Thyroid hormone and central nervous system development.
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Animals↗
Biomedical subjects
M D Kilby
Publications and source records attributed to M D Kilby.
Prenatal diagnosis and outcome in sacrococcygeal teratomas: a review of cases between 1992 and 1998.
A review of sacrococcygeal teratomas diagnosed in the antenatal period in the West Midlands region over a six year interval is reported. The aim of the study was to assess the contribution of ultrasound scanning to the management of cases and to determine the outcome of prenatally diagnosed sacrococcygeal teratomas. A retrospective review of 10 cases was performed to obtain pregnancy details, ultrasound scan data and outcome information. Two fetuses were electively aborted. Perinatal mortality was 62.5% in the remaining cases with all stillbirths and neonatal deaths occurring in babies delivered preterm (at or before 34 weeks' gestation). Marked increase in tumour size (mainly vascular/solid) was observed in five of the fetuses, which was often associated with local compression effects and the development of hydrops. Eight out of 10 cases were delivered vaginally, one following aspiration of the large cystic tumour. Three of the four neonates surviving to surgery underwent successful resection of their benign tumours. As well as guiding prognosis, serial ultrasound scans may also allow the mode of delivery to be planned more effectively. The importance of a multidisciplinary team approach to these difficult cases is emphasized.
Abortion, Induced↗
Prenatal diagnosis of tuberous sclerosis with intracerebral signs at 14 weeks' gestation.
We report the ultrasound detection of cranial abnormalities at 14 weeks' gestation in a fetus subsequently confirmed as having tuberous sclerosis using DNA linkage analysis within the affected family. The presence of asymmetrical ventricular enlargement persisted antenatally. Magnetic resonance imaging at 26 weeks indicated the possibility of poor gyral formation consistent with a neuronal migration disorder. Cardiac rhabdomyomata were not visualized on ultrasound scan until 30 weeks' gestation. Postnatal cranial ultrasound confirmed the significant neuropathology which was manifested by severe developmental delay and intractable fits in the child. The potential benefits of earlier diagnosis of tuberous sclerosis by cranial imaging are discussed, although in this patient the routine booking scan resulted in a path of prenatal diagnosis being undertaken which had originally been declined. A mechanism is proposed to explain the variable expression of tuberous sclerosis within this family based on altered TSC2 activity affecting neuronal migration.
Adult↗
Failure of platelet angiotensin II binding to predict pregnancy-induced hypertension.
OBJECTIVE: To determine whether measurement of platelet angiotensin II binding at 20 weeks' gestation identifies women destined to develop pregnancy-induced hypertension. METHODS: Over a 2-year period, we recruited 325 unselected, normotensive primigravidas from the hospital antenatal department after their routine 20-week scan appointments. Each woman had a singleton pregnancy, was normotensive at the time of entry into the study, and had an unremarkable medical history. Ninety-three nonpregnant women were recruited from the hospital staff for comparison. Platelet angiotensin II binding was measured in all participants. After delivery, the case notes were screened to determine pregnancy outcome. RESULTS: Two hundred sixty-seven women remained normotensive to delivery, 30 developed nonproteinuric pregnancy-induced hypertension, 23 developed proteinuric pregnancy-induced hypertension, four had transient hypertension, and one was diagnosed subsequently as having essential hypertension. The median platelet angiotensin II binding for the nonpregnant subjects was 15.7 fmol/10(9) platelets, which differed significantly from the value for normotensive pregnant subjects (4.8 fmol/10(9) platelets, P < .001) and from the value for those who developed either nonproteinuric pregnancy-induced hypertension (4.95 fmol/10(9) platelets) or proteinuric pregnancy-induced hypertension (7.2 fmol/10(9) platelets, P < .001). There was no significant difference between pregnant women who remained normotensive and those who developed nonproteinuric or proteinuric pregnancy-induced hypertension. CONCLUSION: Measurement of angiotensin II binding in the second trimester has no value as a screening test for nonproteinuric or proteinuric pregnancy-induced hypertension.
Adolescent↗
The 4 year outcome following the demonstration of bilateral renal pelvic dilatation on pre-natal renal ultrasound.
There is little in the literature regarding long-term prognosis in cases of fetal pyelectasis and calyceal dilatation. The aim of this study was to correlate antenatal ultrasound findings with outcome in a large group of children, most of whom had routine antenatal mid-trimester scans. 75 babies with bilateral pyelectasis and calyceal dilatation in the pre-natal period and complete radiological and clinical data were identified over a 3 year period. Pre-natal ultrasound was correlated with results of post-natal investigation and the frequency of post-natal surgery was established. Follow-up was documented to discharge or to at least 4 years of age. Prognosis was related to the degree of pelvic dilatation, but neonatal morbidity was much more likely to be associated with pre-natal calyceal dilatation and/or hydroureter. 68% (51 of 75) of babies had insignificant abnormalities on post-natal investigation, defined as either transient fetal pyelectasis and calyceal dilatation, extrarenal pelves, or transient neonatal pyelectasis and calyceal dilatation. Five babies died in the neonatal period, all classified as either moderate or severe disease. Of the surviving 70 cases (93.3%), 27% had renal anomalies that required treatment by prophylactic antibiotics or surgery. The remaining babies were conservatively managed and followed as outpatients. One child required transplantation and a further two had a severe degree of chronic renal failure by the age of 4 years. These data will be of value in prospective counselling.
Dilatation, Pathologic↗
Twin-twin transfusion syndrome.
Twin-twin transfusion syndrome is a complication of monochorionic twin pregnancies associated with extremely high perinatal morbidity and mortality. This article describes the ultrasound features associated with this condition and possible pathophysiological mechanisms. Management options are outlined, including recent development such as laser ablation of placental vascular communications.
Female↗
A case of recurrent congenital fetal anomalies associated with a familial subtelomeric translocation.
The potential of a new fluorescent in situ hybridization technique is discussed, which uses a complete set of telomeric probes to reveal cryptic chromosome rearrangements that remain undetected by standard cytogenetic analysis. We report the obstetric history of a patient who had a termination of pregnancy at 20 weeks for a fetus with multiple congenital anomalies but a normal male karyotype using conventional G-banding analysis on a mid-trimester placental biopsy. In a subsequent pregnancy, a diaphragmatic hernia and intra-uterine growth restriction were detected at 34 weeks' gestation and a fetal blood sample showed a normal female karotype. However, her child was born with dysmorphic features and additional severe abnormalities including microcephaly, anophthalmos and left fixed talipes. The child has shown marked developmental delay. In view of a strong family history of congenital abnormalities and recurrent miscarriage suggestive of a familial translocation, a fluorescent in situ hybridization technique using specific telomeric probes was performed on blood from the affected child and her parents. An unbalanced subtelomeric translocation was detected involving the long arms of chromosomes 2 and 7 in the child and a balanced translocation was detected in her father. Accurate genetic counselling and the opportunity for early prenatal diagnosis can now be offered to this family.
Abnormalities, Multiple↗
Prenatal diagnosis of mosaicism for partial trisomy 8: a case report including fetal pathology.
A case of prenatally diagnosed partial trisomy 8 is described. The 'syndrome' is associated with skeletal and cardiac anomalies, as well as hepatic calcification. Differing proportions of 47,XY, +der(8) and 46 XY were present in the different fetal tissues sampled. The highest proportion of 47,XY,+der(8) cells was found in the placenta.
Adult↗
Exomphalos (omphalocele)
Exomphalos affects approximately 3 in 10,000 births and can arise from a number of developmental insults. The clinical outcome is dependent upon the associated structural and chromosomal anomalies and the gestation at delivery. Accurate antenatal ultrasound diagnosis and karyotyping are important and allow informed prenatal and postnatal management decisions to be made. Prenatal care and counselling should be multidisciplinary and information should ideally be given to parents regarding prognosis and outcome based on prospectively collected population-based data.
Adult↗
Ontogeny of hepatocyte growth factor (HGF) and its receptor (c-met) in human placenta: reduced HGF expression in intrauterine growth restriction.
Severe intrauterine growth restriction (IUGR) is characterized by abnormal placentation. Mouse gene knockout studies show that an absence of either hepatocyte growth factor (HGF) or its receptor, c-met, leads to intrauterine death secondary to severe IUGR with deficient placentation. In this study, immunocytochemistry localized HGF protein throughout placental villi across gestation, whereas c-met protein was localized only to the perivillous trophoblast and vascular endothelium. Within the IUGR placentae, a reduction in HGF immunostaining within the villous stroma was observed. HGF mRNA was strongly expressed in the perivascular tissue around the stem villous arteries throughout gestation, with weaker expression within the villous stroma and the terminal villi. c-met mRNA expression was limited to the perivillous trophoblast, particularly in the first trimester, with only a faint hybridization signal from the villous stroma. Placental mRNA expression was examined quantitatively using a ribonuclease protection assay: HGF and c-met mRNA expression increased from the first to the second trimester, reaching a zenith before decreasing again through the third trimester to term. HGF mRNA levels were significantly reduced in the IUGR placentae (P = 0.036), whereas c-met mRNA expression was within the normal range for gestation. These findings suggest that HGF derived from the perivascular tissue of stem villous arteries may play an important role in controlling normal villous development. Whereas reduced expression of HGF within IUGR placentae does not prove a causative link with abnormal villous development, the association lends support to this possibility.
Adult↗
Intravenous immunoglobulin therapy in compromised pregnancies associated with antiphospholipid antibodies and systemic lupus erythematosus.
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Adult↗
11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction.
The type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), which inactivates cortisol (F) to cortisone (E), has been suggested to play a role in the ontogeny of the fetal pituitary-adrenal axis and also protect the developing fetus from the deleterious effects of circulating maternal glucocorticoids. The abundance of 11beta-HSD2 in the placenta and other fetal tissues was inferred from the F/E ratio in 17 term deliveries in both umbilical arterial (1.73 +/- 0.24, mean +/- SE) and umbilical venous blood (1.16 +/- 0.14) compared with adult peripheral venous blood (7.76 +/- 0.57, n = 70). Using sensitive assays for 11beta-HSD2 and an in-house human 11beta-HSD2 antibody, the expression and activity of this enzyme in fresh frozen human placenta increased progressively from first (8-12 weeks, n = 16) and second (13-20 weeks, n = 9) to third trimester (term) pregnancies (39-40 weeks, n = 50). Placental 11beta-HSD2 activity was significantly reduced in deliveries complicated by intrauterine growth restriction (IUGR) [25-36 weeks, n = 12, activity 380 pmol/mg/h median (225-671; 95% confidence interval)], compared with the term deliveries [888 (725-1362)] and with appropriately grown pre-term deliveries [27-36 weeks, n = 14, activity 810 (585-1269)], P < 0.05. In human pregnancy placental 11beta-HSD2 activity increases markedly in the third trimester of pregnancy at a time when maternal circulating levels of glucocorticoid are rising. The finding of attenuated placental 11beta-HSD2 activity in IUGR suggests that glucocorticoids may, in part, contribute to impaired fetal growth and that this is closely controlled in normal gestation through placental 11beta-HSD2 expression.
11-beta-Hydroxysteroid Dehydrogenases↗
A new lethal autosomal recessive skeletal dysplasia with associated dysmorphic features.
We report a fetus noted on routine ultrasonography at 21 weeks gestation to have a skeletal dysplasia with reduced ossification of shortened long bones and normal sized ribs. The consanguineous parents elected to continue the pregnancy and spontaneous labour occurred at 33 weeks gestation. The child died in the neonatal period. At necropsy, the main skeletal features were abnormal vertebrae with variation in shape and size, and ossification centres, short angulated long bones with distorted metaphyses and multiple abnormalities and fusions of the phalanges and metacarpals. In addition there was hydrops fetalis, a 'digit like' appendage overlying the left biceps muscle, a small chest with pulmonary hypoplasia and facial dysmorphism. In a subsequent pregnancy the fetus was noted at 13 weeks gestation to have nuchal translucency and bilaterally short femora. The fetus progressively developed hydrops fetalis and intrauterine death occurred at 22 weeks gestation. Post mortem examination revealed features very similar to the previous sibling. We suggest that this a new lethal osteochondrodysplasia syndrome. Recurrence in female siblings and parents who are double first cousins, strongly indicate autosomal recessive inheritance.
Bone and Bones↗
Use of intravenous immunoglobulin therapy in pregnancy in systemic lupus erythematosus and antiphospholipid antibody syndrome.
Systemic lupus erythematosus and antiphospholipid antibody syndrome are associated with an increased risk of intrauterine growth restriction, miscarriage, stillbirth and premature delivery. Recent advances in therapy during pregnancy have improved the outcome but there is still significant fetal and maternal morbidity and mortality. Treatment of patients failing conventional therapy during the second half of pregnancy is difficult and may be complicated by the development of preeclampsia. The addition of intravenous immunoglobulin therapy offers a low risk strategy for reducing autoantibody mediated disease and improving placental function in severely compromised, growth restricted pregnancies.
Antiphospholipid Syndrome↗
Fetal and maternal lipoprotein metabolism in human pregnancy complicated by type I diabetes mellitus.
Serum lipid, apolipoprotein concentration, and lipoprotein composition were determined in maternal and umbilical venous cord blood at delivery by elective Cesarean section (CS) in 10 singleton, full-term pregnancies with maternal insulin-dependent diabetes mellitus (type I DM), which predated pregnancy, and in 22 nondiabetic pregnancies. The objectives of the study were to determine the influence of maternal type I DM, and hence potential fetal overnutrition on fetal lipid metabolism. There were no significant differences in gestational age, fetal weight, or fetal serum insulin concentration between the type I DM group and those with nondiabetic pregnancies, although fetal venous cord blood glucose was 3.4 mmol/L (3.0-4.5 mmol/L) (median and 25th-75th percentiles) and 2.9 mmol/L (2.0-3.4 mmol/L), respectively, and maternal Hemoglobin A1c [9.6% (8.2-10.7%) and 6.8% (6.3-7.8%), respectively], was significantly greater in the type I DM subjects (P < 0.02 and 0.002 respectively). Plasma nonesterified fatty acid (NEFA) concentrations were lower in the type I DM mothers [0.85 mmol/L (0.56-2.31 mmol/L) compared with 1.14 mmol/L (0.88-1.24 mmol/L] in nondiabetic pregnancies; P < 0.0001). Serum high-density lipoprotein phospholipids (HDL-PL) were increased in type I DM mothers because of elevated HDL2 phospholipid [0.39 mmol/L (0.27-0.48 mmol/L) compared with 0.12 mmol/L (0.06-0.21 mmol/L), respectively, P < 0.01). The maternal HDL cholesterol (C) concentration was not significantly different in the uncomplicated and type I DM pregnancies. However, in the umbilical venous cord blood, serum levels of NEFA [0.49 mmol/L (0.33-1.29 mmol/L) in type I DM compared with 0.13 mmol/L (0.06-0.33 mmol/L) in nondiabetics; P < 0.02)], total cholesterol (TC) [2.87 mmol/L (1.65-4.86 mmol/L) in type I DM compared with 1.65 mmol/L (1.46-1.87 mmol/L) in nondiabetics; P < 0.02]; free cholesterol (FC) [0.97 mmol/L (0.60-1.26 mmol/L) in type I DM compared with 0.62 mmol/L (0.37-0.75 mmol/L) in nondiabetics; P < 0.05), and cholesteryl ester (CE) [1.90 mmol/L (1.44-3.33 mmol/L) in type I DM compared with 1.01 mmol/L (0.83-1.24 mmol/L) in nondiabetics; P < 0.02), triglyceride (TG) (1.06 [0.50-1.91) mmol/L in type I DM compared with 0.29 [0.25-0.36] mmol/l in nondiabetics; P < 0.001), phospholipid (PL) (2.52 [1.73-3.03) mmol/L in type I DM compared with 1.34 [1.27-1.48] mmol/L in nondiabetics; P < 0.01], and the apolipoproteins A-I and B had significantly higher concentrations in type I DM. In umbilical venous cord blood, ratios of HDL-TC and HDL-PL to apo AI, reflecting the lipid content of HDL, were reduced when the mother had type I DM during pregnancy (P < 0.02 and P < 0.0001, respectively). These results indicate that maternal type I DM may lead to a fetal serum lipoprotein composition more closely resembling that seen in the adult. In type I DM, maternal TG and PL and fetal TC, TG, PL, CE, and FC were correlated to NEFA levels (P < 0.05), but not to glucose, insulin secretion, or maternal control of type I DM. These data suggest that the enhanced supply of NEFA to the fetus in type I DM pregnancies may drive the synthesis of cholesterol as well as TGs and PLs.
Adult↗
Circulating thyroid hormone concentrations and placental thyroid hormone receptor expression in normal human pregnancy and pregnancy complicated by intrauterine growth restriction (IUGR).
Thyroid hormones are critical to growth and development of the human fetus. Abnormal placental development, a major cause of intrauterine growth restriction (IUGR), is associated with a high perinatal mortality and morbidity. Thyroid status has been postulated to play a role in the pathogenesis of such morbidity. In the present study, we have investigated fetal thyroid function and placental expression of thyroid hormone receptor (TR) alpha and beta variants during normal human pregnancy and in pregnancy associated with IUGR. Measurement of free thyroid hormones and TSH concentrations revealed significant rises in free T4 and free T3 between the second and third trimesters of normal pregnancy. Serum concentrations of free T4 and free T3 were lower in fetuses affected by IUGR, although serum TSH levels were not significantly different. Immunocytochemistry demonstrated the presence of TR alpha1, alpha2, and beta1 proteins within the nuclei of trophoblast and stromal placental cells. Immunostaining for these TR variants increased with increasing gestation in normal placenta. Comparison of IUGR placental samples with normal samples revealed greater immunostaining for TR alpha1, alpha2, and beta1 variants in IUGR. Examination of pretranslational expression of TR alpha1, alpha2, beta1, and beta2 variants by semiquantitative RT-PCR revealed increasing expression of TR alpha1, alpha2, and beta2 messenger RNAs with increasing gestation in normal pregnancy, which "mirrored" post-translational expression. However, and in contrast, there were no significant differences in expression of TR messenger RNAs in normal and IUGR placenta. The present findings of reduction in serum free thyroid hormones and increased expression of TR alpha and beta proteins in association with IUGR highlight the potential importance of thyroid status in influencing long-term fetal outcome in this condition.
Blotting, Western↗
Left ventricular hemodynamics in anemic fetal lambs.
OBJECTIVE: To assess the left ventricular determinants of cardiac output in 12 chronically instrumented fetal lambs, six of which where made anemic. METHODS: Twelve, singleton pregnant ewes were instrumented between 123-126 days gestation and chronic catheters placed in-situ. In six fetal lambs, isovolemic fetal anemia was induced (reducing the hematocrit from a mean of 35% to 20%). In a prospective study, absolute 'beat-to-beat' LV volumes and pressures were obtained (gestational age 131-134 days) using a conductance catheter method and a comparison made with non-anemic fetal lambs. RESULTS: The group of anemic fetuses (n = 6) had a significantly reduced hematocrit as compared to the control group (37% decrease: mean difference--13.4%; P < 0.001). The arterial blood gases of the two groups were not statistically different, with the exception of the pO2 and oxygen content which were significantly lower in the anemic group (P < 0.05). There was no significant change in fetal heart rate, LV preload (as assessed by venous pressure, end-diastolic volume and pressure) or mean arterial pressure between the anemic and control groups. However, a 75% increase in LV stroke volume was observed in the anemic fetal lambs (P < 0.05), secondary to a 61% fall in LV afterload (P < 0.05). There was no significant change in inherent myocardial contractility of the LV, although this did increase to approach statistical significance in the anemic group (P = 0.056). The diastolic time interval was increased by 22% in the anemic fetus, possibly allowing prolonged LV filling time. The indices measuring LV relaxation (Tau and dP/dtmin) were not significantly different in either group. CONCLUSIONS: This is the first study to report absolute left ventricular volumes in the anemic ovine fetus and the relationship of these data to LV pressure during the cardiac cycle. The model used produces a state of moderately severe, non-hydropic, isovolemic, fetal anemia consistent with those previously described. Although the anemic state was not prolonged, an observed increase in LV stroke volume (which is predominantly due to a decrease in afterload) has been described.
Anemia↗
Differential expression of HGF and Met in human placenta.
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Female↗