguinal region is a rare manifestation of lymphatic metastasis. Since the 2014 FIGO staging revision, ovarian cancer patients with inguinal metastasis are classified as stage IVB. However, the clinical significance of such an upstaging remains under investigation. Materials and Methods: Both Scopus and PubMed / MEDLINE databases were utilized, by inputting the following combination of keywords: (Ovarian cancer OR Fallopian tube cancer) AND (Inguinal lymph node AND Metastasis) on June 31st, 2023. The time of publication and text availability were not considered when searching the databases and all relevant articles in English were initially accepted. Results: Twelve patients from equal number of case reports were included in our review. Mean age of diagnosis was 56,5 years old, with 3 out of 12 women to be premenopausal at the time of diagnosis. Regarding the histologic type, 67% (8 out of 12) of the cases were serous adenocarcinoma and 4 patients (33%) were diagnosed with fallopian tube malignancy. All patients, except one, were treated with primary cytoreductive surgery. In all patients optimal cytoreductive surgery was achieved. All patients, except one, received adjuvant chemotherapy. Regarding the disease-free survival, mean DFS is calculated approximately at 2 years (23,1 months). Conclusion: Inguinal lymph node metastases from ovarian / fallopian tube malignancy as initial site of metastasis is extremely rare. However, patients with inguinal masses should be investigated for ovarian / fallopian malignancy. Further investigation ought to be conducted to enlighten the pathway and the oncological significance of inguinal lymph node metastasis in ovarian cancer patients.

Uterine collision tumor (PEComa and endometrioid carcinoma) in a tuberous sclerosis patient: a case report.

Perivascular epithelioid cell tumors are very rare mesenchymal neoplasms arising in various locations, such as the female genital tract, kidney, lung, prostate, bladder, pancreas, soft tissues, and bone. They possess a unique immunophenotype, co-expressing myogenic and melanocytic markers; molecular findings include mutations of tuberous sclerosis complex and translocations of transcription factor E3, a member of the microphthalmia transcription factor gene family. We herewith report a uterine collision tumor consisting of a perivascular epithelioid cell tumor and a moderately differentiated endometrial endometrioid carcinoma in a patient with genetically proven tuberous sclerosis; two leiomyomas were also found in contact with the tumor. Although two such cases one with a benign and another with a malignant perivascular epithelioid cell tumor have previously been reported, ours is, to our knowledge, the first reported in a tuberous sclerosis patient.

Detection and Quantification of Neurotrophin-3 (NT-3) and Nerve Growth Factor (NGF) Levels in Early Second Trimester Amniotic Fluid: Investigation into a Possible Correlation with Abnormal Fetal Growth Velocity Patterns.

BACKGROUND: Abnormal fetal growth is associated with adverse perinatal and long-term outcomes. The pathophysiological mechanisms underlying these conditions are still to be clarified. Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are two neurotrophins that are mainly involved in the neuroprotection process, namely promotion of growth and differentiation, maintenance, and survival of neurons. During pregnancy, they have been correlated with placental development and fetal growth. In this study, we aimed to determine the early 2nd trimester amniotic fluid levels of NGF and NT-3 and to investigate their association with fetal growth. METHODS: This is a prospective observational study. A total of 51 amniotic fluid samples were collected from women undergoing amniocentesis early in the second trimester and were stored at -80 °C. Pregnancies were followed up until delivery and birth weight was recorded. Based on birth weight, the amniotic fluid samples were divided into three groups: appropriate for gestational age (AGA), small for gestational age (SGA), and large for gestational age (LGA). NGF and NT-3 levels were determined by using Elisa kits. RESULTS: NGF concentrations were similar between the studied groups; median values were 10.15 pg/mL, 10.15 pg/mL, and 9.14 pg/mL in SGA, LGA, and AGA fetuses, respectively. Regarding NT-3, a trend was observed towards increased NT-3 levels as fetal growth velocity decreased; median concentrations were 11.87 pg/mL, 15.9 pg/mL, and 23.5 pg/mL in SGA, AGA, and LGA fetuses, respectively, although the differences among the three groups were not statistically significant. CONCLUSIONS: Our findings suggest that fetal growth disturbances do not induce increased or decreased production of NGF and NT-3 in early second trimester amniotic fluid. The trend observed towards increased NT-3 levels as fetal growth velocity decreased shows that there may be a compensatory mechanism in place that operates in conjunction with the brain-sparing effect. Further associations between these two neurotrophins and fetal growth disturbances are discussed.