Hysteroscopic resection of a uterine caesarean scar defect (niche) in women with postmenstrual spotting: a randomised controlled trial.

OBJECTIVE: To compare the effectiveness of a hysteroscopic niche resection versus no treatment in women with postmenstrual spotting and a uterine caesarean scar defect. DESIGN: Multicentre randomised controlled trial. SETTING: Eleven hospitals collaborating in a consortium for women's health research in the Netherlands. POPULATION: Women reporting postmenstrual spotting after a caesarean section who had a niche with a residual myometrium of ≥3 mm, measured during sonohysterography. METHODS: Women were randomly allocated to hysteroscopic niche resection or expectant management for 6 months. MAIN OUTCOME MEASURES: The primary outcome was the number of days of postmenstrual spotting 6 months after randomisation. Secondary outcomes were spotting at the end of menstruation, intermenstrual spotting, dysuria, sonographic niche measurements, surgical parameters, quality of life, women's satisfaction, sexual function, and additional therapy. Outcomes were measured at 3 months and, except for niche measurements, also at 6 months after randomisation. RESULTS: We randomised 52 women to hysteroscopic niche resection and 51 women to expectant management. The median number of days of postmenstrual spotting at baseline was 8 days in both groups. At 6 months after randomisation, the median number of days of postmenstrual spotting was 4 days (interquartile range, IQR 2-7 days) in the intervention group and 7 days (IQR 3-10 days) in the control group (P = 0.04); on a scale of 0-10, discomfort as a result of spotting had a median score of 2 (IQR 0-7) in the intervention group, compared with 7 (IQR 0-8) in the control group (P = 0.02). CONCLUSIONS: In women with a niche with a residual myometrium of ≥3 mm, hysteroscopic niche resection reduced postmenstrual spotting and spotting-related discomfort. TWEETABLE ABSTRACT: A hysteroscopic niche resection is an effective treatment to reduce niche-related spotting.

The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial.

BACKGROUND: A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain. However, there are no randomised trials assessing the effectiveness of a hysteroscopic niche resection. METHODS/DESIGN: We planned a multicentre randomised trial comparing hysteroscopic niche resection to no intervention. We study women with postmenstrual spotting after a CS and a niche with a residual myometrium of at least 3 mm during sonohysterography. After informed consent is obtained, eligible women will be randomly allocated to hysteroscopic resection of the niche or expectant management for 6 months. The primary outcome is the number of days with postmenstrual spotting during one menstrual cycle 6 months after randomisation. Secondary outcomes are menstrual characteristics, menstruation related pain and experienced discomfort due to spotting or menstrual pain, quality of life, patient satisfaction, sexual function, urological symptoms, medical consultations, medication use, complications, lost productivity and medical costs. Measurements will be performed at baseline and at 3 and 6 months after randomisation. A cost-effectiveness analysis will be performed from a societal perspective at 6 months after randomisation. DISCUSSION: This trial will provide insight in the (cost)effectiveness of hysteroscopic resection of a niche versus expectant management in women who have postmenstrual spotting and a niche with sufficient residual myometrium to perform a hysteroscopic niche resection. TRIAL REGISTRATION: Dutch Trial Register NTR3269 . Registered 1 February 2012. ZonMw Grant number 80-82305-97-12030.

No effect of the FitFor2 exercise programme on blood glucose, insulin sensitivity, and birthweight in pregnant women who were overweight and at risk for gestational diabetes: results of a randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of an exercise programme for pregnant women who were overweight or obese and at risk for gestational diabetes mellitus (GDM). DESIGN: Randomised controlled trial. SETTING: Hospitals and midwifery practices in the Netherlands. POPULATION: Pregnant women who were overweight or obese and at risk for GDM between 2007 and 2011. METHODS: Normal care was compared with an exercise training programme during pregnancy. The training consisted of aerobic and strength exercises, and was aimed at improving maternal fasting blood glucose, insulin sensitivity, and birthweight. Linear regression analyses were performed to determine the effects. MAIN OUTCOME MEASURES: Maternal outcome measures were fasting blood glucose (mmol/l), fasting insulin (pmol/l) and HbA1c (%), body weight (kg), body mass index (kg/m(2) ), and daily physical activity (minute/week). Offspring outcome measures were birthweight and fetal growth. RESULTS: A total of 121 women were randomly allocated to either a control (n = 59) or an intervention (n = 62) group. Intention-to-treat analysis showed that the exercise programme did not reduce maternal fasting blood glucose levels nor insulin sensitivity. Also, no effect was found on birthweight. CONCLUSIONS: The exercise intervention performed over the second and third trimester of pregnancy had no effects on fasting blood glucose, insulin sensitivity, and birthweight, most probably because of low compliance. The high prevalence of women at risk for GDM calls for further research on possible interventions that can prevent GDM, and other types of interventions to engage this target group in physical activity and exercise.

The identification of a human myometrial corticotropin-releasing hormone receptor that increases in affinity during pregnancy.

The concentration of immunoreactive, placentally derived CRH is increased in the peripheral circulation during the third trimester of human pregnancy. However, the function of this placental CRH is entirely unknown. A number of observations have led us to believe that CRH might influence myometrial contractility and, hence, parturition via specific receptor mechanisms. 1) In idiopathic preterm labor, plasma immunoreactive-CRH concentrations are significantly elevated compared to control values. 2) CRH and oxytocin exhibit a marked synergistic effect on myometrial contractility which is prostaglandin dependent and can be inhibited by the CRH receptor antagonist [alpha-helical CRF-(9-41)]. In view of this, we searched for specific CRH-binding sites in myometrial tissue obtained at biopsy from pregnant (cesarian section) and nonpregnant (hysterectomy) patients. To test for the presence of CRH receptors, we prepared myometrial membranes and performed binding studies using [125I]tyr-o-CRH as a ligand. The binding was found to be pH, time, temperature, and divalent cation concentration dependent and was fully reversible on addition of 1 microM unlabeled ovine CRH. In both tissues, there was a single, specific, homogenous, high affinity population of CRH receptors. Scatchard analysis of the specific binding sites revealed dissociation constants of 250-300 and 30-60 pM for the nonpregnant and pregnant myometrium, respectively. This compares with dissociation constants of 130 pM (rat anterior pituitary receptor) and 100 pM (human CRH-binding protein). This would mean that in the nonpregnant state, the equilibrium for binding is in favor of the binding protein, but during the later stages of pregnancy, the change in affinity of the receptor alters the binding in favor of the myometrial receptor.

Serum concentrations of alkaline phosphatase isoenzymes and osteocalcin in normal pregnancy.

We measured serum alkaline phosphatase isoenzymes and osteocalcin levels in 40 healthy women at 4-week intervals throughout uncomplicated pregnancies and 6 weeks after delivery in 17 women. Serum bone alkaline phosphatase was significantly higher in the third trimester than in early pregnancy (P less than 0.001), and this elevation was still apparent at the end of the puerperium, suggesting increased bone turnover. Serum osteocalcin was not detected (less than 0.2 micrograms/L) after the first trimester in the majority of women, and it reappeared within 48 h after delivery. The disappearance of osteocalcin after the first trimester and its rapid reappearance after delivery suggest placental clearance of this peptide. We conclude that serum osteocalcin measurements cannot be used as a marker of bone metabolism during pregnancy.

Placental corticotrophin releasing factor may modulate human parturition.

The interactions of corticotrophin releasing factor (CRF) and oxytocin on myometrial contractility were studied in isolated gestational myometrium in vitro. Acting alone oxytocin showed a significant dose related inotropic effect (P less than 0.001), whereas CRF did not. Dose-response curves of oxytocin in the presence of a fixed dose of CRF showed a threefold increase in the response to oxytocin without CRF present (P = 0.0019). When this combined priming and potentiating effect was investigated separately, priming of the myometrial strips with CRF prior to stimulation with oxytocin significantly enhanced the inotropic effect of oxytocin (P = 0.01) and when given together a significant potentiating effect was seen (P = 0.008). It is suggested that placental CRF may act as an important modulator of the inotropic effect of oxytocin on myometrium. The interaction between the two peptides may be similar to that which occurs between CRF and vasopressin in the anterior pituitary gland.

A prenatal diagnosis of umbilical cord oedema made by ultrasound; a case report.

A case of marked oedema of the umbilical cord is described associated with premature onset of labour. The diagnosis was made by ultrasound at 33 weeks gestational age. There were no other malformations of the fetus, cord or placenta.

Role for cyclic adenosine monophosphate in the synergistic interaction between oxytocin and corticotrophin-releasing factor in isolated human gestational myometrium.

OBJECTIVE: We wished to investigate the role of cAMP in the synergistic effect of corticotrophin-releasing factor and oxytocin on human myometrial contractility. DESIGN: Isolated human gestational myometrium obtained from Caesarean sections at term was studied in vitro. Static incubation techniques as well as tension recordings were applied to the tissue obtained. PATIENTS: The subjects were healthy pregnant women undergoing lower segment Caesarean section at term, prior to labour. MEASUREMENTS: Specimens obtained were immediately dissected into small strips and either incubated in multi-well trays (strip weight 2.75 mg) or superfused and used for tension recordings (strip weight 2.00 mg). cAMP accumulation was measured after incubation with oxytocin (0.1-10 nM), corticotrophin-releasing factor (1 nM) or a combination of both peptides. Tension generated by the muscle strips was recorded isometrically and response to oxytocin (0.01-10 nM), corticotrophin-releasing factor (1 nM) and forskolin (10 nM) expressed in force per gram wet tissue (N/g). RESULTS: Oxytocin (0.1 nM) causes a statistically significant dose-related decrease in cAMP when combined with 1 nM corticotrophin-releasing factor (P less than 0.001), as compared with cAMP stimulation by corticotrophin-releasing factor alone. Time course studies suggest a maximal effect at 1 minute. The hypothesis that an intracellular reduction of cAMP is a prerequisite for the synergistic response in contraction force was tested with tension recordings. Prevention of a decrease in cAMP in the tissue by addition of 10 nM forskolin to the superfusate abolished the potentiation between oxytocin and corticotrophin-releasing factor. CONCLUSIONS: These results indicate that a fall in cAMP concentration plays a vital mediating role in the synergistic interaction between oxytocin and corticotrophin-releasing factor.

Maternal serum markers in second-trimester oligohydramnios.

The levels of the maternal serum markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), and unconjugated oestriol (uE3) in 35 pregnant women with early second-trimester oligohydramnios differed from those in a reference population of 1699 singleton pregnancies. Maternal serum AFP levels above the 95th centile of the population distribution were observed in 80 per cent (16/20) of oligohydramnios cases with a normal fetus and in only 20 per cent (3/15) of the cases with a fetus displaying urogenital tract malformations. Elevated levels of hCG (above the 95th centile) and decreased levels of uE3 (below the fifth centile) were encountered in 26 per cent (9/35) and 17 per cent (6/35) of the women, irrespective of the fetal condition. The abnormal profile of the serum markers in early second-trimester oligohydramnios resulted in 57 per cent (20 out of 35) of screen-positive cases for either fetal Down's syndrome or neural tube defects, compared with 8.4 per cent (143 out of 1699) in the reference population.

Ovulation induction in polycystic ovarian disease by pure FSH (Metrodin). A comparison between chronic low-dose pulsatile administration and i.m. injections.

A randomized cross-over study was performed to assess the value of pulsatile versus i.m. administration of pure FSH in polycystic ovarian disease. All patients admitted to the study had failed to respond to treatment with clomiphene citrate, while four had also been unsuccessfully treated with i.m. Pergonal. Sixteen cycles with i.m. FSH and 15 cycles with pulsatile s.c. FSH were analysed. The results showed no statistically significant differences in the dosage, the rate of ovulation or pregnancy rate. Hyperstimulation occurred in 30% of both the treatment groups. It is concluded that chronic low-dose pulsatile administration of pure FSH (Metrodin, Serono) has no advantage over chronic low-dose i.m. administration.

Role of prostaglandins and leukotrienes in the synergistic effect of oxytocin and corticotropin-releasing hormone (CRH) on the contraction force in human gestational myometrium.

We have recently demonstrated that corticotropin releasing hormone (CRH) potentiates the contractile response to oxytocin of human gestational myometrium, using a high flow microsuperfusion system and electrical field stimulation. We now report this potentiation to be equivalent to that of 1 nM prostaglandin F2 alpha (PGF2 alpha), while 10 nM PGF2 alpha did not potentiate the response to oxytocin. Prostaglandin E2 (PGE2) also showed no augmentation of the contraction force of the myometrium in response to oxytocin. The CRH potentiated response was inhibited by the lipoxygenase and cyclooxygenase inhibitor BW755C (1 microM) and by indomethacin (0.1 microM), but not by the lipoxygenase inhibitor BW4C (1 microM). Measurements of prostaglandins in the superfusate showed no significant trends. It is concluded that the potentiation of contraction force to oxytocin by CRH is dependent on prostaglandins, probably PGF2 alpha and that leukotrienes, generated via the lipoxygenase pathway are not involved.

Clinical implications of fetal magnetocardiography.

OBJECTIVES: To test the usefulness and reliability of fetal magnetocardiography as a diagnostic or screening tool, both for fetuses with arrhythmias as well as for fetuses with a congenital heart defect. METHODS: We describe 21 women with either a fetal arrhythmia or a congenital heart defect discovered during prenatal evaluation by sonography. Four fetuses showed a complete atrioventricular block, two an atrial flutter, nine ventricular extrasystole, and one a complete irregular heart rate. Five fetuses were suspected to have a congenital heart defect. In all cases magnetocardiograms were recorded. RESULTS: Nine fetuses with extrasystole showed a range of premature atrial contractions, premature junctional beats or premature ventricular contractions. Two fetuses with atrial flutter showed typical flutter waves and four fetuses with complete atrioventricular block showed an uncoupling of P-wave and QRS complex. One fetus showed a pattern suggestive of a bundle branch block. In three of four fetuses with confirmed congenital heart defects the magnetocardiogram showed abnormalities. CONCLUSION: Fetal magnetocardiography allows an insight into the electrophysiological aspects of the fetal heart, is accurate in the classification of fetal arrhythmias, and shows potential as a tool in defining a population at risk for congenital heart defects.

Monitoring the fetal heart non-invasively: a review of methods.

Doppler ultrasound, ultrasound M-mode analysis, fetal electrocardiography, and fetal magnetocardiography are methods by which the fetal heart can be monitored non-invasively. In this paper, they are evaluated and compared. Customarily, it is solely the fetal heart rate, which is monitored using the Doppler ultrasound technique since it is both simple to use and cheap. However, this method inherently produces an averaged heart rate and therefore cannot give the beat-to-beat variability. Fetal electrocardiography has similar advantages, but in addition offers the potential for monitoring beat-to-beat variability and performing electrocardiogram morphological analysis. Its disadvantage is that its reliability is only 60%, although it is the only technique that offers truly long-term ambulatory monitoring. Ultrasound M-mode analysis allows a estimation of atrial and ventricular coordination, as well as an estimation of PR intervals. Bradycardias, supraventricular tachycardias, extra systoles are readily diagnosed using this method although timing will be inaccurate. Fetal magnetocardiograms can be detected reliably and used for accurate beat-to-beat measurements and morphological analysis. Consequently, they can be used for the classification of arrhythmias and the diagnosis of a long QT syndrome and some congenital heart diseases.

Early invasive prenatal diagnosis in HBsAg-positive women.

From 1982 to 1989, pregnant women in two large city hospitals in The Netherlands had serum samples screened for hepatitis B surface antigen (HBsAg). Infants of mothers found to be HBsAg-positive received hepatitis B immune globulin immediately after birth and hepatitis B vaccine in the first year of life. Blood samples of infants were regularly tested for HBsAg and antibodies directed against HBsAg. A retrospective analysis of the pregnancy outcome in HBsAg-positive women who had invasive tests for prenatal diagnosis was carried out to determine whether amniocentesis and chorionic villus sampling (CVS) are risk factors for the intrauterine transmission of the hepatitis B virus. Amniocentesis was carried out in 17 HBsAg-positive women and CVS in one case. Only two women were HBsAg- and HBeAg-positive. Prenatal diagnosis led to the termination of pregnancy for fetal chromosome abnormality in three cases. The remaining 15 pregnancies were uneventful; all infants were negative for HBsAg and developed an active immune response to the vaccine. These data suggest that amniocentesis in HBsAg-positive women constitutes a low risk for the intrauterine transmission of the hepatitis B virus, but definite conclusions in HBeAg-positive women cannot be drawn.

A longitudinal study of maternal digoxin-like immunoreactive substances in normotensive pregnancy and pregnancy-induced hypertension.

The serum of women in the third trimester of pregnancy demonstrates cross-reactivity with some commercially available antibodies to digoxin. A number of studies have suggested that levels of this digoxin-like immunoreactive substance(s) are further increased in patients with pregnancy-induced hypertension, and some have proposed that the digoxin-like immunoreactive substance could be useful as a predictor of pregnancy-induced hypertension. We measured digoxin-like immunoreactive substance levels every 2 weeks throughout the third trimester in 170 women; of these, 20 developed hypertension. Digoxin-like immunoreactive substance levels rose with gestational age. A graph of the slope of digoxin-like immunoreactive substance plotted against gestational age was fitted for the results obtained from each woman. There was no significant difference in the mean rate of increase of digoxin-like immunoreactive substance level per week between pregnancy-induced hypertension and normotensive pregnancy, nor was there any difference between these two groups at any gestational age studied. These results suggest that measuring digoxin-like immunoreactive substance levels is not useful as a predictor of pregnancy-induced hypertension.