Maternal thyrotropin is independently related to small for gestational age neonates at term.

OBJECTIVE: Small for gestational age (SGA) newborns constitute still a major cause of perinatal morbidity and mortality. Overt thyroid disease is a known cause of preterm birth and low birthweight but in its untreated condition it is rare today. In this study, we investigated the possible relation between maternal thyroid function assessed in euthyroid women at each trimester and the incidence of term born SGA neonates. DESIGN: A prospective cohort study was performed. PATIENTS: Thyroid function was assessed at 12, 24 and 36 weeks gestation in 1051 healthy Caucasian women who delivered at ≥ 37 weeks gestation. MEASUREMENTS: One-way anova was used to compare mean TSH and FT4 levels between women with SGA neonates and controls. Multiple logistic regression analysis was performed to adjust for known risk factors of SGA. RESULTS: Seventy (6·7%) SGA neonates were identified and they were significantly more often born to women with a TSH ≥ 97·5th at first and third trimester. Multiple logistic regression analysis showed that smoking (OR: 4·4, 95% CI: 2·49-7·64), pre-eclampsia (OR: 2·8, 95% CI: 1·19-6·78) and TSH ≥ 97·5th percentile (OR 3·3, 95% CI 1·39-7·53) were significantly related to SGA. Maternal FT4 levels and TPO-Ab status were not associated with SGA offspring. CONCLUSIONS: Our data show that TSH levels in the upper range of the reference interval at different trimesters (3·0-3·29 mIU/l) are independently related to an increased risk of delivering SGA neonates at term.

A clinical prediction model to assess the risk of operative delivery.

OBJECTIVE: To predict instrumental vaginal delivery or caesarean section for suspected fetal distress or failure to progress. DESIGN: Secondary analysis of a randomised trial. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: 5667 labouring women with a singleton term pregnancy in cephalic presentation. METHODS: We developed multinomial prediction models to assess the risk of operative delivery using both antepartum (model 1) and antepartum plus intrapartum characteristics (model 2). The models were validated by bootstrapping techniques and adjusted for overfitting. Predictive performance was assessed by calibration and discrimination (area under the receiver operating characteristic), and easy-to-use nomograms were developed. MAIN OUTCOME MEASURES: Incidence of instrumental vaginal delivery or caesarean section for fetal distress or failure to progress with respect to a spontaneous vaginal delivery (reference). RESULTS: 375 (6.6%) and 212 (3.6%) women had an instrumental vaginal delivery or caesarean section due to fetal distress, and 433 (7.6%) and 571 (10.1%) due to failure to progress, respectively. Predictors were age, parity, previous caesarean section, diabetes, gestational age, gender, estimated birthweight (model 1) and induction of labour, oxytocin augmentation, intrapartum fever, prolonged rupture of membranes, meconium stained amniotic fluid, epidural anaesthesia, and use of ST-analysis (model 2). Both models showed excellent calibration and the receiver operating characteristics areas were 0.70-0.78 and 0.73-0.81, respectively. CONCLUSION: In Dutch women with a singleton term pregnancy in cephalic presentation, antepartum and intrapartum characteristics can assist in the prediction of the need for an instrumental vaginal delivery or caesarean section for fetal distress or failure to progress.

Fetal blood sampling in addition to intrapartum ST-analysis of the fetal electrocardiogram: evaluation of the recommendations in the Dutch STAN® trial.

OBJECTIVES: To evaluate the recommendations for additional fetal blood sampling (FBS) when using ST-analysis of the fetal electrocardiogram. DESIGN: Prospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. METHODS: In labouring women allocated to the STAN® arm of a previously published randomised controlled trial who underwent one or more FBS during delivery, we assessed whether FBS was performed according to the trial protocol and how fetal acidosis, defined as an FBS pH < 7.20, was related to ST-waveform analysis. MAIN OUTCOME MEASURES: The number of FBS showing fetal acidosis, related to the different STAN® criteria where additional FBS is recommended. RESULTS: Among 2827 women monitored with STAN®, 297 underwent FBS, of whom 171 (57.6%) were performed according to the predefined criteria and 126 were performed in absence of these criteria. In the first group, rates of fetal acidosis (pH < 7.20) were two of 18, none of nine, 12 of 111 and three of 33 when FBS was taken for abnormal cardiotocogram (CTG) at the start, intermediary CTG at the start, abnormal CTG >60 minutes, and poor electrocardiogram quality, respectively. When the predefined criteria were not met and ST-analysis showed no ST-events, only two incidents of fetal acidosis were seen. CONCLUSIONS: The performance of FBS is valuable in the advised STAN® criteria. When these criteria are not met, performance of FBS does not seem helpful in the detection of fetal acidosis.

Value of a single early third trimester fetal biometry for the prediction of birth weight deviations in a low risk population.

OBJECTIVE: To analyze the value of a single ultrasound biometry examination at the onset of the third trimester of pregnancy for the detection of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) at birth in a low risk population. The aim of this study was to develop a simple and useful method for the detection of growth deviations during pregnancy in primary care (midwife or general practitioner) practices. SETTING: A Dutch primary care midwifery practice. STUDY DESIGN: In an earlier study, we developed parity and sex specific fetal growth charts of abdominal circumference (AC) and head circumference (HC) on the basis of ultrasound data of a low-risk midwifery population in the Netherlands. In the present study, we calculated sensitivity, specificity and predictive values at different cut-off points of AC and HC for the prediction of growth deviations at birth. Patients booked for perinatal care between 1 January 1993 and 31 December 2003 (n=3449) were used for the identification of cut-off points (derivation cohort) and those admitted between 1 January 2004 and 31 December 2005 (n=725) were used to evaluate the performance of these cut-offs in an independent population (validation cohort). For the determination of SGA and macrosomia at birth, we used the recently published Dutch birth weight percentiles. RESULTS: Most promising cut-offs were AC or=75(th) percentile for the prediction of macrosomia (birth weight >or=90(th) percentile). Within the validation cohort these cut-offs performed slightly better than in the derivation cohort. For the prediction of SGA, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 53% (95% CI 49-58%), 81% (95% CI 80-83%), 26% (95% CI 23-29%), and 93% (95% CI 93-94%), respectively. The false positive rate was 74%. For the prediction of macrosomia, the values of these parameters were 64% (95% CI 59-69%), 80% (95% CI 78-81%), 23% (95% CI 20-26%), and 96% (95% CI 95-97%), respectively. Here, false positive rate was 77%. No cut-offs were found that predicted extreme birth weight deviations (or=97.7 percentile) sufficiently well. CONCLUSIONS: In a low risk population, we could predict future growth deviations with a higher sensitivity and in a significant earlier stage (at the onset of the third trimester of pregnancy) than with the use of conventional screening methods (i.e., palpation of the uterus only and fundus-symphysis measurement). Sonographic measurement of fetal abdominal circumference enables to detect more than half of cases of SGA at birth and more than two-thirds of cases of macrosomia with acceptable false-positive rates. We suggest that fetuses with biometry results below the 25(th) percentile or above the 75(th) percentile at the onset of the third trimester of pregnancy should be more intensively investigated in order to distinguish between pathology (e.g., IUGR or macrosomia) and physiology and to decide about the appropriate level of further perinatal care.

Perinatal audit on avoidable mortality in a Dutch rural region: a retrospective study.

OBJECTIVE: To analyse the mode and cause of perinatal mortality. SETTING: a rural Dutch region. STUDY DESIGN: Over a two-year period (1994-1995), data were collected in the 's Hertogenbosch region. A perinatal audit group investigated and classified the cause of death in an "intention to treat" and concensus model. We then analyzed who was responsible for the patient at the moment perinatal death occurred, or became inevitable. RESULTS: Out of 8509 newborns, 73 died between the 24th week of pregnancy till the 7th day post-partum (8.58 promille). Twenty-three cases (31.50%) were classified as probably or possibly avoidable. In the primary health care group (midwives, general practitioners) 6 out of 32 (18.75%), in the secondary care group (obstetricians) 15 out of 35 (44.86%) and in the tertiary care group 1 out of 4 (25.00%) were judged as probably or possibly avoidable. The degree of concensus in the perinatal audit committee was high (Kappa=0.9). IMPACT: The analysis of perinatal mortality identifies the cause of death and may help to improve perinatal health care. CONCLUSION: In this study, 31.55% of perinatal mortality was avoidable in the three levels of care. Intra-uterine growth retardation, congenital malformations and antepartum haemorrhage were the most determinant factors for perinatal mortality. The Dutch obstetrical care system as such, for example home deliveries, did not effect the perinatal mortality rate. Perinatal mortality rates presented by the Dutch Central Bureau of Statistics still shows a slight underregistration.

[The incidence of irregular antibodies in pregnancy: a prospective study in the region of the 's-Hertogenbosch]. / Het vóórkomen van irregulaire antistoffen in de zwangerschap; een prospectief onderzoek in de regio 's-Hertogenbosch.

OBJECTIVE: To determine the incidence and clinical relevance of irregular erythrocyte antibodies (IEA), in multiparous women and in primigravidal with a history of blood transfusion. DESIGN: Prospective longitudinal cohort study. METHODS: In the 's-Hertogenbosch area, the Netherlands, both primigravidae with a previous blood transfusion and multiparous women were tested for IEA in addition to the regular blood tests during the first trimester of pregnancy. If IEA were discovered, the partners were tested for the presence of the antigen involved. Blood samples of children of positive fathers were tested immediately post partum for signs of haemolytic disease of the newborn (HDN). RESULTS: During a 2.5-year period (August 1995-January 1998) a total of 2392 pregnant women were screened for IEA: 2204 multiparous women and 188 primigravidae women. In 65 women 81 IEA were discovered. In the group of 30 children positive for the antigen involved, 12 (40%) had clinical symptoms of HDN; intrauterine death was diagnosed once, one child died immediately after delivery. One child had signs of hydrops fetalis and two children needed an exchange transfusion. Phototherapy and/or regular blood transfusion were given to 7 children. Most cases of HDN were caused by anti-D, anti-Kell and anti-c antibodies. CONCLUSION: Non-RhD-IEA were found in 1.6% of pregnant women screened. First-trimester screening for IEA is recommended as it can be of help in early diagnosis and treatment of HDN.

An open-label study of the effects of a 24-day regimen of gestodene 60 microg/ethinylestradiol 15 microg on endometrial histological findings in healthy women.

OBJECTIVES: This open-label, non-comparative study was conducted at a single center to evaluate the effects on the endometrium of a 24-day regimen of a combined oral contraceptive containing gestodene (GTD) 60 microg and ethinylestradiol (EE) 15 microg. METHODS: Healthy parous women who were > or = 18 years old and had had regular menstrual cycles for the prior 3 months were randomly assigned to one of two groups. Subjects in group A underwent endometrial biopsies during the late luteal phase of the pretreatment cycle and between days 15 and 24 of cycle 6. Subjects in group B had biopsies between days 15 and 24 of cycle 3 and during the late luteal phase of the post-treatment cycle. GTD 60 microg/EE 15 microg was taken for the first 24 days of a 28-day cycle, followed by placebo pills for 4 days, for a total of six cycles. RESULTS: Data from 27 women were included in the analyses. Eleven of the 13 evaluable baseline biopsies were classified as secretory. Three of nine subjects with evaluable biopsies at cycle 3 and four of nine subjects with evaluable biopsies at cycle 6 had an atrophic endometrium. Post-treatment biopsies showed a typical secretory endometrium in seven of 11 subjects with evaluable biopsies. CONCLUSIONS: The results of this study show that the 24-day regimen of GTD 60 microg/EE 15 microg produced effective endometrial suppression.

Low-sodium diet in pregnancy: effects on blood pressure and maternal nutritional status.

In ninety-four Dutch nulliparous women the effects of a low-Na diet in pregnancy on blood pressure, energy and nutrient intake, Ca metabolism, Zn and Mg status and body composition were studied longitudinally. The women were randomly divided into an intervention group (n 41), which used a low-Na diet (mean urinary Na excretion 61 mmol/24 h) from week 14 of pregnancy until delivery and a control group (n 53; mean urinary Na excretion 142 mmol/24 h). No effect of the diet on blood pressure was observed. The use of a low-Na diet resulted in significantly reduced intakes of energy, protein, carbohydrates, fat, Ca, Zn, Mg, Fe and cholesterol. However, the women on the low-Na diet appeared to be able to adapt quite well to the reduced intake since Ca, Zn and Mg homeostasis was maintained. In the case of Ca and Mg this was probably due to the observed reduced urinary excretions of these nutrients. Non-significant reductions in weight gain (1.5 kg) and fat-mass gain (0.9 kg) over pregnancy were found in the women on the low-Na diet. No significant effects of the diet on birth weight or placental weight were observed.

[An enlarged ovary during pregnancy; perform surgery or not?]. / Een vergroot ovarium tijdens de graviditeit: wel of niet opereren?

In a 35-year-old gravida II para I at 8 weeks gestation a structure of approximately 5 cm across with varying echogenicity was identified by accident at the side of her right ovary. The findings were believed to be related to previously diagnosed endometriosis and therefore no surgical intervention was performed during pregnancy. Serum CA 125 level was increased. After delivery an endometrioid adenocarcinoma of the right ovary, FIGO stage 1C and histologically grade 3, was diagnosed, followed by a staging laparotomy and chemotherapy. Initially this resulted in a complete remission. After 7 months a relapse occurred, for which once more chemotherapy and later experimental treatment was started. In case of a tumour persisting after the 16th week of gestation, larger than 8-10 cm and/or with echodense/multilocular characteristics and/or with a persistently elevated serum CA 125 level, surgery during gestation ought to be considered.

The effects of continuous combined transdermal oestrogen-progestogen treatment on bleeding patterns and the endometrium in postmenopausal women.

Fifty postmenopausal women requiring hormone replacement therapy for the treatment of climacteric symptoms were recruited in six centers. All patients received a new combined norethisterone acetate (NETA)/oestradiol (E2)-TTS, (Estragest TTS, Ciba-Geigy Ltd), delivering 0.25 mg NETA and 50 micrograms E2 per day, continuously for 12 calendar months. Bleeding occurred in 38 (76%) of the 50 patients at any time during the 1 year treatment. The percentage of patients without bleeding increased gradually each month, from 24% in the second month to a relatively stable level of approximately 80% in month 7 and thereafter. Twenty-seven patients (54%) did not complete the whole trial period; 15 of which discontinued the treatment within the first few months due to irregular bleeding. In patients who remained in the trial, a clear decrease in the frequency and intensity of the bleeding was observed with time. Bleeding was mostly light or consisted of spotting only. None of the post-trial biopsies showed proliferation or hyperplasia of the endometrium. The treatment resulted in a substantial decrease of climacteric symptoms (Kupperman index) within 4 months and was well tolerated. It was concluded that the continuous NETA/E2-TTS treatment is an effective and safe alternative for the treatment of climacteric symptoms in selected patients.

Single-dose oral fluconazole versus single-dose topical miconazole for the treatment of acute vulvovaginal candidosis.

OBJECTIVES: To compare efficacy, safety and patient preference of a single oral dose of 150 mg fluconazole with a single intravaginal dose of 1200 mg miconazole in vaginal candidosis. To investigate the effect of treatment on Candida colonization of throat and rectum. DESIGN: Double-blind, double-dummy, parallel, randomized trial. Ninety-nine patients with symptomatic and mycologically verified candidosis were given 150 mg fluconazole with an intravaginal dummy, or 1200 mg miconazole with an oral dummy. Patients with an inadequate short-term response were given a second dose. RESULTS: At each visit a patient self assessment and an investigators' global assessment were recorded, and cultures were set up. Adverse events were recorded and laboratory tests were performed. Clinical cure or improvement (investigators' assessment) was obtained in 100% (short-term) and 95% (long term) of the fluconazole group and in 94% and 90%, respectively, of the miconazole group. Patients considered the treatment excellent or good in 81% (short-term) and 88% (long-term) in the fluconazole group and in 84% and 76%, respectively, of the miconazole group. Mycological cure was achieved in 98% (short-term) and 73% (long-term) of the fluconazole group and in 96% and 82% respectively in the miconazole group. The differences in results were not significant. Both treatments significantly reduced the number of positive rectal cultures: neither treatment had a significant effect on throat cultures. Four percent of the patients preferred intravaginal therapy. CONCLUSION: A single dose fluconazole is as safe and effective as a single dose of miconazole.

Amniotic oxytocin and vasopressin in relation to human fetal development and labour.

Previous experiments in rats revealed increased amniotic oxytocin (OXT) levels in the course of normal development and increased vasopressin (AVP) levels in retarded fetal growth. In order to see whether similar changes would also occur in human, OXT and AVP levels were determined in amniotic fluid, maternal and fetal plasma before or during labour. Positive correlations were found between umbilical AVP levels on the one hand and gestation length, birth weight, placental weight and brain size on the other. This suggests a maturation process taking place in the AVP-producing system. A marked increase in maternal plasma OXT and umbilical AVP was found during labour. Increased amniotic fluid AVP levels were found in conditions indicative of fetal stress (viz., lower pH, higher PCO2) without any correlation to fetal growth parameters, while increased amniotic OXT levels were correlated with higher PO2. Furthermore, fetal brain size correlated positively with amniotic OXT levels. In conclusion, a rise in amniotic OXT levels seems to reflect normal development of the human fetus, similarly to what has been found in the rat. Increased amniotic AVP levels seem indicative of fetal acidosis.

[Oxytocin and vasopressin in amniotic fluid in humans and rats]. / Oxytocine en vasopressine in het amnionvocht bij de mens en de rat.

Oxytocin and vasopressin are hormones having a number of peripheral and (more recently detected) central activities. The two peptides are found to be present in both human amniotic fluid and in that of rats. The origin of these substances was studied in combined clinical and experimental investigations, as were also the relationships of these compounds with intra-uterine growth and the process of labour. Oxytocin was not found to originate from the foetal brain, the foetal adrenals being suggested as a possible alternative source. There was found to be a positive correlation between amniotic oxytocin and measures of the foetal brain, amniotic vasopressin possibly reflecting a poor condition of the foetus (stress?).

Circulating neurohypophyseal hormones in anencephalic infants.

Human anencephalic infants have always been considered not to have circulating levels of oxytocin or vasopressin. However, this article shows that amniotic oxytocin levels in anencephalic infants without hydramnios fall within the control range. In addition, low levels of both oxytocin and vasopressin are present in the umbilical circulation. These peptides are probably derived from fetal sources other than the fetal brain, for example, the fetal adrenal cortex.

Localisation of oxytocin, vasopressin and parts of precursors in the human neonatal adrenal.

Being a possible alternative source for the production of vasopressin (AVP) and oxytocin (OXT), a study was undertaken of the fetal adrenal. The concentrations of these peptides within the fetal adrenal turned out to be low, viz., approx. 1 pg/mg in the rat and within the pg/g range in the human. Immunocytochemistry was performed either on conventional autopsy material kept till 12 years in paraffin blocks, or on more recently obtained formalin or glutaraldehyde-paraformaldehyde fixed material. In both types of material staining was good. In order to localize AVP cells, anti-AVP, an antibody against its associated neurophysin (anti-NSN) or an antibody raised against the c-terminal glycopeptide part of the AVP precursor (anti-GP) was used. OXT cells were localized by means of anti-OXT or an auto-antibody of a multiple sclerosis patient (auto-MS) probably recognizing OXT-neurophysin. The antibodies were characterized on human and rat brain material. In the external zone of the definitive cortex, apart from parenchyma cells, anti-AVP, anti-NSN and anti-GP stained fibre-like structures running in the connective tissue septa and around parenchyma cells and the cytoplasma of these cells. Anti-OXT and auto-MS stained droplets in the cytoplasm of the fetal zone cells. Similar distinct staining patterns for AVP and OXT cells were obtained in human anencephalics. These observations show that the peptides are not derived from the fetal brain, but are rather produced in the fetal adrenal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased amniotic vasopressin levels in experimentally growth-retarded rat fetuses.

Arginine-vasopressin (AVP) and oxytocin are neuropeptides that are not only released as hormones into the peripheral circulation, but are also involved in central processes, e.g., in brain development. Earlier experiments suggested an inverse relationship between amniotic AVP and fetal growth. To see whether increased peptide levels reflect fetal growth retardation, and to determine cause and effect of this relationship, AVP and oxytocin content were determined in amniotic fluid of growth-retarded fetuses by radioimmunoassay. Growth retardation was established either by intraperitoneal administration of methylazoxymethanol to the mother, or by undernourishment of the mother. Elevated amniotic AVP levels were found in the methylazoxymethanol-treated and undernourished rats, partly concomitant with smaller amount of amniotic fluid. Amniotic AVP levels were inversely related to fetal body weight, while a similar trend was found for fetal brain weight. In addition, a positive correlation was found between fetal body weight and amniotic oxytocin in control rats.

Oxytocin and vasopressin in the rat do not readily pass from the mother to the amniotic fluid in late pregnancy.

In order to see whether the mother contributes to the vasopressin or oxytocin levels of amniotic fluid, these peptides were measured under conditions (1) in which the fetus lacks vasopressin (Brattleboro strain) and (2) where high maternal oxytocin and vasopressin plasma levels were induced by means of a controlled-delivery Accurel-collodion device. No vasopressin could be demonstrated in amniotic fluid of vasopressin-deficient fetuses present in a heterozygous (i.e., vasopressin-synthetizing mother). High peptide levels on the maternal side of Wistar rats generally failed to affect the amniotic fluid levels. The increase that was occasionally seen in amniotic vasopressin was probably due to fetal release concomitant with growth retardation. Amniotic vasopressin is derived from the fetus. Since amniotic fluid oxytocin is neither derived from the mother nor from the fetal brain, other fetal sources should be considered.

Exclusion of the fetal brain as the main source of rat and human amniotic fluid oxytocin.

At term relatively high oxytocin concentrations are found in maternal plasma and in rat and human amniotic fluid. To determine the contribution of the fetal brain to these oxytocin levels, the peptide was measured in maternal rat plasma and amniotic fluid 2 days after intrauterine removal of the fetal brains, and in the amniotic fluid of 16 human anencephalics. After removal of the fetal rat brains and in human anencephalic pregnancies normal maternal plasma concentrations and amniotic fluid oxytocin contents were found. Consequently, both maternal plasma oxytocin and amniotic fluid oxytocin are not determined to any substantial degree by the fetal brain.