Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial.

OBJECTIVE: To evaluate long-term effects of maintenance tocolysis with nifedipine on neurodevelopmental outcome of the infant. DESIGN, SETTING AND POPULATION: Follow up of infants of women who participated in a multicentre randomised controlled trial on maintenance tocolysis with nifedipine versus placebo. METHODS: Two years after the APOSTEL II trial on maintenance tocolysis with nifedipine versus placebo, we asked participants to complete the Ages and Stages Questionnaire. MAIN OUTCOME MEASURES: Infant development was measured in five domains. Developmental delay was defined as a score of ≤1 SD in one or more developmental domains. We performed exploratory subgroup analysis in women with preterm prolonged rupture of the membranes, and in women with a cervical length <10 mm at study entry. RESULTS: Of the 276 women eligible for follow up, 135 (52.5%) returned the questionnaire, encompassing data of 170 infants. At 2 years of age, infants of women with nifedipine maintenance tocolysis compared with placebo had a higher overall incidence of fine motor problems (22.2 versus 7.6%, OR 3.43, 95% CI 1.29-9.14, P = 0.01), and a lower incidence of poor problem-solving (21.1 versus 29.1%, OR 0.27, 95% CI 0.08-0.95, P = 0.04). CONCLUSIONS: This follow-up study revealed no clear benefit of nifedipine maintenance tocolysis at 2 years of age. As short-term adverse perinatal outcome was not reduced in the original APOSTEL II trial, we conclude that maintenance tocolysis does not appear to be beneficial at this time. TWEETABLE ABSTRACT: No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2-year infant outcome.

Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases.

BACKGROUND: In current literature, no data on safety in pregnancy for new drugs in the treatment of multiple sclerosis (MS) like natalizumab (Tysabri®), a humanized monoclonal antibody against α4 integrins, are yet available. In the management of MS, natalizumab is the first monoclonal antibody approved to the market. METHODS: We describe the pregnancy and outcome in two women with MS using natalizumab. The first patient used it in the periconceptional period, and the second patient used it in both the periconceptional period and throughout gestation. RESULTS: The antenatal course of the first patient was complicated by an exacerbation of MS. The second patient did not experience MS relapses during pregnancy, while still using natalizumab. The newborns did not show any abnormalities postnatal and at 6 weeks' follow-up. CONCLUSIONS: This is the first detailed report on pregnancy and delivery of two babies after maternal treatment of MS with natalizumab. From the small number of cases on the usage of natalizumab during pregnancy in literature, we cannot conclude whether the use of natalizumab is safe, and long-term effects are not known. Further research is needed to establish the exact effects on pregnancy and intrauterine development as well as the long-term effects. Prenatal counseling with thorough explanation of the risks and careful decision making is advisable.

Natural killer cells and HLA-G expression in the basal decidua of human placenta adhesiva.

Retained placenta is caused by abnormal adherence of the placenta to the uterine wall, leading to delayed expulsion of the placenta and causing postpartum haemorrhage. The mildest form of retained placenta is the placenta adhesiva (PA), of which the cause is unknown. The aim of our study was to explore possible differences in immune response in the basal decidua between PA and control placentas (CP). We performed a descriptive analysis of immunohistochemical differences in 17 PA and 10 CP. Our results show that in PA the amount of uterine natural killer (uNK) cells is significantly reduced (0.2 uNK cell/standardised area) as compared to CP (9.8 uNK cell/standardised area, p < 0.001) whereas the number of trophoblast cells and the expression of HLA-G by trophoblast are similar in the decidua of PA and CP. We speculate that adequate numbers of uNK cells in the basal decidua are needed for normal expulsion of the placenta.

Placental urocortin-2 and -3: endocrine or paracrine functioning during healthy pregnancy?

OBJECTIVES: Placental urocortins may affect uterine quiescence by modulating in an endocrine or paracrine way the estradiol secretion by the adjacent placenta. The aim of this study was to investigate the role of placental urocortin-2 and -3 as endocrine or as auto/paracrine messengers in concert with placental estradiol generation. STUDY DESIGN: In a cross-sectional study, plasma was obtained from healthy pregnant women, between 10 and 42 gestational weeks, and from nonpregnant women. Third trimester plasma pools were used for urocortin-2 and -3 peptide characterization by HPLC and RIA. Plasma samples (gestational age 10 and 42 wk) were analyzed using validated radioimmunoassays specific for urocortins and corticotropin-releasing factor (CRF). To reveal possible local actions of urocortins the influence of urcortin-2 on the estradiol secretion from placental tissue cultures was investigated. RESULTS: Reversed-phase HPLC fractionation of plasma extracts revealed several peaks containing immunoreactive-like urocortin-2 or -3, of which the main peaks had the same retention time as the synthetic urocortin-2 or -3 peptides. In contrast to plasma CRF, no gestational age dependent changes in plasma urocortin-1, -2 and -3 levels occurred. The mean plasma urocortin levels during gestation did not differ from postpartum levels. In vitro, urocortin-2 stimulated dose-dependently the placental estradiol secretion, a stimulation inhibited by antisauvagine-30, a CRF-receptor 2 antagonist. CONCLUSION: Placentas of healthy pregnant women do not, or not to any great extent, secrete urocortin-2 and -3 in the plasma. We show that urocortins can regulate the estradiol secretion from placental tissue cultures via the CRF-R2 mediated pathway. Therefore, placental urocortin-2 and -3 peptides are more likely to function as auto/paracrine messengers during healthy pregnancy, than as endocrine messengers.

The number of multinucleated trophoblastic giant cells in the basal decidua is decreased in retained placenta.

AIMS: Retained placenta (RP) is a major cause of obstetric haemorrhage. The aim of the study was to obtain a better understanding of the mechanisms that cause some placentas to become retained, while most are not. METHODS: 23 RPs clinically diagnosed as placenta adhesiva and 10 control placentas (CPs) were examined for differences in trophoblast fusion into multinucleated trophoblastic giant cells (MTGCs), defects in the basal decidua, and decidual attachment of myometrial fibres. RESULTS: The number of MTGCs in the basal decidua was significantly smaller in RPs (0.23 MTGC/standard length) than in CPs (1.11 MTGC/standard length) (p<0.001). Defects in the decidua were observed in 4% of the RPs and in 0% of the CPs. Myometrial fibres were attached to the decidua in 78% of the RPs and in 0% of the CPs (p<0.001). CONCLUSIONS: In placenta adhesiva compared with CPs, significantly less MTGCs were present in the basal decidua, the basal decidua was intact, and myometrial fibres were more frequently attached to the basal decidua. It is speculated that these findings may indicate that defective fusion of trophoblastic cells into MTGCs plays a causative role in placenta adhesiva.

Placental urocortins and CRF in late gestation.

Placental corticotropin-releasing factor (CRF) are thought to induce labor via activation of CRF receptor type 1 (CRF-R1) leading to several feed forward mechanisms in the placental, fetal and maternal compartments. Recently, receptor type 2 (CRF-R2) selective ligands called urocortin 2 and 3 (Ucn 2, Ucn 3) were characterized as neuropeptides in the brain. We studied the expression of Ucn 1, 2 and 3 in feto-placental tissues qualitatively (by immunohistochemistry) and quantitatively (by radioimmunoassay) and compared these with expression of placental CRF. The presented placental Ucn 2 and 3 peptide quantification, characterization and ex-vivo release results are novel. Reversed-phase HPLC fractionation of placental extracts revealed several peaks containing immune-reactive (ir)-like Ucn 2 or 3, of which the main peaks had the same retention time as the synthetic Ucn 2 and 3 peptides. Placental tissues contained between 6 and 10 times more ir-CRF than ir-Ucn 1, 2 or 3. The placental Ucn 1, 2 and 3 peptide contents correlated with each other. Our immunohistochemical results showed that all urocortins were mainly localized in the syncytiotrophoblasts of the placental villi. Placental urocortins were actively released during ex-vivo perfusion of cotyledons. From these results it can be concluded that Ucn 2 and 3 peptides are present in placental and fetal membrane tissues, and released by ex-vivo perfused cotyledons. Therefore, placental urocortins may function as paracrine or endocrine messengers during pregnancy and parturition.

[Tertiary obstetric care: the aims of the planning decree on perinatal care of 2001 have not yet been achieved]. / Derdelijns verloskundige zorg: doelstellingen van het 'planningsbesluit bijzondere perinatologische zorg' uit 2001 nog niet gehaald.

OBJECTIVE: To compare the actual situation in tertiary perinatal care in the Netherlands with the objectives laid down in the 2001 decree on perinatal care by the Dutch Ministry of Health, Welfare and Sport. DESIGN: Descriptive, retrospective. METHOD: Data on tertiary perinatal care, the transfer or refusal of women with very endangered pregnancies and the personnel of obstetric high care (OHC) units in 2006 were compared with the targets laid down in the planning decree on perinatal care and in a report by the Dutch Health Council from 2000. Parameters of tertiary perinatal care output were the number of admissions, and the number of beds in OHC units and neonatal intensive care units (NICU). RESULTS: In 2006, 128 of the 250 beds intended for OHC had been obtained. The degree of capacity utilisation was 94%, while the norm is 80%. 312 women were transferred due to lack of capacity of OHC units and NICU. The number of staff, specialised physicians as well as nurses, was considerably lower than the planned capacity. But training for obstetric perinatologists and OHC nurses was given. CONCLUSION: The targets for the number of beds for tertiary obstetric care and associated medical personnel have not been achieved as yet. As a consequence, the number of transfers is still too high. The funding of OHC units is not attuned to the complexity of tertiary perinatal care. Closer supervision of the execution of the planning decree and an adequate financing system are needed to achieve the objectives of the planning decree in the next 3 years.

Fetal/neonatal allo-immune thrombocytopenia (FNAIT): past, present, and future.

UNLABELLED: We reviewed the English, American, and German literature for articles describing the prevalence, clinical presentation, outcome, therapeutic options, and screening possibilities for fetal/neonatal allo-immune thrombocytopenia (FNAIT), published between January 1950 and March 2007. The reported prevalence of FNAIT in human platelet antigen (HPA)-1a-negative women varies between 1/600 to 1/5000 live births among various populations. The typical picture is that of a neonate presenting with purpura minutes to hours after birth, born to a healthy mother with no history of infection or abnormal bleeding, after an uneventful pregnancy with a normal maternal platelet count. Thrombocytopenia in FNAIT can be severe, with intracranial hemorrhage occurring in 10% to 30% of severe FNAIT cases. Several types of neonatal treatment have been proposed, of which transfusion of HPA-compatible platelets is most effective. Antenatal management of FNAIT consists of weekly maternal intravenous immunoglobulin (IVIG) infusions, with or without oral steroid therapy. Serial fetal platelet transfusions can be provided in cases of failure of IVIG therapy, but the multiple cordocenteses that would be required to administer the platelets entail substantial risk. The possibilities for antenatal screening of first pregnancies are limited. Postnatal screening does not prevent neonatal morbidity and mortality. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the many and varied causes of neonatal thrombocytopenia, explain that fetal/neonatal allo-immune thrombocytopenia (FNAIT) is a rare but devastating cause with potential high risk of recurrence, and recall the treatment options for FNAIT as well as their potential side effects.

First case of vaginal radical trachelectomy in a pregnant patient.

Women who present with cervical carcinoma during pregnancy pose for us a clinical problem. In general, three treatment options exist: (i) radical hysterectomy with termination of pregnancy, (ii) a planned delay, or (iii) chemotherapy until lung maturation has occurred, both followed by a radical hysterectomy. Vaginal radical trachelectomy is an alternative approach to preserve the pregnancy. We report on a woman with a stage IBI cervical carcinoma, diagnosed at 16 weeks of gestation treated with vaginal radical trachelectomy. At a gestational age of 36 weeks, a cesarean section was performed, followed by radical hysterectomy. Follow-up of 9 months is uneventful for both the mother and the child. The vaginal radical trachelectomy is a new approach in the treatment of cervical carcinoma during pregnancy.

Delayed intrauterine repair of an experimental spina bifida with a collagen biomatrix.

BACKGROUND/PURPOSE: The aim of the study was to evaluate whether a collagen biomatrix is useful for delayed intrauterine coverage of a surgically created spina bifida in a fetal lamb. METHODS: In 20 fetal lambs, surgery was performed at 72 or 79 days' gestation. In 15 lambs a spina bifida was created surgically. In 8 lambs it was covered with a collagen biomatrix 2 weeks later and in 7 lambs it was left uncovered. Five lambs served as sham operated controls. Neurological examination was performed at 1 week of age and afterwards the lambs were sacrificed for further histological evaluation. RESULTS: None of the 5 surviving lambs with the defect covered showed loss of spinal function and the architecture of the spinal cord was preserved in 4 of the 5 lambs. In the uncovered group, 1 of the 4 surviving lambs had loss of spinal function, 5 lambs were available for histological evaluation and 4 of them showed disturbance of the architecture of the spinal cord. CONCLUSIONS: Collagen biomatrices can be used for intrauterine coverage of an experimental spina bifida and can preserve the architecture of the spinal cord. Neurological outcome is not different between fetuses with their spinal cord covered and fetuses with uncovered cords.

Histological evaluation of acute covering of an experimental neural tube defect with biomatrices in fetal sheep.

OBJECTIVE: The aim of the study was to determine the histological effect on the neural tissue of in utero covering of an experimental neural tube defect in fetal lambs, with the use of two different biomatrices. MATERIALS AND METHODS: In 23 fetal sheep, surgery was performed at 79 days' gestation. In 19 of these, a neural tube defect was created, while 4 fetuses served as sham-operated controls. In 7 of the 19 operated fetuses the defect was left uncovered. In the remaining 12 animals the defect was covered either with a collagen biomatrix (4 animals), skin (3 animals), or small intestinal submucosa biomatrix (5 animals). The lambs were sacrificed at 1 week of age and histological examination was performed. RESULTS: All lambs with an uncovered neural tube defect showed histological damage of the spinal cord. In lambs in which the neural tube defect was covered, one half showed a normal architecture of the spinal cord while minor histological damage was present in the other half. Between the three groups in which the defect was covered, the histological outcome was comparable. CONCLUSIONS: Acute covering of an experimental neural tube defect in fetal lambs prevents severe histological damage to the spinal cord independent of the two biomatrices used in this study.

Cervical dilatation related to uterine electromyographic activity and endocrinological changes during prostaglandin F(2alpha)-induced parturition in cows.

The temporal relationship between changes in cervical dilatation, uterine electromyographic (EMG) activity, and maternal plasma concentrations of estradiol 17beta (E(2)), progesterone (P(4)), and 13,14-dihydro-15-keto-prostaglandin-F(2alpha) (PGFM), was investigated in six parturient cows. Calving was induced with a single injection of a synthetic analogue of prostaglandin F(2alpha) (PG) on Day 274 of gestation. Cervical dilatation was measured continuously by measuring the transit time between two implanted ultrasound crystals while at the same time uterine EMG activity was measured through two silver electrodes sutured on the myometrial surface until the expulsive stage of calving had been reached. In blood samples collected at 4-h intervals, starting at the moment of PG injection, the mean plasma E(2) concentration gradually increased and was significantly elevated at 28 h after PG injection. At 4 h after PG treatment, the mean P(4) concentration had dropped significantly and continued to decrease until a value of around 1 ng/ml was reached, where it stayed until the onset of expulsion. Mean plasma PGFM concentrations increased steadily after PG injection, reaching significantly elevated concentrations at 20 h after treatment. In the five cows that delivered calves in anterior positions, uterine EMG activity, expressed as root mean square (RMS in microV), started to increase at a mean interval (+/- SD) of 13.1 +/- 3.7 h following PG treatment. The increase in EMG activity was significantly correlated with changes in plasma PGFM concentrations. In these cows, dilatation of the caudal cervix started after a mean (+/- SD) interval of 28.5 +/- 1.5 h following PG treatment and dilatation progressed at a mean (+/- SD) rate of 2.25 +/- 0.24 cm/h. In one cow with a calf in the posterior position, uterine EMG activity and dilatation started at 15.8 h and 31.8 h, respectively, after induction of calving. We conclude that a predictable sequence of physiological changes occurs around induction of calving, which allows specific timing of future studies on cellular and biochemical changes within the cervix during parturition.

Ultrasonic cervimetry to study the dilatation of the caudal cervix of the cow at parturition.

The objective of this study was to investigate the temporal changes in dilatation of the caudal cervix during induced calvings (n = 5). We used ultrasound cervimetry, allowing the continuous recording of the distance between a transmitting and receiving ultrasound crystal, which were implanted opposite to each other on the caudal rim of the cervix. We started recording between 19 and 21 h after injecting a prostaglandin analogue (PG) on day 272 of gestation. A fluid-filled catheter had been introduced transcervically between the fetal membranes and the uterine wall for measurements of intra-uterine pressure (IUP). While the characteristics of calving varied widely between the five animals, it appeared possible to divide the process of dilatation into four phases. During the latent phase, which lasted until 25-43 h after PG, no net gain in dilatation occurred. We found an acceleration phase (4.3-6.8 h), in which the dilatation rate speeds up (0.49-0.84 cm/h) in three of the cows. During the phase of maximum slope (lasting 0.5-4.8 h), we measured an even higher rate (1.47-8.48 cm/h), decreasing again during the deceleration phase (rate 0.24-2.28 cm/h) in four cows. The quality of the IUP measurements precluded us from continuously investigating the relationship between cervical dilatation and uterine contractions. However, short term simultaneous recordings revealed that the cervical opening changed momentarily in the absence of IUP during the latent phase, while during the phase of maximum slope, temporary changes of dilatation coincided with uterine contractions. We concluded that the method of ultrasound cervimetry used in this study provides a valuable way to study the process of cervical dilatation in parturient cows in vivo.

[An inherited hemostatic disorder as the cause of menorrhagia]. / Een erfelijke hemostaseafwijking als oorzaak van menorragie.

Two women aged 39 and 30 years were investigated for possible coagulation disorders because of menorrhagia, anaemia and postoperative haemorrhages. These investigations revealed that they had type 1 Von Willebrand's disease. During the treatment with desmopressin, factor VIII and Von Willebrand factor (VWF) activity normalised. About one third of the patients referred to a gynaecologist for menorrhagia have an inherited bleeding disorder, of which type 1 Von Willebrand's disease is the most prevalent. Once a gynaecological cause of the menorrhagia has been excluded, or in the case of an increased risk on the basis of the medical history, a limited haemostatic investigation can establish or exclude an inherited coagulation disorder. For women with a coagulation disorder the menorrhagia can be treated. Surgical interventions can be carried out safely following treatment with desmopressin or factor VIII/VWF concentrates.

Effect of preeclampsia in the mother on the leucine metabolism in the newborn infant.

The leucine turnover in newborn infants is influenced by factors such as nutritional state and corticosteroid treatment. Little is known about maternal factors influencing the leucine turnover in the newborn. In order to approach the effect of preeclampsia in the mother on neonatal protein turnover, we studied the leucine turnover in preterm infants soon after birth and again after 7 days. Ten infants from preeclamptic mothers (birth weight 1,280 +/- 240 g, gestational age 31 +/- 2 weeks) and 15 control patients (birth weight 1,320 +/- 210 g, gestational age 30 +/- 2 weeks) were enrolled. The leucine turnover was measured using a primed constant 5-hour intravenous infusion of [1-(13)C]leucine within the first 24 h after delivery and again on day 7 of life. The turnover (leucine flux; micromol.kg(-1).h(-1)) was calculated from the enrichment in alpha-ketoisocaproic acid in plasma. The leucine turnover on day 1 was 300 +/- 65 in the preeclampsia group and 358 +/- 70 in the controls (ANOVA, p < 0.05). The values on day 7 were 474 +/- 73 in the preeclampsia group and 485 +/- 80 in the control group (n.s.). To conclude, the leucine turnover on day 1 is lower in infants of preeclamptic mothers as compared with controls. This difference has disappeared on day 7 of life after receiving the same protein and energy intake.

Pelvic pain during pregnancy is associated with asymmetric laxity of the sacroiliac joints.

OBJECTIVE: The aim of this study was to investigate the association between pregnancy-related pelvic pain (PRPP) and sacroiliac joint (SIJ) laxity. METHODS: A cross-sectional analysis was performed in a group of 163 women, 73 with moderate or severe (PRPP+) and 90 with no or mild (PRPP-) PRPP at 36 weeks of pregnancy. SIJ laxity was measured by means of Doppler imaging of vibrations in threshold units (TU). Pain, clinical signs and disability were assessed with visual analog scale (VAS), posterior pelvic pain provocation (PPPP) test, active straight leg raise (ASLR) test, and Quebec back pain disability scale (QBPDS), respectively. RESULTS: Mean SIJ laxity in the PRPP+ group was not significantly different from the PRPP- group (3.0 versus 3.4 TU). The mean left-right difference, however, was significantly higher in the PRPP+ group (2.2 TU) than in the PRPP- group (0.9 TU). In the PRPP- group, only 4% had asymmetric laxity of the SIJs in contrast to 37% of the PRPP+ group. Between the PRPP+ subjects with asymmetric and symmetric laxity of the SIJs significant differences were found with respect to mean VAS for pain (7.9 versus 7.0), positive PPPP test (59% versus 35%), positive ASLR test (85 versus 41%) and mean QBPDS score (61 versus 50). CONCLUSIONS: Increased SIJ laxity is not associated with PRPP. In fact, pregnant women with moderate or severe pelvic pain have the same laxity in the SIJs as pregnant women with no or mild pain. However, a clear relation between asymmetric laxity of the SIJs and PRPP is found.

Automated cardiac output measurements by ultrasound are inaccurate at high cardiac outputs.

OBJECTIVE: The sonographic technique of automated cardiac output measurement (ACM) is a promising new method to measure cardiac output and could be of use in a high-risk obstetric unit in the treatment of pre-eclamptic patients. The aim was to determine the accuracy of the ACM method. DESIGN: Comparative study of the sonographic technique of ACM versus cardiac output measured by thermodilution (TD). METHODS: The study included 39 intensive care patients, 21 men, 13 non-pregnant women and five severely pre-eclamptic pregnant patients, with a wide range of cardiac outputs, in whom TD catheters had been inserted for clinical reasons. Two separate experienced observers, blinded to the results obtained with the other method, performed four successive measurements in each patient with either the ACM or TD technique. The averaged cardiac output value per patient and method was used for comparison. RESULTS: Cardiac output was successfully measured with ACM and TD in 85 and 100% of patients, respectively. Mean cardiac output measured by ACM (6.77 +/- 1.90 L/min) was significantly lower than that measured by TD (9.12 +/- 3.06 L/min). Although cardiac output values obtained with ACM were significantly correlated with those measured by TD, the ACM values were consistently lower than TD values in the higher cardiac output range; the relationship was represented by ACM = 0.35 TD + 3.55 L/min (r = 0.57, P < 0.001). The (ACM - TD) difference increased significantly with cardiac output, through a difference in stroke volume, not in heart rate. CONCLUSION: The ACM is not an accurate tool to measure cardiac output in patients with a high cardiac output, including treated pre-eclamptic women.