The association between first trimester placental biomarkers and placental lesions of maternal vascular malperfusion.

INTRODUCTION: Abnormal levels of first trimester placental biomarkers are associated with the development of placental syndrome (PS). However, prediction performance is moderate, possibly explained by the clinical heterogeneity of PS. Aim of this study is to investigate the association between first trimester biomarkers and the presence of maternal vascular malperfusion (MVM), as a marker for placental insufficiency. METHODS: This retrospective study included 195 women with available first trimester blood sample and placenta histological sections for examination at the Maastricht University Medical Centre. Women were divided into 4 groups, based on the presence of having MVM lesions and/or PS. Levels of PAPP-A, PlGF and sFlt-1 were measured and MVM lesions were classified according to the Amsterdam Placental Workshop Group Consensus Statement. RESULTS: MVM occurrence was observed in 32% of the uncomplicated pregnancies. Women with MVM (regardless of the PS) had lower levels of PAPP-A (p = 0.038) and sFLt-1 (p = 0.006), and a non-significant trend for lower PlGF and sFlt-1/PlGF ratio compared to women without MVM. Low PAPP-A levels individually and in combination with the presence of PS was significantly associated with MVM lesions (aOR = 3.0 and 6.1, respectively), as did the combination of low PlGF levels and PS (aOR = 4.6). In women with PS, having MVM increased the incidence of fetal growth restriction, small for gestational age neonates, lower birthweight and adverse neonatal outcome. DISCUSSION: Our findings suggest that MVM lesions were found to be associated with increased obstetric risks due to early placental dysfunction that can potentially be predicted by the use of first trimester biomarkers.

In vitro secretion of peptide hormones by the human placenta: I. ACTH.

In order to address the question of autonomy of placental hormone secretion, fresh human term placentae were utilized for the preparation of small tissue fragments. The fragment pool was divided over four parallel chambers in a superfusion apparatus and could thus serve as both control and experiment under identical in vitro conditions. Oxygen consumption was substantial and could be maintained for at least 5 h. Adrenocorticotrophic hormone (ACTH) concentrations in the effluent buffer were estimated by radioimmunoassay and bioassay. Both non-specific (membrane depolarization with 45 mM KCl) and specific (isoproterenol at 10(-7) M) stimulation increased the ACTH secretion from 10 to 20 pg/min/g to 60 to 80 pg/min/g. Propranolol blocked the adrenergic stimulation almost completely, indicating the specificity of the effect. Thus, in terms of in vitro ACTH secretion, the human placenta can be stimulated and therefore does not seem to behave in an autonomous manner.

Fluid transport across human fetal membranes affected by human amniotic fluid prolactin: an in vitro study.

The aim of the study was to investigate the effects of human amniotic fluid (AF) prolactin (PRL) on the transfer of fluids across human fetal membranes, detected in vitro by weight change. We have developed a system, consisting of an inner compartment (4 ml), suspended in an outer compartment (40 ml), and separated from it by a 2 cm2 circular piece of fresh human fetal membrane (amnion, chorion and adhering decidua). The weight of the inner compartment was continuously registered with an electronic precision balance. Osmolality changes or hydrostatic pressure differences did not affect the rate of mass transfer through the membranes. Potassium cyanide significantly influenced the mass transfer in favour of the applied hydrostatic pressure difference (+2 cm H2O to the amniotic side) or osmotic pressure difference (amniotic side 265 mosm/kg/decidual side 285 mosm/kg). The PRL preparations used were human and ovine pituitary PRL, as well as three fractions isolated from human AF by fractionated ammonium sulphate and ethanol precipitations, followed by Sephacryl chromatography. All PRL preparations were tested in physiologic concentrations (0.5 to 5 micrograms/ml). Only the two largest AF-PRL variants significantly disturbed the balance of fluid transfer across the membranes when added to the fetal (amniotic) side of the membrane. This resulted in a net increase in fetomaternal transfer of 120 to 180 microliters. This effect could be repeated and lasted for at least 25 minutes. Using an antibody against hPRL the effect was completely blocked. Neither AF-PRL added to the maternal (decidual) side of the membrane nor oPRL or human pituitary PRL added to the amniotic or decidual side changed the rate of mass transfer across the membranes.

Automated assignment of behavioural states in the human near term fetus.

Thirty-five 2-h recordings of fetal heart rate and fetal movements, made at 38-39 weeks of gestational age, have been analyzed in a partly automated procedure. Involved were 17 nulliparous and 19 multiparous women. To minimize subjectivity the classification of the heart rate was performed in a Delphi group opinion procedure consisting of three rounds. In the third round, three independent investigators classified 89.1% of the total tracing time as pattern A through D. The investigators could not classify 6.1% of the tracing time in any of the available categories. The percentages of coincidence of state parameters did not differ significantly between the fetuses of nulli- and multiparous women. Fifty percent of the fetuses showed true behavioural states, both in the nulli and the multiparous women. The percentage of time spent in state 1F was higher in the multiparous group (P less than 0.05). The other percentages of states did not differ significantly, neither did the duration of the enclosed epochs. The advantages and disadvantages of the automated assignment of fetal behavioural states are discussed.

Validity of a selective policy for ultrasound examination of fetal congenital anomalies.

The validity of the Stage II ultrasound examination for fetal congenital anomalies has been determined. Only pregnancies that fulfilled certain criteria, i.e. obstetric complications (IUGR, polyhydramnios, immature-premature uterus contractions), or women with a history of congenital anomalies qualified. Five hundred and fifteen pregnant women were examined. Follow-up evaluation was available on 481 pregnancies (494 neonates). Of these children 102 (21%) appeared to have one or more structural anomaly following birth. In 88 of them at least one congenital anomaly had been detected antenatally by the Stage II ultrasound examination. The sensitivity of the ultrasound scanning procedure was 86%, the specificity 100%. The validity of the applied selection criteria for the Stage II ultrasound examination was studied in 2059 women who had delivered consecutively in our hospital. One hundred and eighty-one had the Stage II ultrasound examination performed. Thirty-six of these 181 women delivered an infant with a structural anomaly (20.0%). The remaining 1878 did not qualify for the Stage II ultrasound examination. From these pregnancies 24 infants were born with a structural anomaly (1.3%). The sensitivity of the applied selection criteria was 60% and the specificity 93%. The incidence of congenital anomalies was strikingly higher in pregnancies scanned for reasons of obstetric complications than in the pregnancies scanned for a history of congenital anomalies. The necessity of the Stage II ultrasound examination in every pregnancy is questioned on the basis of the results.

A randomized clinical trial of antibiotic prophylaxis in cesarean section: maternal morbidity, risk factors and bacteriological changes.

In the United States, several well-designed studies have demonstrated the efficacy of short-course antibiotic prophylaxis in cesarean sections. The present prospective study was conducted on 150 patients in a Dutch university hospital in a randomized double-blind fashion. Cefoxitin was administered according to a three-dose, 12 h regimen, the first injection given immediately after clamping of the umbilical cord. The rate of infection among the patients was significantly reduced by prophylaxis, judging from febrile morbidity, endometritis, wound infections, urinary tract infections and need for postoperative antibiotic therapy. The prophylactic use of the cefoxitin was especially effective in the secondary cesarean section population. Three risk factors significantly correlated with increased risk of infection: labor, rupture of membranes and pelvic examination. Postoperative cervical cultures showed a significant reduction of bacteria in the cefoxitin group. No shift towards resistant pathogens was demonstrable.

The fetal skeleton; ultrasonographic evaluation of the normal growth.

A longitudinal study of normal fetal growth is presented as a basis for prenatal diagnosis of skeletal dysplasias. The lengths of fetal limb bones, abdominal circumference, thoracic circumference, head circumference, foot length and orbital diameters were measured in 63 normal fetuses between 12 and 40 weeks of gestation. From these data, ratios were calculated which may have relevance for the prenatal diagnosis of skeletal dysplasias. In addition, rates were calculated for fetal limb growth. From these parameters (absolute measurements, ratios and growth rates), the 10th, 50th and 90th centiles were determined as reference values.

Twin pregnancy: case reports illustrating variations in transfusion syndrome.

The twin transfusion syndrome is diagnosed in 5.5% to 14.6% of monochorionic twins and the classical picture reveals a small anemic donor and a large plethoric recipient. Many other clinical discrepancies have been described. Today, by ultrasound it is possible to diagnose the syndrome in (early) pregnancy. In these case reports different clinical pictures and the importance of ultrasound are described. In twin pregnancies repeated ultrasound examinations should be considered with the consequences of vascular anastomoses.

Single- versus three-dose cefoxitin prophylaxis in caesarean section: a randomized clinical trial.

The present study was undertaken to determine the minimal effective antibiotic dosage in caesarean section prophylaxis. The study was conducted at the Academisch Ziekenhuis der Vrije Universiteit in Amsterdam (Amsterdam Free University Hospital) to compare the efficacy of one dose of cefoxitin (2 g) with three administrations of 2, 1 and 1 g respectively. In this prospective and double-blind study, 66 patients were given one dose and 72 patients received three doses. In terms of febrile morbidity, endometritis, wound infection, urinary tract infection and need for postoperative antibiotic therapy, the three-dose group showed fewer postoperative infections: as to wound infections (p less than 0.05) and therapeutic antibiotic use (p less than 0.025) these differences were statistically significant. The numbers of days of hospitalization after the caesarean section also showed differences: 10.6 +/- 2.6 versus 9.8 +/- 1.5 days in the one- and three-dose groups respectively (p less than 0.05). It is concluded that, contrary to several reports in the literature, prophylaxis consisting of three administrations of cefoxitin is to be preferred. No significant allergic or adverse reactions were observed in our patients.

Secretion of cefoxitin in breast milk following short-term prophylactic administration in caesarean section.

In this study we investigated whether cefoxitin administered prophylactically to the mother in caesarean section could be demonstrated in breast milk. For this purpose 25 samples of breast milk were obtained from 18 patients to whom either 2 or a total of 4 g of cefoxitin had been administered during and following caesarean section. Cefoxitin was determined by means of a modified HPLC method and appeared demonstrable in only one case in a concentration of 0.9 micrograms/ml. On these grounds nursing need not be advised against when prophylactic cefoxitin is briefly administered to the mother during and following caesarean section.

Fetal behavioural states in epileptic pregnancies.

Possible negative effects of maternal antiepileptic medication on fetal motility and heart rate patterns were examined at 32 and 38 wk of gestation. Fetal eye and body movements were recorded using 2 real-time ultrasound units. Comparison between pregnancies with antiepileptic medication and control pregnancies did not show marked differences in patterns of motility and heart rate. Duration of sleep states, occurrence and duration of body movements in state 2F and statistical parameters of heart rate level and heart rate variability were very similar for both groups. This preliminary study, limited to mostly combined treatment with antiepileptic drugs, could not demonstrate any obvious effect on fetal neuromuscular development from maternal antiepileptic medication.

Ratios between growth parameters for the prenatal ultrasonographic diagnosis of skeletal dysplasias.

The clinical applicability and usefulness of nine ratios that express the relation between particular fetal growth parameters were tested in ten fetuses affected by skeletal dysplasia. The results were compared with the ratios calculated from five growth-retarded fetuses without structural anomalies. Femur/foot, femur/head circumference, head circumference/thoracic circumference and abdominal circumference/thoracic circumference ratios are useful additional parameters for the prenatal ultrasonographic diagnosis of skeletal dysplasias. They reduce the problem of an unknown gestational age and help to distinguish between fetal skeletal dysplasia and intra-uterine growth-retardation caused by other factors.

Fetal hiccups; characteristics and relation to fetal heart rate.

In 35 two-hour recordings of fetal heart rate and fetal movements, 14 periods of fetal hiccups were present (1.2% of the recording time) with a median duration of 3.5 min (range 1 to 8 min). No specific relation to behavioural states or movement patterns could be identified. The hiccupping frequency varied from 10 to 21 per min. Within a hiccupping spell, the mean frequency decreased from 20 +/- 11 to 12 +/- 6.2 per min. A small but evident increase in baseline frequency was present during the hiccupping spells, independent from other movements performed by the fetus.

Fetal mouth movements during behavioural states 1F and 2F.

The aim of this study was to investigate the characteristics of mouth movements during behavioural states 1F (quiet sleep) and 2F (active sleep) in the near term human fetus. Thirty-six women participated. Fetal heart rate and fetal movements were recorded for 2 hours continuously. Videotapes with enclosed periods 1F and 2F were replayed to record fetal mouth movements in detail. During 1F, regular mouthing movements dominated (present in 74%), while jaw opening, yawn and grimace were only observed in 5 to 16% of the recordings. Tongue protrusion was not observed in 1F. In all 2F periods jaw opening was present (100%), while tongue protrusion, yawn and grimace were also frequently observed. Regular mouthing was observed in 2F in only two fetuses. For regular mouthing and sucking, onset-to-onset intervals of clusters, cluster duration, and number and frequency of movements within clusters were calculated. In all aspects the differences between these two types of movement were statistically significant. Within the clusters of regular mouthing a decline in the mouthing frequency was found. The data on fetal regular mouthing correspond with observations in the neonate.

Fetal heart rhythms during behavioural state 1F.

Behavioural state 1F (quiet sleep) of the term fetus is defined on the basis of absence of eye and body movements, and the presence of a specific heart rate pattern (FHRP A), characterized by a stable heart rate with a small oscillation bandwidth. In the present paper the fetal heart rate pattern was studied in 39 enclosed periods with absence of fetal eye and body movements. In 37 periods the heart rate pattern met the criteria of FHRP A. Within FHRP A various distinct types of heart rhythm could be distinguished related to presence of breathing or regular mouthing and complete absence of movements. The bandwidth in the various heart rhythms differed significantly and was largest during breathing movements. During regular mouthing an oscillatory pattern was present with a frequency similar to the frequency of the clusters of mouthing movements. In 2 periods the heart rate deviated from the definition for FHRP A, i.e. a sinusoidal-like rhythm associated with sucking movements. These observations demonstrate the strong association between the fetal heart rate pattern and fetal movements during behavioural state 1F.

Clinical report on the L95P mutation in a Dutch family with paraganglioma.

OBJECTIVE: To describe the new L95P mutation of the paraganglioma 1 gene for glomus tumors in a Dutch paraganglioma 1 family with six affected family members and to report the clinical findings and results of treatment in nine glomus tumors with a maximum follow-up of 34 years. SETTING: Tertiary referral centers. RESULTS: Mutation analysis of the SDHD gene of paraganglioma 1 showed the L95P mutation in six affected family members and two nonaffected carriers protected from becoming affected by genomic imprinting. In six affected family members, nine glomus tumors (five glomus caroticum tumors, two glomus vagale tumors, and two glomus jugulare tumors) were traced. The ages at presentation varied from 25 to 61 years. In two of six affected family members with a total of four tumors, all the tumors were traced in the extended family study, using magnetic resonance imaging; at that time these tumors were silent. After radiotherapy in one patient at the age of 34 years, a T4 planocellular carcinoma of the tongue occurred within the previous radiation field 27 years later, when the patient was 61 years old. Volume measurements of three untreated glomus tumors (two glomus vagale tumors, one glomus caroticum tumor) during 25 months showed an increase in two tumors (left glomus caroticum, left glomus vagale tumor) and a decrease in one tumor (right glomus vagale tumor). Surgery to remove two bilateral and one unilateral glomus caroticum tumors was successful. A wait-and-see policy is being applied to two glomus vagale tumors. CONCLUSIONS: In family members of paraganglioma 1 patients, mutation analysis can be used to make an early diagnosis of glomus tumors. Radiotherapy may have induced a carcinoma. Modalities of treatment can include a wait-and-see policy. Long-term follow-up studies on the natural course of glomus tumors are needed to improve decisions about treatment modalities.

Some variants of lethal neonatal short-limbed platyspondylic dysplasia: a radiological ultrasonographic, neuropathological and histopathological study of 22 cases.

Data on twenty-two infants with lethal neonatal short-limbed platyspondylic dysplasia are reported. Thanatophoric dysplasia (TD) is the most frequent diagnosis in this group. TD combined with a cloverleaf skull (CS), has been variably classified. TD type 1 with curved femora is rarely combined with CS; TD type 2 with straight femora is almost always associated with CS. Other varieties of TD, known as 'Torrance', 'San Diego' or 'Luton' types, are separate entities. Apart from the differences in radiography and osteochondrohistology, the temporal-lobe abnormalities seen in TD were absent in one of the cases of the 'Torrance' variety. There were also differences in the composition of the cartilage glycosaminoglycans between this case and TD. Nearly all of the cases of these different types mentioned in the literature, including those of this study group, have been sporadic and may result from new dominant mutations. Documentation and classification by full (postmortem) radiography and osteochondrohistology is essential for two reasons. It will be the foundation for the clinical geneticist to inform the parents about the risk of recurrence. It will also be the basis for a biochemical or molecular-biological classification in the near future.