Hepatocyte regeneration is driven by embryo-like DNA methylation reprogramming.

As a result of partial hepatectomy, the remaining liver tissue undergoes a process of renewed proliferation that leads to rapid regeneration of the liver. By following the early stages of this process, we observed dramatic programmed changes in the DNA methylation profile, characterized by both de novo and demethylation events, with a subsequent return to the original adult pattern as the liver matures. Strikingly, these transient alterations partially mimic the DNA methylation state of embryonic hepatoblasts (E16.5), indicating that hepatocytes actually undergo epigenetic dedifferentiation. Furthermore, Tet2/Tet3-deletion experiments demonstrated that these changes in methylation are necessary for carrying out basic embryonic functions, such as proliferation, a key step in liver regeneration. This implies that unlike tissue-specific regulatory regions that remain demethylated in the adult, early embryonic genes are programmed to first undergo demethylation, followed by remethylation as development proceeds. The identification of this built-in system may open targeting opportunities for regenerative medicine.

Congenital diaphragmatic hernia: quality improvement using a maximal lung protection strategy and early surgery-improved survival.

To evaluate the effectiveness of a novel protocol, adopted in our institution, as a quality improvement project for congenital diaphragmatic hernia (CDH). A maximal lung protection (MLP) protocol was implemented in 2019. This strategy included immediate use of high-frequency oscillatory ventilation (HFOV) after birth, during the stay at the Neonatal Intensive Care Unit (NICU), and during surgical repair. HFOV strategy included low distending pressures and higher frequencies (15 Hz) with subsequent lower tidal volumes. Surgical repair was performed early, within 24 h of birth, if possible. A retrospective study of all inborn neonates prenatally diagnosed with CDH and without major associated anomalies was performed at the NICU of Schneider Children's Medical Center of Israel between 2009 and 2022. Survival rates and pulmonary outcomes of neonates managed with MLP were compared to the historical standard care cohort. Thirty-three neonates were managed with the MLP protocol vs. 39 neonates that were not. Major adverse outcomes decreased including death rate from 46 to 18% (p = 0.012), extracorporeal membrane oxygenation from 39 to 0% (p < 0.001), and pneumothorax from 18 to 0% (p = 0.013). CONCLUSION:  MLP with early surgery significantly improved survival and additional adverse outcomes of neonates with CDH. Prospective randomized studies are necessary to confirm the findings of the current study. WHAT IS KNOWN: • Ventilator-induced lung injury was reported as the main cause of mortality in neonates with congenital diaphragmatic hernia (CDH). • Conventional ventilation is recommended by the European CDH consortium as the first-line ventilation modality; timing of surgery is controversial. WHAT IS NEW: • A maximal lung protection strategy based on 15-Hz high-frequency oscillatory ventilation with low distending pressures as initial modality and early surgery significantly reduced mortality and other outcomes.

Fetal surgery using fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia: a single-center experience.

PURPOSE: To provide a comprehensive report of the experience gained in the prenatal treatment of congenital diaphragmatic hernia (CDH) using fetoscopic endoluminal tracheal occlusion (FETO) following its implementation at a newly established specialized fetal medicine center. METHODS: Mothers of fetuses with severe CDH were offered prenatal treatment by FETO. RESULTS: Between 2018 and 2021, 16 cases of severe CDH underwent FETO. The median gestational age (GA) at balloon insertion was 28.4 weeks (IQR 27.8-28.6). The median GA at delivery was 37 weeks (IQR 34.4-37.8). The survival rate was 8/16 cases (50%). None of the survivors required home oxygen therapy at 6 months of age. Comparison between the survivors and deceased showed that survivors had balloon insertion 1 week earlier (27.8 vs. 28.4 weeks, p = 0.007), a higher amniotic fluid level change between pre- to post-FETO (3.4 vs 1.3, p = 0.024), a higher O/E LHR change between pre- to post-FETO (50.8 vs. 37.5, p = 0.047), and a GA at delivery that was 2 weeks later (37.6 vs. 35.4 weeks, p = 0.032). CONCLUSIONS: The survival rate at 6 months of age in cases of severe CDH treated with FETO in our center was 50%. Our new fetal medicine center matches the performance of other leading international centers.

Muscle injury causes long-term changes in stem-cell DNA methylation.

Injury to muscle brings about the activation of stem cells, which then generate new myocytes to replace damaged tissue. We demonstrate that this activation is accompanied by a dramatic change in the stem-cell methylation pattern that prepares them epigenetically for terminal myocyte differentiation. These de- and de novo methylation events occur at regulatory elements associated with genes involved in myogenesis and are necessary for activation and regeneration. Local injury of one muscle elicits an almost identical epigenetic change in satellite cells from other muscles in the body, in a process mediated by circulating factors. Furthermore, this same methylation state is also generated in muscle stem cells (MuSCs) of female animals following pregnancy, even in the absence of any injury. Unlike the activation-induced expression changes, which are transient, the induced methylation profile is stably maintained in resident MuSCs and thus represents a molecular memory of previous physiological events that is probably programmed to provide a mechanism for long-term adaptation.

Experience of 300 cases of prenatal fetoscopic open spina bifida repair: report of the International Fetoscopic Neural Tube Defect Repair Consortium.

BACKGROUND: The multicenter randomized controlled trial Management of Myelomeningocele Study demonstrated that prenatal repair of open spina bifida by hysterotomy, compared with postnatal repair, decreases the need for ventriculoperitoneal shunting and increases the chances of independent ambulation. However, the hysterotomy approach is associated with risks that are inherent to the uterine incision. Fetal surgeons from around the world embarked on fetoscopic open spina bifida repair aiming to reduce maternal and fetal/neonatal risks while preserving the neurologic benefits of in utero surgery to the child. OBJECTIVE: This study aimed to report the main obstetrical, perinatal, and neurosurgical outcomes in the first 12 months of life of children undergoing prenatal fetoscopic repair of open spina bifida included in an international registry and to compare these with the results reported in the Management of Myelomeningocele Study and in a subsequent large cohort of patients who received an open fetal surgery repair. STUDY DESIGN: All known centers performing fetoscopic spina bifida repair were contacted and invited to participate in a Fetoscopic Myelomeningocele Repair Consortium and enroll their patients in a registry. Patient data entered into this fetoscopic registry were analyzed for this report. Fisher exact test was performed for comparison of categorical variables in the registry with both the Management of Myelomeningocele Study and a post-Management of Myelomeningocele Study cohort. Binary logistic regression analyses were used to assess the registry data for predictors of preterm birth at <30 weeks' gestation, preterm premature rupture of membranes, and need for postnatal cerebrospinal fluid diversion in the fetoscopic registry. RESULTS: There were 300 patients in the fetoscopic registry, 78 in the Management of Myelomeningocele Study, and 100 in the post-Management of Myelomeningocele Study cohort. The 3 data sets showed similar anatomic levels of the spinal lesion, mean gestational age at delivery, distribution of motor function compared with upper anatomic level of the lesion in the neonates, and perinatal death. In the Management of Myelomeningocele Study (26.16±1.6 weeks) and post-Management of Myelomeningocele Study cohort (23.3 [20.2-25.6] weeks), compared with the fetoscopic registry group (23.6±1.4 weeks), the gestational age at surgery was lower (comparing fetoscopic repair group with the Management of Myelomeningocele Study; P<.01). After open fetal surgery, all patients were delivered by cesarean delivery, whereas in the fetoscopic registry approximately one-third were delivered vaginally (P<.01). At cesarean delivery, areas of dehiscence or thinning in the scar were observed in 34% of cases in the Management of Myelomeningocele Study, in 49% in the post-Management of Myelomeningocele Study cohort, and in 0% in the fetoscopic registry (P<.01 for both comparisons). At 12 months of age, there was no significant difference in the number of patients requiring treatment for hydrocephalus between those in the fetoscopic registry and the Management of Myelomeningocele Study. CONCLUSION: Prenatal and postnatal outcomes up to 12 months of age after prenatal fetoscopic and open fetal surgery repair of open spina bifida are similar. Fetoscopic repair allows for having a vaginal delivery and eliminates the risk of uterine scar dehiscence, therefore protecting subsequent pregnancies of unnecessary maternal and fetal risks.

Fetal Urinoma Due to Circulatory Disorders in an Umbilical Artery: Case Report.

Fetal urinoma is defined as an encapsulated accumulation of extravasated urine within the perirenal space or retroperitoneum. It is an uncommon finding in prenatal practice, and the vast majority of known cases are strongly associated with the existence of a urinary obstruction, such as posterior urethral valves, ureteropelvic junction obstruction, or ureterocele. We report a unique case of prenatally detected fetal bladder urinoma that occurred in the absence of an apparent obstructive uropathy, but was associated with extensive ischemic necrosis and calcifications of adjacent bladder wall, coexistent with signs of vascular supply decompensation.

BOLD-MRI demonstrates acute placental and fetal organ hypoperfusion with fetal brain sparing in response to phenylephrine but not ephedrine.

INTRODUCTION: We previously reported blood oxygen level dependent MRI (BOLD-MRI) for monitoring placental and fetal hemodynamic changes in mice following maternal hypercapnia. Here we use BOLD-MRI to compare the placental and fetal hemodynamic effects of different maternal vasopressors in mice. METHODS: Pregnant ICR mice (n = 16; E17.5) anesthetized with pentobarbital (80 mg/kg i.p.) were placed supine in a 4.7-T Bruker Biospec MRI. Following baseline images, equipotential doses of ephedrine (10 mg/kg) or phenylephrine (10mcg/kg) were administered intravenously. Changes in placental and fetal signal were analyzed from T2*-weighted gradient echo MR images (TR/TE = 147/10 ms). Different regions of interest (placenta, fetal heart, fetal liver and fetal brain) were identified. Percentage change of BOLD-MRI signal intensity (SI) were presented as time curves. RESULTS: Ephedrine and phenylephrine elicited markedly different effects. Phenylephrine caused an approximate 50% reduction in placental, fetal heart and fetal liver BOLD-MRI-SI, but fetal brain BOLD-MRI-SI was unchanged (statistically different from placenta and other fetal organs; p < 0.001), and the fetal brain/liver BOLD-MRI-SI ratio was markedly increased versus baseline (p < 0.001). Following ephedrine, placental BOLD-MRI-SI increased 30% and fetal heart BOLD-MRI-SI was reduced 26%; other fetal organs were unchanged. Blood gases were unchanged. DISCUSSION: Phenylephrine induced BOLD-MRI-SI changes suggestive of placental and fetal hypoperfusion with brain sparing. Ephedrine induced BOLD-MRI-SI changes suggestive of increased cardiac output; we speculate that reduced fetal heart BOLD-MRI-SI may be due to increased fetal myocardial oxygen extraction or metabolic acidosis. The result demonstrates the potential of BOLD-MRI as a non-invasive hemodynamic tool for assessing pharmacodynamics effects in the placental and fetus.

Determining gestational age using genome methylation profile: A novel approach for fetal medicine.

Gestational age determination by traditional tools (last menstrual period, ultrasonography measurements and Ballard Maturational Assessment in newborns) has major limitations and therefore there is a need to find different approaches. In this study, we looked for a molecular marker that can be used to determine the accurate gestational age of the newborn. To this end, we performed reduced representation bisulfite sequencing (RRBS) on 41 cord blood and matching placenta samples from women between 25 and 40 weeks of gestation and generated an epigenetic clock based on the methylation level at different loci in the genome. We identified a set of 332 differentially methylated regions (DMRs) that undergo demethylation in late gestational age in cord blood cells and can predict the gestational age (r = -.7, P = 2E-05). Once the set of 411 DMRs that undergo de novo methylation in late gestational age was used in combination with the first set, it generated a more accurate clock (R = .77, P = 1.87E-05). We have compared gestational age determined by Ballard score assessment with our epigenetic clock and found high concordance. Taken together, this study demonstrates that DNA methylation can accurately predict gestational age and thus may serve as a good clinical predictor.

[ADVANCES IN FETAL THERAPY IN COMPLICATED MONOCHORIONIC PREGNANCIES AND IN SEVERE CONGENITAL DIAPHRAGMATIC HERNIA: FIVE YEARS EXPERIENCE].

INTRODUCTION: : Minimally invasive fetal therapeutic procedures reduce the morbidity and mortality in monochorionic (MC) twins and in fetuses with congenital diaphragmatic hernia (CDH). MC pregnancies share their blood systems due to communicating vessels over their single placenta and may develop specific complications: Twin-to-Twin transfusion syndrome (TTTS), Selective intrauterine growth restriction (sIUGR), Twin Anemia-Polycythemia Sequence (TAPS), Twin Reverse Arterial Perfusion Syndrome (TRAP) or anomalies in one. Half of complicated MC require intrauterine interventions. Severe CDH is linked to a high rate of neonatal death due to pulmonary hypoplasia. Fetoscopic tracheal occlusion (FETO) with a balloon improves postnatal outcome. AIMS: A fetal therapy center was established in the Hadassah Medical Centers, Jerusalem in 2011 for intrauterine interventions. We report our 5 years' experience. METHODS: This prospective cohort follows the outcome of MC pregnancies and cases of severe CDH which underwent therapeutic fetal procedures in Hadassah between the years 2011-16. RESULTS: Out of 114 procedures, 95 were in MC: 84 monochorionic diamniotic twins, 7 monochorionic monoamniotic twins, 2 dichorionic triamniotic triplets and 2 monochorionic triplets. We treated 65 TTTS cases with fetoscopy and laser ablation of communicating vessels. The survival rate of both twins was 58.5% and at least one survived in 81.5% of the cases. In 2nd/3rd trimesters selective termination of 15 cases the survival rate of the remaining twin was 87%. In 11 cases of TRAP sequence treated with laser ablation of the feeding vessel the survival of the remaining twin was 91%. In 19 fetoscopies in severe CDH, 12 were for balloon insertion and 7 for removal. Endotracheal balloon was successfully placed in 11 of 12 cases (10 left-sided, 1 right-sided CDH). Balloon removal was prenatally performed by elective fetoscopy (n=7) or by intrapartum urgent puncture. There were no intrauterine fetal deaths. In isolated left-sided CDH the survival was 57%, whereas none survived in non-isolated left-sided CDH and right sided CDH. CONCLUSIONS: In-utero procedures are safe for the mother and increase newborn survival in MC pregnancies, thus specialized clinics are life-saving. FETO is a therapeutic option for severe CDH. Our results meet similar achievements reported by other leading world centers.

Increased incidence of preeclampsia in mothers of advanced age conceiving by oocyte donation.

PURPOSE: The aim of this study was to evaluate the risk of preeclampsia in women of advanced age who conceived through donated oocytes as compared with natural conceptions. METHODS: A historical prospective study of singleton live births of parturients ≥ 45 years of age at four university hospitals was conducted. For the purpose of the study, the population was divided by the mode of conception into two groups: oocyte donation and natural conception. The main outcome variable in this study was preeclampsia. Secondary outcomes included pregnancy-induced hypertension and Small for Gestational Age. RESULTS: Two hundred and seventy pregnancies were achieved naturally and 135 women conceived by oocyte donation. Mean age at delivery for the natural conception and oocyte donation groups was 45.7 and 47.8, respectively. Preeclampsia complicated 3 out of 270 (1.1%) natural conception pregnancies and 17 out of 135 (12.6%) oocyte donation conceptions. After adjusting for confounders, oocyte donation pregnancies were found to be associated with a 12-fold increased risk for preeclampsia (P = 0.001). Among oocyte donation pregnancies, the risk of preeclampsia was not affected by parity or age. CONCLUSIONS: A substantially increased risk for preeclampsia was found in oocyte donation pregnancies, suggesting that the foreign oocyte may play a specific biologic role in the development of preeclampsia after the age of 45.

BOLD-MRI demonstrates acute placental and fetal organ hypoperfusion with fetal brain sparing during hypercapnia.

INTRODUCTION: We evaluated changes in placental and fetal hemodynamics in rodents during acute hypercapnia using BOLD-MRI and Doppler ultrasound. METHODS: Animals were anesthetized with pentobarbital and, in consecutive 4-min periods, breathed: air, 21%O2:5%CO2, and 95%O2:5%CO2. BOLD-MRI: Pregnant ICR mice (n = 6; E17.5) were scanned in a 4.7-T Bruker Biospec spectrometer. Placenta and fetal liver, heart and brain were identified on True-FISP images. Percent change in signal intensity (SI) were analyzed every 30 s from T2*-weighted GE images (TR/TE = 147/10 ms). Doppler: Pregnant Wistar rats (n = 6; E18-20) were anesthetized with pentobarbital and received abdominal Doppler ultrasound. Umbilical artery pulsatility index (PI) and fetal heart rate were assessed at baseline and after two minutes of both hypercapnic challenges. RESULTS: BOLD-MRI: Normoxic-hypercapnia caused immediate marked reduction in SI in placenta (-44% ± 5.5; p < 0.001), fetal liver (-32% ± 6.4; p < 0.001) and fetal heart (-53% ± 9.9; p < 0.001) but only minor changes in fetal brain (-13% ± 3.4; p < 0.01), suggesting fetal brain sparing. Doppler: Normoxic-hypercapnia caused a marked increase in umbilical artery PI (+27.4% ± 7.2; p < 0.001) and a reduction in fetal heart rate (-48 bpm; 95%CI -9.3 to -87.0; p = 0.02), suggesting acute fetal asphyxia. CONCLUSIONS: Brief maternal hypercapnic challenge caused BOLD-MRI changes consistent with acute placental and fetal hypoperfusion with fetal brain sparing. The same challenge caused increased umbilical artery PI and fetal bradycardia on Doppler ultrasound, suggestive for acute fetal asphyxia. BOLD-MRI may be a suitable noninvasive imaging strategy to assess placental and fetal organ hemodynamics.

Influence of late-age births on maternal longevity.

PURPOSE: To examine the association between the mother's age at last birth and maternal long-term survival. METHODS: Data from three national censuses (1972, 1983, and 1995) and national birth and death records (1972-2009) were used to examine the association between age at last birth and mortality while accounting for potential confounders, such as parity. Age-adjusted mortality rates and Cox proportional hazard models were used in the analysis. RESULTS: A total of 887 women who delivered their last child after 45 years of age were identified from among 178,507 women (1,592,379 person-years). Age-adjusted mortality rates from 55 years of age were highest for childless women (9.2 per 1000) and decreased linearly (P < .001) for parous women with increased age at last birth (5.2 per 1000 for women aged ≥45 years at last birth). In models adjusted for age at first birth and parity, mortality risks were lowest among parous women with late-age births (≥45 years) compared with parous women with their last births before 35 years of age (hazard ratio, 0.58; 95% confidence interval, 0.40-0.86). CONCLUSIONS: This study provides new empirical evidence that late-age births are associated with maternal longevity, although a direct causal relation cannot be established with the information available.

Rejuvenating effect of pregnancy on the mother.

Aging is associated with reduced tissue regenerative capacity. In recent years, studies in mice have shown that transfusion of blood from young animals to old ones can reverse some aging effects and increase regenerative potential similar to that seen in young animals. Because pregnancy is a unique biological model of a partially shared blood system, we have speculated that pregnancy would have a rejuvenating effect on the mother. Recent studies support this idea. In this review, we will summarize the current knowledge of the rejuvenating effect of pregnancy on the mother.

The rejuvenating effect of pregnancy on muscle regeneration.

Aging is characterized by reduced tissue regenerative capacity attributed to a diminished responsiveness of tissue-specific stem cells. With increasing age, resident precursor cells in muscle tissues show a markedly impaired propensity to proliferate in response to damage. However, exposure to factors present in the serum of young mice restores the regenerative capacity of aged precursor cells. As pregnancy represents a unique biological model of a partially shared blood system between young and old organisms, we hypothesized that pregnancy in aged mice would have a rejuvenating effect on the mother. To test this hypothesis, we assessed muscle regeneration in response to injury in young and aged pregnant and nonpregnant mice. Muscle regeneration in the aged pregnant mice was improved relative to that in age-matched nonpregnant mice. The beneficial effect of pregnancy was transient, lasting up to 2 months after delivery, and appeared to be attributable to activation of satellite cells via the Notch signaling pathway, thus supporting the possibility that pregnancy induces activation of aged dormant muscle progenitor cells.

Outcomes of subsequent pregnancies after conservative treatment for placenta accreta.

OBJECTIVE: To estimate the association between conservative treatment for placenta accreta and subsequent pregnancy outcomes. METHODS: In a retrospective study, data were analyzed on women who received conservative treatment for placenta accreta (removal of the placenta with uterine preservation) at a tertiary hospital in Jerusalem, Israel, between 1990 and 2000. Data were collected on subsequent pregnancies and neonatal outcomes until 2010, and compared with those from a matched control group of women who did not have placenta accreta. RESULTS: A total of 134 women were included in both groups. Placenta accreta occurred in 62 (22.8%) of 272 subsequent deliveries in the study group for which data were available and 5 (1.9%) of 266 in the control group (relative risk [RR] 12.13; 95% confidence interval [CI] 4.95-29.69; P<0.001). Early postpartum hemorrhage occurred in 23 (8.6%) of 268 deliveries in the study group and 7 (2.6%) of 268 in the control group (RR 3.29; 95% CI 1.43-7.53; P<0.001). The odds ratio for recurrent placenta accreta in subsequent deliveries in the study group was 15.41 (95% CI 6.09-39.03; P<0.001). CONCLUSION: Although subsequent pregnancies after conservative treatment for placenta accreta were mostly successful, the risk of recurrent placenta accreta and postpartum hemorrhage is high in future deliveries.

Adrenal gland length in euploid and trisomy 18 fetuses at 11-13 weeks.

OBJECTIVES: To establish a normal range for fetal adrenal gland length at 11-13 weeks' gestation and to investigate whether the length is altered in fetal trisomy 18. METHODS: Fetal adrenal gland length was measured by three-dimensional ultrasound in fetuses at low risk of aneuploidies (n = 400) and another group at high risk, including 380 euploid fetuses and 41 with trisomy 18. The data of the low-risk group were used to establish a reference range of adrenal gland length with crown-rump length (CRL). In the high-risk group, adrenal gland length in the euploid and trisomy 18 groups was compared. RESULTS: In the low-risk group, fetal adrenal gland size increased exponentially with fetal CRL from a median of 2.3 mm at CRL of 45 mm to about 4.4 cm at CRL of 84 mm. In trisomy 18, the median adrenal gland length for CRL was significantly lower than the median in the low-risk group (-1.37 mm; interquartile range: - 1.67 to - 0.99 mm, p < 0.0001). In euploid fetuses, the adrenal gland size was not significantly from the low-risk group (p = 0.100). CONCLUSION: Trisomy 18 is associated with adrenal gland hypoplasia which is apparent at 11-13 weeks' gestation.

Hepatic artery Doppler in trisomy 21 and euploid fetuses at 11-13 weeks.

OBJECTIVE: To determine possible differences in hepatic artery flow between trisomy 21 and euploid fetuses at 11-13 weeks' gestation. METHODS: Hepatic artery pulsatility index (PI) and peak systolic velocity (PSV) were measured in fetuses at low risk of aneuploidies (n = 350) and another group at high risk, including 283 euploid and 47 with trisomy 21. The association of hepatic artery PI and PSV with trisomy 21, fetal nuchal translucency (NT) thickness, tricuspid regurgitation, and reversed a-wave in the ductus venosus was investigated. RESULTS: In the low-risk group, the median hepatic artery PSV was 10.0 cm/s and the 95th centile was 14.3 cm/s. The distribution of hepatic artery PI was skewed, but for PI of 2 or more the distribution was Gaussian. In 325 (92.9%) cases, the PI was 2 or more (high PI) and in 25 (7.1%) it was below 2 (low PI). In 33 (70.2%) of the trisomy 21 pregnancies, the PSV was above the 95th centile and the PI was below 2. Multiple regression analysis showed that in the prediction of hepatic artery PSV there were significant contributions from fetal karyotype, tricuspid regurgitation, and reversed a-wave in the ductus venosus, but not delta NT, pregnancy-associated plasma protein-A, or free ß-human chorionic gonadotrophin. CONCLUSION: Trisomy 21 at 11-13 weeks is associated with increased flow in the hepatic artery.

Liver volume in trisomy 21 and euploid fetuses at 11 to 13 weeks.

OBJECTIVES: To compare liver volume between trisomy 21 and euploid fetuses at 11 to 13 weeks' gestation. METHODS: Fetal liver volume was measured by 3D ultrasound in fetuses at low risk of aneuploidies (n = 200) and another group at high risk, including 148 euploid and 37 with trisomy 21. The association of liver volume with fetal nuchal translucency (NT) thickness, tricuspid regurgitation and reversed a-wave in the ductus venosus was investigated. RESULTS: In the low-risk group, fetal liver volume increased exponentially with fetal crown-rump length (CRL) from a median of 0.5 cm(3) at CRL of 45 mm to about 2.5 cm(3) at CRL of 84 mm. In 27 (73.0%) of the trisomy 21 fetuses liver volume was above the 95th percentile of the low-risk group, whereas in the euploid fetuses liver volume was not significantly altered (P = 0.521). There were no significant contributions to liver volume from fetal NT (P = 0.508), tricuspid regurgitation (P = 0.958) or reversed a-wave in the ductus venosus (P = 0.872). CONCLUSION: In trisomy 21 fetuses at 11 to 13 weeks liver volume is increased.

Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch.

Regenerative capacity is progressively lost with age. Here we show that pregnancy markedly improved liver regeneration in aged mice concomitantly with inducing a switch from proliferation-based liver regeneration to a regenerative process mediated by cell growth. We found that the key mediator of this switch was the Akt/mTORC1 pathway; its inhibition blocked hypertrophy, while increasing proliferation. Moreover, pharmacological activation of this pathway sufficed to induce the hypertrophy module, mimicking pregnancy. This treatment dramatically improved hepatic regenerative capacity and survival of old mice. Thus, cell growth-mediated mass reconstitution, which is relatively resistant to the detrimental effects of aging, is employed in a physiological situation and holds potential as a therapeutic strategy for ameliorating age-related functional deterioration.