Nicholas M. Fisk

Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study

Abstract Objective: To investigate whether maternal anxiety in the third trimester is associated with an increased uterine artery resistance index. Design: Cohort based study. Subjects: 100 pregnant women, with a mean gestation of 32 weeks. Outcome measures: Self rating Spielberger questionnaire for state anxiety and trait anxiety, and uterine blood flow waveform patterns as assessed by colour Doppler ultrasound. Results: A significant association was found between uterine artery resistance index and scores for both Spielberger state anxiety and trait anxiety (rs=0.31, P<0.002 and 0.28P<0.005 respectively). Women with state anxiety scores >40 (n=15) had a higher mean uterine resistance index than those with scores —40 (mean difference with mean resistance index 24%, 95% confidence interval 12% to 38%; P<0.0001). Similarly, women with trait anxiety scores >40 (n=32) had a higher mean resistance index than those with scores —40, although to a lesser extent. The presence of notches in the waveform pattern produced by uterine artery blood flow was found in 4/15 (27%) women with high state anxiety scores compared with 4/85 (5%) with low anxiety scores (P<0.02). Conclusions: This study shows an association between maternal anxiety in pregnancy and increased uterine artery resistance index. It suggests a mechanism by which the psychological state of the mother may affect fetal development, and may explain epidemiological associations between maternal anxiety and low birth weight. The influence of maternal anxiety may be one mechanism by which the intrauterine environment contributes to later disease in offspring.

Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.

The biological properties of stem cells are key to the success of cell therapy, for which MSC are promising candidates. Although most therapeutic applications to date have used adult bone marrow MSC, increasing evidence suggests that MSC from neonatal and mid‐gestational fetal tissues are more plastic and grow faster. Fetal stem cells have been isolated earlier in development, from first‐trimester blood and hemopoietic organs, raising the question of whether they are biologically closer to embryonic stem cells and thus have advantages over adult bone marrow MSC. In this study, we show that human first‐trimester fetal blood, liver, and bone marrow MSC but not adult MSC express the pluripotency stem cell markers Oct‐4, Nanog, Rex‐1, SSEA‐3, SSEA‐4, Tra‐1‐60, and Tra‐1‐81. In addition, fetal MSC, irrespective of source, had longer telomeres (p < .001), had greater telomerase activity (p < .01), and expressed more human telomerase reverse transcriptase (p < .01). Fetal MSC were also more readily expandable and senesced later in culture than their adult counterparts (p < .01). Compared with adult MSC, first‐trimester fetal tissues constitute a source of MSC with characteristics that appear advantageous for cell therapy.

Placental angioarchitecture in monochorionic twin pregnancies: Relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome ☆ ☆☆

OBJECTIVE We sought to correlate placental vasculature with fetal growth and outcome in monochorionic twins. STUDY DESIGN Eighty-two patients with consecutive monochorionic pregnancies underwent biweekly ultrasonography for determination of fetal growth and well-being. After delivery, blinded placental injection studies delineated vascular anastomoses and territory share. Degree of balance in arteriovenous anastomoses equaled the number of arteriovenous anastomoses in one direction minus the number in the other. RESULTS Pregnancies affected by fetofetal transfusion syndrome (n = 21) had numbers of arteriovenous and venovenous anastomoses that were similar to those in pregnancies without fetofetal transfusion syndrome but fewer arterioarterial anastomoses (P <.0001). Fetofetal transfusion syndrome occurred in 78% of pregnancies with >/=1 arteriovenous and no arterioarterial anastomoses. Birth weight discordancy correlated with placental territory discordancy (P <.0001) and the degree of balance in arteriovenous anastomoses (P =.004). The larger placental share twin had a greater growth velocity than its smaller placental share co-twin (P =.008) for all but one anastomotic pattern. Where arteriovenous anastomoses were aligned with the net venous outflow to the fetus with the smaller territory, co-twins had similar birth weights and growth velocities irrespective of placental share. Fetal survival was higher in pregnancies with an arterioarterial anastomosis (P =.01) but lower with a venovenous anastomosis (P =. 01). Survival of both fetuses was inversely associated with birth weight discordancy (P <.0001). CONCLUSION Although interrelationships among the various types of anastomoses are complex, our data suggest that the placental territory share and the pattern of arteriovenous anastomoses influence fetal growth, that arterioarterial anastomoses protect against fetofetal transfusion syndrome, and that venovenous anastomoses reduce perinatal survival.

Fetal plasma cortisol and β-endorphin response to intrauterine needling

Abstract Summary The purpose of this study was to investigate whether the fetus mounts a hormonal stress response to a potentially painful procedure, intrauterine needling. Cortisol and β-endorphin concentrations in fetal plasma obtained during uncomplicated fetal blood sampling or intrauterine transfusions by needling the fetal intra-abdominal portion of the umbilical vein (intrahepatic vein) were compared to hormone concentrations in fetal plasma obtained by the conventional technique of needling the placental cord insertion, which is not innervated. Cortisol and β-endorphin concentrations did not increase within 10 minutes of fetal abdominal needling (n=15). However, more prolonged needling during transfusion at the intrahepatic vein was associated with an increase in fetal plasma cortisol (median increase 48 nmol/L; 95% Cl, 23-86) and β-endorphin (207 pg/mL; 113-307) concentrations compared to transfusion at the placental cord insertion (p These data suggest that the fetus mounts a hormonal stress response to invasive procedures. They raise the possibility that the human fetus feels pain in utero, and may benefit from anaesthesia or analgesia for invasive procedures.

Angioarchitecture of monochorionic placentas in relation to the twin-twin transfusion syndrome

OBJECTIVE Twin-twin transfusion syndrome in the midtrimester is associated with a perinatal mortality rate exceeding 80%. Although attributed to intertwin transfusion along vascular anastomoses, these occur in all monochorial placentas, not just the 10% with twin-twin transfusion syndrome. We compared fetoplacental angioarchitecture in monochorionic twin placentas with and without twin-twin transfusion syndrome. STUDY DESIGN The fetoplacental circulations of both twins in 20 monochorial placentas were perfused immediately after delivery under optimal physiologic conditions and anastomoses delineated by dye-contrast injection. Ten were from pregnancies with evidence of midtrimester twin-twin transfusion syndrome and 10 were from pregnancies without twin-twin transfusion syndrome. RESULTS Placentas from pregnancies with twin-twin transfusion syndrome had significantly fewer anastomoses than did those without twin-twin transfusion syndrome, both overall (median one versus six, respectively; p < 0.001) and for each of the different types (arterioarterial, venovenous, and arteriovenous, p < 0.001). Whereas multiple anastomoses were present in all controls, only one twin-twin transfusion syndrome placenta had more than a single communication. Anastomoses in the twin-twin transfusion syndrome group were more likely to be of the deep than the superficial type (80% vs 36% in controls, p < 0.01). CONCLUSIONS Placental vascular anastomoses in monochorial pregnancies complicated by twin-twin transfusion syndrome are both fewer in number and of a different type than those without twin-twin transfusion syndrome. These differences seem implicated in the underlying pathophysiologic features of twin-twin transfusion syndrome and are of relevance to the development of newer therapies such as placental laser surgery.

Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy

Fetal cells enter maternal blood during pregnancy and persist in women with autoimmune disease. The frequency of subsequent fetomaternal microchimerism in healthy women and its cell type is unknown. To test the hypothesis that fetal mesenchymal stem cells persist in maternal organs, we studied female bone marrow and ribs. Male cells were identified by XY fluorescence in-situ hybridisation in marrow-derived mesenchymal stem cells and in rib sections from all women with male pregnancies, but not in controls (9/9 vs 0/5, p=0.0005). We conclude that fetal stem cells transferred into maternal blood engraft in marrow, where they remain throughout life. This finding has implications for normal pregnancy, for obstetric complications that increase fetomaternal trafficking, and for graft survival after transplantation.

Superior osteogenic capacity for bone tissue engineering of fetal compared with perinatal and adult mesenchymal stem cells

Mesenchymal stem cells (MSCs) from human adult bone marrow (haMSCs) represent a promising source for bone tissue engineering. However, their low frequencies and limited proliferation restrict their clinical utility. Alternative postnatal, perinatal, and fetal sources of MSCs appear to have different osteogenic capacities, but have not been systematically compared with haMSCs. We investigated the proliferative and osteogenic potential of MSCs from human fetal bone marrow (hfMSCs), human umbilical cord (hUCMSCs), and human adult adipose tissue (hATMSCs), and haMSCs, both in monolayer cultures and after loading into three‐dimensional polycaprolactone‐tricalcium‐phosphate scaffolds.Although all MSCs had comparable immunophenotypes, only hfMSCs and hUCMSCs were positive for the embryonic pluripotency markers Oct‐4 and Nanog. hfMSCs expressed the lowest HLA‐I level (55% versus 95%–99%) and the highest Stro‐1 level (51% versus 10%–27%), and had the greatest colony‐forming unit–fibroblast capacity (1.6×–2.0×; p < .01) and fastest doubling time (32 versus 54–111 hours; p < .01). hfMSCs had the greatest osteogenic capacity, as assessed by von‐Kossa staining, alkaline phosphatase activity (5.1×–12.4×; p < .01), calcium deposition (1.6×–2.7× in monolayer and 1.6×–5.0× in scaffold culture; p < .01), calcium visualized on micro‐computed tomography (3.9×17.6×; p < .01) and scanning electron microscopy, and osteogenic gene induction. Two months after implantation of cellular scaffolds in immunodeficient mice, hfMSCs resulted in the most robust mineralization (1.8×–13.3×; p < .01).The ontological and anatomical origins of MSCs have profound influences on the proliferative and osteogenic capacity of MSCs. hfMSCs had the most proliferative and osteogenic capacity of the MSC sources, as well as being the least immunogenic, suggesting they are superior candidates for bone tissue engineering. STEM CELLS 2009;27:126–137

Survey of obstetricians' personal preference and discretionary practice

OBJECTIVE To determine obstetricians personal choices in relation to Down syndrome screening and mode of delivery for themselves or their partners. STUDY DESIGN Structured anonymous postal survey. All 282 obstetric consultants, senior registrars and registrars in NHS obstetric units within Londons M25 region were surveyed. RESULTS The response rate was 73% (206). Fifty one per cent (105) chose to have elective amniocentesis/CVS without a previous screening test when maternal age was > or = 35 years and 11% (23) when < 35 years. Of the remainder, the majority wanted both maternal serum screening and nuchal translucency rather than a single screening test. In relation to mode of delivery, 17% (33) of obstetricians chose elective caesarean section (CS) in the absence of any clinical indication. Of those who chose CS, 88% did so out of fear of perineal damage. However when faced with a mid-cavity instrumental delivery in the second stage, only 5% (8) wanted CS, the remainder choosing operative vaginal delivery. With an uncomplicated breech presentation, only 27% (55) opted for external cephalic version while 57% (114) chose elective CS. CONCLUSION This study demonstrates interventionist attitudes among a sizeable percentage of obstetricians in relation to antenatal screening and their own preferred mode of delivery. It suggests that obstetricians regard management options not normally available to pregnant women as valid choices for themselves or their partners.

Fetal outcome in obstetric cholestasis

Summary. Obstetric cholestasis has been associated with a high incidence of stillbirth and perinatal complications. Between 1975 and 1984, 83 pregnancies were complicated by cholestasis. Meconium staining occurred in 45%, spontaneous preterm labour in 44%, and intrapartum fetal distress in 22%. Of 86 infants two were stillborn and one died soon after birth. Perinatal mortality fell from 107 in a previous series from this hospital (1965–1974) to 35/1000 in this series. Cardiotocography, estimations of oestriol, liver function tests and ultrasonic assessment of amniotic fluid volume failed to predict fetal compromise, whereas amniocentesis revealed meconium in 8 of 26 pregnancies. Early intervention was indicated in 49 pregnancies, 12 because of fetal compromise. This study suggests that intensive fetal surveillance, including amniocentesis for meconium, and induction of labour at term or with a mature lecithin/sphyngomyelin ratio, may reduce the stillbirth rate in this ‘high‐risk’ condition.

Clinical and echographic features of in utero cardiac dysfunction in the recipient twin in twin-twin transfusion syndrome.

OBJECTIVE--Fetal twin-twin transfusion syndrome (TTTS) presenting in the second trimester has been associated with almost no perinatal survival until recently, when serial drainage of amniotic fluid has improved the prognosis to 70%-80%. Most recipient twins now survive but develop cardiac dysfunction. The study was undertaken to evaluate the abnormal echocardiographic features and clinical complications of cardiac disease in the recipient twin of TTTS. DESIGN--Antenatal and postnatal echocardiographic and clinical observational study. SETTING--Antenatal studies in a tertiary referral centre. Postnatal management and follow up were performed by the same paediatric cardiologist, either at the obstetric hospital or at the regional referral centre. PATIENTS--Twin pregnancies complicated by TTTS with severe polyhydramnios diagnosed earlier than 25 weeks that proceeded until viability (n = 5). INTERVENTION--Serial fetal echocardiography with colour Doppler. Postnatal echocardiography in the first week and between two and seven months. Serial amnioreduction was performed in all pregnancies. Digoxin treatment, pericardiocentesis, paracentesis, or laser ablation of placental anastomoses was undertaken when there was hydrops. RESULTS--Increased cardiothoracic ratio and tricuspid regurgitation were seen in all recipient twins. High pulmonary artery velocities developed in three. One recipient twin died a week after delivery of endocardial fibroelastosis and infundibular pulmonary stenosis. Two other had balloon dilatation for pulmonary stenosis, one shortly after birth and one at four months. A further twin has apical thickening of the right ventricle at six months. The remaining recipient twin had normal echocardiographic findings at follow up. CONCLUSION--This report characterises for the first time a cardiac disease acquired in utero in the recipient twin in pregnancies complicated by TTTS. Clinical manifestations in utero range from mild to critical pulmonary stenosis or lethal cardiomyopathy. Although perinatal prognosis seems to be related to the severity of dysfunction when first diagnosed in utero, follow up in infancy is recommended in view of the possibility of progressive pulmonary stenosis.