Roel de Heus

Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study

Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations. Design Prospective cohort study. Setting 28 hospitals in the Netherlands and Belgium. Participants 1920 consecutive women treated with tocolytics for threatened preterm labour. Main outcome measures Maternal adverse events (those suspected of being causally related to treatment were considered adverse drug reactions) leading to cessation of treatment. Results An independent panel evaluated the recorded adverse events, without knowledge of the type of tocolytic used. Of the 1920 women treated with tocolytics, 1327 received a single course of treatment (69.1%), 282 sequential courses (14.7%), and 311 combined courses (16.2%). Adverse drug reactions were categorised as serious or mild in 14 cases each. The overall incidence of serious adverse drug reaction was 0.7%. Compared with atosiban, the relative risk of an adverse drug reaction for single treatment with a β adrenoceptor agonist was 22.0 (95% confidence interval 3.6 to 138.0) and for single treatment with a calcium antagonist was 12 (1.9 to 69). Multiple drug tocolysis led to five serious adverse drug reactions (1.6%). Multiple gestation, preterm rupture of membranes, and comorbidity were not independent risk factors for adverse drug reactions. Conclusions The use of β adrenoceptor agonists or multiple tocolytics for preventing preterm birth is associated with a high incidence of serious adverse drug reactions. Indometacin and atosiban were the only drugs not associated with serious adverse drug reactions. A direct comparison of the effectiveness of nifedipine and atosiban in postponing preterm delivery is needed.

Acute tocolysis for uterine activity reduction in term labor: a review.

This review critically evaluates the efficacy of different tocolytics in reducing uterine pressure and contractions in term labor. The available evidence supports the use of beta-adrenergic-receptor agonists such as terbutaline or ritodrine; they appear to have an immediate and comparable profound effect on uterine activity in term labor. However, the preferred type of beta-adrenergic receptor agonist and dosage are unclear. The oxytocin receptor antagonist atosiban has a high specificity for the uterus with limited or no systemic effects and could therefore be an attractive alternative for use in term labor. The evidence on the tocolytic potency of a single bolus of atosiban for tocolysis in term labor is encouraging but limited and needs further research. Moreover, atosiban lacks United States Food and Drug Administration approval. Literature documenting efficacy and safety of nitroglycerin or magnesium sulfate in term labor is far from convincing. The theoretical basis for the use of tocolytics for nonreassuring intrapartum fetal heart rate patterns is to reduce the aggravating influence of uterine contractions. However, the clinical evidence that tocolytics in term active labor are actually beneficial in improving neonatal outcome is very limited. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to outline the available literature pertaining to tocolysis for term labor and appraise the effectiveness of various tocolytics in term labor.

The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow

Background. The choice of first-line tocolytic agent is a topic of worldwide debate. The oxytocin receptor antagonist atosiban and the calcium antagonist nifedipine appear to be effective in postponing delivery. However, information is lacking on their possible effects on the fetal biophysical profile. Objective. To study the direct fetal effects of tocolysis with atosiban or nifedipine combined with a course of betamethasone. Method. We performed a randomised controlled study including women with preterm labour requiring tocolytic treatment. Primary outcome measures were the effects on fetal heart rate (FHR) and its variation. Secondary endpoints were the effects on fetal movement and blood flow (pulsatility index – PI) of the umbilical (UA) and medial cerebral arteries (MCA). Results. One-hour recordings of FHR and fetal movements were made on each of five successive days (days 0–4). Fetal blood flow velocity patterns were studied daily by Doppler ultrasound. Baseline characteristics of 31 women who had not delivered at day 0 and needed no escape tocolysis did not differ between the study groups. Multilevel analysis showed no significant effect of either tocolytic on FHR and movement parameters over the 5-day study period. The use of tocolytics also did not significantly alter the time courses of PI-values for UA (p = 0.37) and MCA (p = 0.62). Conclusion. This study demonstrates for the first time the direct effects of atosiban on fetal movement, heart rate and blood flow. Tocolysis with either atosiban or nifedipine combined with betamethasone administration appears to have no direct fetal adverse effects.

Management of preterm labor: atosiban or nifedipine?

Preterm birth is strongly associated with neonatal death and long-term neurological morbidity. The purpose of tocolytic drug administration is to postpone threatening preterm delivery for 48 hours to allow maximal effect of antenatal corticosteroids and maternal transportation to a center with specialized neonatal care facilities. There is uncertainty about the value of atosiban (oxytocin receptor antagonist) and nifedipine (calcium channel blocker) as first-line tocolytic drugs in the management of preterm labor. For nifedipine, concerns have been raised about unproven safety, lack of placebo-controlled trials, and its off-label use. The tocolytic efficacy of atosiban has also been questioned because of a lack of reduction in neonatal morbidity. This review discusses the available evidence, the pros and cons of either drug and aims to provide information to support a balanced choice of first-line tocolytic drug: atosiban or nifedipine?

Differential effects of betamethasone on the fetus between morning and afternoon recordings

Background. Fetal heart rate (FHR) variation and fetal movements show a diurnal rhythm, a rise in the afternoon and evening compared to morning hours. A previous study showed that reductions in fetal parameters occurring two to three days after betamethasone administration are most likely caused by suppression of the normal rise during the day. Therefore monitoring during the morning could circumvent the suppressive effects of betamethasone. Objective. To study the effects of betamethasone on fetal diurnal rhythms, by comparing morning and afternoon recordings over five successive days. Methods. This was a prospective longitudinal study of 20 women at 25–34 weeks of gestation. One-hour recordings of FHR and fetal movements were made on each of five successive days in the morning and afternoon. Betamethasone was administered on day 0 and day 1. Results. We found no reduction of FHR variation on days 2 and 3 in the morning. In contrast, in the afternoon a reduction of FHR variation occurred on day 2. Time courses of fetal body and breathing movements during the morning were not affected by betamethasone administration. Conclusions. Transient reductions in fetal movement and FHR variation after glucocorticoid administration are not observed in the morning. For fetal monitoring and especially for assessing trends in fetal heart rate variation and movements with time, morning recordings should be preferably used in the period around glucocorticoid administration.

First-trimester Placental Vascular Development in Multiparous Women differs from that in Nulliparous Women

Abstract Objective: Multiparas differ from nulliparas by delivering larger babies with larger placentas and by having a lower risk of developing placental syndromes. We postulate that these differences result from a different initial course of placental vascular development. Study design: We measured placental flow index (FI), vascularization index (VI) and placental volume by 3D power Doppler and obtained blood samples at 8, 10 and 12 weeks pregnancy in 34 healthy nulliparous and 16 multiparous women with an uneventful pregnancy. Results: Between 8 and 12 weeks multiparas differed from nulliparas in a more rapid initial rise in FI, a higher angiopoietin-2 (ang2) level at eight weeks and no decline in the VEGF/sVEGF-R ratio. Nevertheless, at 12 weeks the FI and placental volume were indistinguishable between both study groups. Conclusions: These results combining serially measured placental vascularization, placental volume and circulating angiogenetic factors show initial differences in placental development, that howeve, did not maintain till the end of first trimester. The results support the concept that early placental vascular development differs between nulliparas and multiparas. Nevertheless, it is unclear whether these differences contribute to the development later on in pregnancy of intergroup differences in birthweight and incidence of placental syndromes.

Sequential use of mifepristone and misoprostol in treatment of early pregnancy failure appears more effective than misoprostol alone: a retrospective study.

OBJECTIVE Is treatment of early pregnancy failure (EPF) with sequential use of mifepristone and misoprostol more effective than treatment with misoprostol alone? STUDY DESIGN In a retrospective cohort study at the Department of Obstetrics and Gynaecology of the Radboud University Medical Centre, 301 women with early pregnancy failure receiving medical treatment between January 2008 and March 2013 were included. Of these, 199 women were pre-treated with 200mg mifepristone (orally) followed by 2 consecutive doses of 800mcg misoprostol (vaginally) and 102 women were treated with 2 consecutive doses of 800mcg misoprostol (vaginally) alone. RESULTS Complete expulsion was achieved in 66.8% of the women treated with a sequential combination of mifepristone and misoprostol versus 54.9% of the women treated with misoprostol alone. The difference in rates of complete expulsion was 11.9% (P<0.05; 95% CI 0.3-23.6%). CONCLUSIONS Medical treatment of early pregnancy failure with a sequential combination of mifepristone and misoprostol was more effective than treatment with misoprostol alone. Our findings will have to be confirmed by a large prospective multicentre double blinded-randomized trial.

Growth patterns in fetuses with isolated cardiac defects

There is evidence that in fetuses with congenital heart defects (CHDs), head growth is affected. However, scanty data are available on longitudinal growth patterns of other biometric parameters such as abdominal circumference (AC) and femur length (FL). The aim was to evaluate growth patterns in fetuses with isolated CHD diagnosed prenatally in different categories of lesions.

Accuracy of diagnosis and counseling of fetal brain anomalies prior to 24 weeks of gestational age

Abstract Objective: To evaluate the accuracy of prenatal neurosonography in diagnosing underlying causes of fetal ventriculomegaly, posterior fossa anomalies and microcephaly before 24 weeks’ gestational age (GA) and to study the accuracy of prenatal counseling on postnatal prognosis. Methods: A retrospective cohort study based on 146 cases of these fetal brain anomalies before 24 weeks’ GA. Counseling on prognosis was compared with postnatal outcome. Data on genetic testing was analyzed. Results: Out of 146 cases, 135 (92%) were diagnosed correctly before 24 weeks’ GA. Accuracy was 98% (97/99) in cases with multiple anomalies and 81% (38/47) in cases with an isolated abnormality. Counseling on prognosis was correct in 143 out of 146 cases (98%). Prenatal genetic diagnostics detected an anomaly in 51/113 (45%) of cases. In 14/62 (23%) cases prenatal karyotyping was normal, but postnatal array-CGH detected a pathogenic anomaly. Conclusions: Despite the challenges of early gestation, accuracy in diagnosing and counseling fetal brain anomalies before 24 weeks’ GA was high. Prenatal genetic testing is a valuable diagnostic tool and should be offered to all women with fetal brain anomalies. Considering the many different types of anomalies and diverse etiologies, a multidisciplinary approach is essential for counseling on postnatal outcome.

Intra- and interobserver agreement for fetal cerebral measurements in 3D-ultrasonography

The aim of this study is to evaluate intra‐ and interobserver agreement for measurement of intracranial, cerebellar, and thalamic volume with the Virtual Organ Computer‐aided AnaLysis (VOCAL) technique in three‐dimensional ultrasound images, in comparison to two‐dimensional measurements of these brain structures. Three‐dimensional ultrasound images of the brains of 80 fetuses at 20–24 weeks’ gestational age were obtained from YOUth, a Dutch prospective cohort study. Two observers performed offline measurement of the occipitofrontal diameter, intracranial volume, transcerebellar diameter, cerebellar volume, and thalamic width, area, and volume, independently. VOCAL was used for calculation of the volumes. The two‐way random, single measures intraclass correlation coefficient (ICC) was used for analysis of agreement and Bland–Altman plots were configured. Intra‐ and interobserver agreement was almost perfect for occipitofrontal diameter (intra ICC 0.88, 95% CI 0.82–0.92; inter ICC 0.91, 95% CI 0.85–0.94), intracranial volume (intra ICC 0.96, 95% CI 0.91–0.98; inter ICC 0.97, 95% CI 0.96–0.98) and transcerebellar diameter (intra ICC 0.91, 95% CI 0.86–0.94; inter ICC 0.86, 95% CI 0.78–0.910). For cerebellar volume, the intraobserver agreement was almost perfect (0.85, 95% CI 0.76–0.90), whereas the interobserver agreement was substantial (0.75, 95% CI 0.44–0.88). Agreement was only moderate for thalamic measurements. Bland–Altman plots for the volume measurements are normally distributed with acceptable mean differences and 95% limits of agreement. The intra‐ and interobserver agreement of the measurement of intracranial and cerebellar volume with VOCAL was almost perfect. These measurements are therefore reliable, and can be used to investigate fetal brain development. Thalamic measurements are not reliable enough.