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Objective: To stratify the risk of spontaneous preterm delivery using cervical length (CL) and fetal fibronectin (fFN) in women with threatened preterm labor who remained pregnant after 7 days., Design: Prospective observational study., Setting: Nationwide cohort of women with threatened preterm labor from the Netherlands., Population: Women with threatened preterm labor between 24 and 34 weeks with a valid CL and fFN measurement and remaining pregnant 7 days after admission., Methods: Kaplan-Meier and Cox proportional hazards models were used to estimate cumulative percentages and hazard ratios (HR) for spontaneous delivery., Main Outcome Measures: Spontaneous delivery between 7 and 14 days after initial presentation and spontaneous preterm delivery before 34 weeks., Results: The risk of delivery between 7 and 14 days was significantly increased for women with a CL < 15 mm or a CL ≥15 to <30 mm and a positive fFN, compared with women with a CL ≥30 mm: HR 22.3 [95% confidence interval (CI) 2.6-191] and 14 (95% CI 1.8-118), respectively. For spontaneous preterm delivery before 34 weeks the risk was increased for women with a CL < 15 mm [HR 6.3 (95% CI 2.6-15)] or with a CL ≥15 to <30 mm with either positive fFN [HR 3.6 (95% CI 1.5-8.7)] or negative fFN [HR 3.0 (95% CI 1.2-7.1)] compared with women with a CL ≥ 30 mm., Conclusions: In women remaining pregnant 7 days after threatened preterm labor, CL and fFN results can be used in risk stratification for spontaneous delivery., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women., Methods: We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792)., Findings: Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred., Interpretation: For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered., Funding: ZonMw., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Noninvasive prenatal testing (NIPT) and direct karyotyping of cytotrophoblast were normal for a male fetus, but cultured chorionic villus mesenchymal cells and umbilical cord fibroblasts showed nonmosaic trisomy 18. This observation provides direct evidence for the cytotrophoblastic origin of cell-free fetal DNA and yields a biological explanation for falsely reassuring NIPT results.

Objective: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage., Design: A randomised double-blind placebo controlled multicentre trial., Patients: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery., Setting: Delivery rooms of 11 Dutch hospitals., Intervention: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT)., Main Outcome Measures: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage., Results: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64))., Conclusions: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls., Trial Registration Number: NCT00189007, Dutch Trial Register NTR1383., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The risk of manifestations of ischaemic heart disease (IHD) in fertile women is elevated during pregnancy and the post-partum period. With increasing maternal age and a higher prevalence of cardiac risk factors, the incidence of IHD during pregnancy is rising. However, information in the literature is scarce. We therefore performed a retrospective cohort study and systematically reviewed the overall (1975-2013) and contemporary (2005-2013) literature concerning IHD presenting during pregnancy or in the post-partum period. We report two cases of IHD with atypical presentation during pregnancy or post-partum. In our review, we describe 146 pregnancies, including 57 contemporary cases (2005-2013). Risk factors for IHD were present in 80 %. Of the cases of IHD, 71 % manifested in the third trimester or the post-partum period, and 95 % presented with chest pain. The main cause was coronary dissection (35 %), or thrombus/emboli (35 %) in the more contemporary group. Maternal mortality was 8 % (6 % in the contemporary group), and the main cardiac complication was ventricular tachycardia (n = 17). Premature delivery rate was 56 %, and caesarean section was performed in 57 %. Perinatal mortality was 4 %. In conclusion, IHD during pregnancy or in the post-partum period has high maternal mortality and morbidity rates. Also, premature delivery and perinatal mortality rates are high.

Objective: The objective of this study was to determine outcomes in pregnant women with pre-existing coronary artery disease (CAD) or following an acute coronary syndrome (ACS) including myocardial infarction (MI)., Background: The physiological changes of pregnancy can contribute to myocardial ischaemia. The pregnancy risk for women with pre-established CAD or a history of ACS/MI is not well studied., Methods: This was a retrospective multicentre study. Adverse maternal cardiac, obstetric and fetal/neonatal events were examined. The primary outcome was a composite endpoint of cardiac arrest, ACS/MI, ventricular arrhythmia or congestive heart failure. The prevalence of new or progressive angina during pregnancy was also examined., Results: Fifty pregnancies in 43 women (mean age 35±5 years) were included. Coronary atherosclerosis (40%) and coronary thrombus (36%) were the most common underlying diagnoses. The primary outcome occurred in 10% (5/50) of pregnancies and included one maternal death secondary to cardiac arrest. Other events included ACS/MI (3/50) and heart failure (1/50). New or progressive angina occurred in 18% of pregnancies. Ischaemic complications of any type (new or progressive angina, ACS/MI, ventricular arrhythmia, cardiac arrest) occurred more commonly in women with coronary atherosclerosis compared with those without (50% vs 10%, p=0.003). A high rate of adverse obstetric (16%) and fetal/neonatal (30%) events was observed., Conclusions: Pregnant women with pre-existing CAD or ACS/MI before pregnancy are at increased risk of adverse events during pregnancy. Those with coronary atherosclerosis are at highest risk of adverse maternal cardiac events due to myocardial ischaemia during pregnancy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test., Study Design: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women., Results: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women., Conclusion: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: The APOSTEL-II trial was a multicenter randomized placebo-controlled trial, assessing the effectiveness of maintenance tocolysis with nifedipine. The trial showed maintenance tocolysis not to have an effect on perinatal outcome. Objective of the current study is to evaluate the effect of a negative trial on the length of hospital admission of women with threatened preterm labor., Materials and Methods: We evaluated length of hospital admission of all patients admitted with threatened preterm labor with a gestational age <32 weeks in 8 perinatal centers that participated in the APOSTEL-II trial. We studied only the first admission with threatened preterm labor, readmissions were excluded. We distinguished between the period before, the period during and the period after the trial. In a subgroup analysis, we differentiated for the group of women who delivered and for the group of women who did not deliver during the initial admission., Results: The mean length of hospital admission was 9.3 days before the start of the trial, 8.4 days during the recruitment period and 8.1 days after the trial was completed. The difference in mean length of hospital admission before and during the recruitment period was significantly different (p<001)., Comments: The length of hospital admission of women with threatened preterm labor is found to be reduced during the recruitment period of the APOSTEL-II trial. This shows that the conduct of a randomized controlled trial itself has the potential to change daily practice., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the management of imminent preterm delivery with respect to prescription of antenatal corticosteroids (ACS) and referral to a tertiary center., Study Design: A retrospective cohort study existing of 1 perinatal center and 9 referring hospitals. All women who received their first dose of ACS in 1 of the 10 hospitals between 24+0 and 32+0 weeks of gestation and/or delivered before 32 weeks of gestation from 2005 until 2010. Patients were identified using the electronic database of hospital pharmacies. Main outcome measures were time interval from administration to delivery for different indications and number of women who were not referred in time to a tertiary center., Results: In total, 1375 women received ACS. Main indications were suspected preterm labor (44.7%), preterm prelabor rupture of membranes (15.9%), maternal indication (12.8%), fetal indication (9.2%) and vaginal blood loss (8.4%). Overall, 467 (34.0%) women delivered ≤7 days after ACS administration; 8.7% of women with vaginal blood loss and 54.5% of women with maternal indication. Among the 931 women who received ACS in the secondary hospitals, 452 (48.5%) women were referred to a tertiary hospital and 89 (6.5%) women delivered in a secondary hospital with a gestational age of less than 32 weeks., Conclusion: One-third of all women receiving ACS delivered within 7 days and half of the women who received ACS in a secondary hospital were referred to a tertiary center. There seems to be room for improvement regarding the timing of ACS administration and subsequently referral to a tertiary center., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The primary aim of this study was to investigate the correlation between pregnancy outcome and bile acid (BA) levels in pregnancies that were affected by intrahepatic cholestasis of pregnancy (ICP). In addition, correlations between maternal and fetal BA levels were explored., Study Design: We conducted a retrospective study that included women with pruritus and BA levels ≥10 μmol/L between January 2005 and August 2012 in 3 large hospitals in the Netherlands. The study group was divided in mild (10-39 μmol/L), moderate (40-99 μmol/L), and severe (≥100 μmol/L) ICP. Main outcome measures were spontaneous preterm birth, meconium-stained amniotic fluid, asphyxia, and perinatal death. Univariate and multivariate logistic regression analysis was used to study associations between BA levels and adverse outcome., Results: A total of 215 women were included. Gestational age at diagnosis and gestational age at delivery were significantly lower in the severe, as compared with the mild, ICP group (P < .001). Spontaneous preterm birth (19.0%), meconium-stained fluid (47.6%), and perinatal death (9.5%) occurred significantly more often in cases with severe ICP. Higher BA levels were associated significantly with spontaneous preterm birth (adjusted odds ratio [aOR], 1.15; 95% confidence interval [CI], 1.03-1.28), meconium-stained amniotic fluid (aOR, 1.15; 95% CI, 1.06-1.25), and perinatal death (aOR, 1.26; 95% CI, 1.01-1.57). Maternal BA levels at diagnosis and at delivery were correlated positively with umbilical cord blood BA levels (P = .006 and .012, respectively)., Conclusion: Severe ICP is associated with adverse pregnancy outcome. Levels of BA correlate between mother and fetus., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Post-term pregnancy, a pregnancy exceeding 294 days or 42 completed weeks, is associated with increased perinatal morbidity and mortality and is considered a high-risk condition which requires specialist surveillance and induction of labour. However, there is uncertainty on the policy concerning the timing of induction for post-term pregnancy or impending post-term pregnancy, leading to practice variation between caregivers. Previous studies on induction at or beyond 41 weeks versus expectant management showed different results on perinatal outcome though conclusions in meta-analyses show a preference for induction at 41 weeks. However, interpretation of the results is hampered by the limited sample size of most trials and the heterogeneity in design. Most control groups had a policy of awaiting spontaneous onset of labour that went far beyond 42 weeks, which does not reflect usual care in The Netherlands where induction of labour at 42 weeks is the regular policy. Thus leaving the question unanswered if induction at 41 weeks results in better perinatal outcomes than expectant management until 42 weeks., Methods/design: In this study we compare a policy of labour induction at 41 + 0/+1 weeks with a policy of expectant management until 42 weeks in obstetrical low risk women without contra-indications for expectant management until 42 weeks and a singleton pregnancy in cephalic position. We will perform a multicenter randomised controlled clinical trial. Our primary outcome will be a composite outcome of perinatal mortality and neonatal morbidity. Secondary outcomes will be maternal outcomes as mode of delivery (operative vaginal delivery and Caesarean section), need for analgesia and postpartum haemorrhage (≥1000 ml). Maternal preferences, satisfaction, wellbeing, pain and anxiety will be assessed alongside the trial., Discussion: This study will provide evidence for the management of pregnant women reaching a gestational age of 41 weeks., Trial Registration: Dutch Trial Register (Nederlands Trial Register): NTR3431. Registered: 14 May 2012.

Chondosarcoma of the proximal femur is a rare malignant disorder in women of (pre-) childbearing age, for which a radical resection through a hemipelvectomy could be indicated. We describe a case of a 36-year-old primigravida with a hemipelvectomy (2004) who had a history of radiotherapy of the pelvic and uterine regions after an atypical cartilaginous tumour. After an uncomplicated pregnancy, she had a spontaneous rupture of the membranes at 41+2 weeks and an uncomplicated vaginal delivery with physiological development of the infant. On the basis of the literature review, vaginal delivery after hemipelvectomy should be advocated and discussed with the patient and involved care providers. Women with radiotherapy in the pelvic and uterine areas have an increased risk of stillbirth, placental attachment disorders, impaired fetal growth, fetal malposition and preterm labour, but no association with prolonged rupture of the membranes has been described., (2014 BMJ Publishing Group Ltd.)

Objective: To explore hospital costs by pregnant women with a history of early-onset preeclampsia or HELLP syndrome, managed according to customary, but non-standardized prenatal care, by relating maternal and child outcome to maternal health care expenditure., Study Design: This was a cohort study, in women of 18 years or older who suffered from early-onset preeclampsia or HELLP syndrome in their previous pregnancy (n=104). We retrieved data retrospectively from hospital information systems and medical records of patients who had received customary, non-standardized prenatal care between 1996 and 2012. Our analyses focused on the costs generated between the first antenatal visit at the outpatient clinic and postpartum hospital discharge. Outcome measures were hospital resource use, costs, maternal and child outcome (recurrence of preeclampsia or HELLP syndrome, incidence of eclampsia, gestational age at delivery, intrauterine fetal demise, small-for-gestational-age birth and low 5min Apgar score). We used linear regression analyses to evaluate whether maternal and child outcome and baseline characteristics correlated with hospital costs., Results: Maternal hospital costs per patient averaged € 8047. The main cost drivers were maternal admissions and outpatient visits, together accounting for 80% of total costs. Primary cost drivers were preterm birth and recurrent preeclampsia or HELLP syndrome., Conclusion: Hospital costs in the next pregnancy of formerly preeclamptic women varied widely with over 70% being medically unexplainable. The results of this study support the view that care standardization in these women can be expected to improve costs and efficacy of care without compromising outcome., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To validate a previously published prediction model for recurrent early-onset preeclampsia (PE)., Methods: We included 229 pregnant women with a history of early-onset PE and computed their risk using the prediction model, compared the predicted risk to their pregnancy outcomes and assessed performance of the model., Results: Early-onset PE recurred in 6.6% of participants. The area under the receiver operating characteristic curve was 59% (95% CI: 45-73). The model created groups that were only moderately different in terms of their risk., Conclusions: The model's discriminate ability was poor and predictive performance insufficient to classify women into relevant risk groups.

Objective: To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor., Methods: We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk., Results: Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk., Conclusion: Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days., Level of Evidence: II.

Introduction: In the developed world, preterm birth is in quantity and in severity the most important issue in obstetric care. Adverse neonatal outcome is strongly related to gestational age at delivery. Since the pathophysiological mechanism of preterm birth is not yet completely unraveled, the development of successful preventive strategies is hampered. When preterm labor is actually threatening, current pharmacological therapies focus on inhibition of preterm contractions. This allows for transportation of the mother to a center with a neonatal intensive care unit and administration of corticosteroids to enhance fetal lung maturation. Globally, however, large practice variation exists., Areas Covered: The aim of this review is to provide an overview of current pharmacological therapies for preterm labor., Expert Opinion: For the initial tocolysis, the use of atosiban or nifedipine for 48 h is recommended based on the largest effectiveness and most favorable side effect profile. However, since data that convincingly indicate the beneficial effect of tocolytics on neonatal outcome are lacking, it might well be that tocolytics are ineffective. The role of progesterone in treatment of acute tocolysis is limited, but it might play a role in the prevention of preterm labor or as sensitizer for other tocolytic agents.

Background: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects., Methods/design: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, β 0.2 at alpha 0.05)., Discussion: This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour., Clinical Trial Registration: NTR2947, date of registration: June 20th 2011.

Objective: To evaluate the prescribing patterns of the first antenatal corticosteroids (ACS) course in our tertiary referral centre from 2005 until 2010., Study Design: We conducted a retrospective cohort study including all women who received ACS between 24(+0) and 34(+0) weeks of gestation. Main outcome measure was the number of women who delivered within 7 d after ACS administration. The time interval from administration to delivery was compared between women with different indications. Furthermore, all women delivering between 24(+0) and 34(+0) weeks of gestation who did not receive ACS were identified., Results: 1008 women received ACS, 15 (1.5%) women were lost to follow up. Main indications were suspected preterm labour, preterm prelabour rupture of membranes, maternal indication, foetal indication and vaginal blood loss (VBL). Overall, 447 (45.4%) women delivered ≤7 d after ACS administration. This percentage was 13.6% in women with VBL and 61.5% in women with maternal indication. During the study period, 1267 women delivered before 34 weeks of gestation, 126 (9.9%) women did not receive ACS., Conclusions: The time interval from ACS administration to delivery differs per indication. Women with VBL are most often over treated. The timing of the first ACS course should be improved.

Objective: Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia., Design: We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007)., Patients: We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study., Setting: Delivery rooms of 11 Dutch hospitals., Intervention: 500 mg allopurinol, intravenously to the mother, immediately prior to delivery., Main Outcome Measures: Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events)., Results: Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion., Conclusions: A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects., Trial Registration: The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

Free radical-induced reperfusion injury is a recognized cause of brain damage in the newborn after birth asphyxia. The xanthine oxidase inhibitor allopurinol reduces free radical synthesis and crosses the placenta easily. Therefore, allopurinol is a promising therapeutic candidate. This study tested the hypothesis that maternal treatment with allopurinol during fetal asphyxia limits ischemia-reperfusion (I/R) damage to the fetal brain in ovine pregnancy. The I/R challenge was induced by 5 repeated measured compressions of the umbilical cord, each lasting 10 minutes, in chronically instrumented fetal sheep at 0.8 of gestation. Relative to control fetal brains, the I/R challenge induced significant neuronal damage in the fetal hippocampal cornu ammonis zones 3 and 4. Maternal treatment with allopurinol during the I/R challenge restored the fetal neuronal damage toward control scores. Maternal treatment with allopurinol offers potential neuroprotection to the fetal brain in the clinical management of perinatal asphyxia.

Background: Pregnant women with congenital heart disease (CHD) are susceptible to cardiovascular, obstetric, and offspring complications. In women with CHD, cardiac dysfunction may compromise uteroplacental flow and contribute to the increased incidence of obstetric and offspring events., Methods and Results: We performed a prospective multicenter cohort study of pregnant women with CHD and healthy pregnant women. We compared clinical, laboratory, echocardiographic, and uteroplacental Doppler flow (UDF) parameters at 20 and 32 weeks gestation, and pregnancy outcome. We related cardiovascular parameters to UDF parameters and pregnancy outcome in women with CHD. We included 209 women with CHD and 70 healthy women. Cardiovascular parameters (N-terminal pro-B-type natriuretic peptide, left and right ventricular function) differed between both groups. UDF parameters were impaired in CHD women (umbilical artery pulsatility and resistance index at 32 weeks in CHD versus healthy women, P=0.0085 and P=0.017). The following cardiovascular parameters prepregnancy and at 20 weeks gestation were associated with UDF (umbilical artery resistance index) at 32 weeks at multivariable analysis: (1) right ventricular function (tricuspid annular plane systolic excursion) (P=0.002), (2) high N-terminal pro-B-type natriuretic peptide (P=0.085), (3) systemic (P=0.001), and (4) pulmonary (P=0.045) atrioventricular valve regurgitation. Women with CHD had more obstetric (58.9% versus 32.9%, P<0.0001) and offspring events (35.4% versus 18.6%, P=0.008) than healthy women. Impaired UDF was associated with adverse obstetric and offspring outcome., Conclusions: UDF parameters are abnormal in pregnant women with CHD. Cardiovascular function is associated with an abnormal pattern of UDF. Compromised UDF may be a key factor in the high incidence of offspring and obstetric complications in this population.

Objectives: In fetal tachycardia, pharmacological therapy with digoxin, flecainide and sotalol has been reported to be effective. In a recent retrospective multicenter study, sotalol was considered to be less effective than the other drugs in treatment of fetal supraventricular tachycardia (SVT). The aim of this study was to re-evaluate the efficacy and safety of maternally administered sotalol in the treatment of fetal tachycardia., Methods: This was a retrospective review of the records of 30 consecutive fetuses with tachycardia documented on M-mode echocardiography between January 2004 and December 2010 at Wilhelmina Children's Hospital, a tertiary referral university hospital. Patients were subdivided into those diagnosed with supraventricular tachycardia and those with atrial flutter (AF) and presence of hydrops was noted. Other variables investigated included QTc interval measured on maternal electrocardiogram before and after initiation of antiarrhythmic therapy, fetal heart rhythm and heart rate pre- and postnatally, oral maternal drug therapy used, time to conversion to sinus rhythm (SR), percentage of fetuses converted following transplacental treatment, maternal adverse effects, presence or absence of tachycardia as noted on postnatal ECG, postnatal therapy or prophylaxis and neonatal outcome. Findings are discussed with reference to the literature., Results: A total of 28 patients (18 with SVT, 10 with AF) were treated with sotalol as first-line therapy. Fetal hydrops was present in six patients (five with SVT, one with AF). All hydropic patients converted antenatally to SR (67% with sotalol as a single-drug therapy, 33% after addition of flecainide). Of the non-hydropic patients, 91% converted to SR (90% with sotalol only, 10% after addition of flecainide or digoxin). In 9% (with AF) rate control was achieved. There was no mortality. No serious drug-related adverse events were observed. Postnatally, rhythm disturbances were detected in 10 patients, two of whom still had AF. In eight, SVT was observed within 3 weeks postnatally, and in five of these within 72 hours., Conclusions: Sotalol can be recommended as the drug of first choice for treatment of fetal AF and has been shown to be an effective and safe first-line treatment option for SVT, at least in the absence of hydrops. Postnatal maintenance therapy after successful prenatal therapy is not necessarily indicated, as the risk of recurrence is low beyond 72 hours of age., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

Introduction: In an earlier paper we reported on the development of a model aimed at the prediction of preeclampsia recurrence, based on variables obtained before the next pregnancy (fasting glucose, BMI, previous birth of a small-for-gestational-age infant, duration of the previous pregnancy, and the presence of hypertension)., Objective: To externally validate and recalibrate the prediction model for the risk of recurrence of early-onset preeclampsia., Methods: We collected data about course and outcome of the next ongoing pregnancy in 229 women with a history of early-onset preeclampsia. Recurrence was defined as preeclampsia requiring delivery before 34 weeks. We computed risk of recurrence and assessed model performance. In addition, we constructed a table comparing sensitivity, specificity, and predictive values for different suggested risk-thresholds., Results: Early-onset preeclampsia recurred in 6.6% of women. The model systematically underestimated recurrence risk. The model's discriminative ability was modest, the area under the receiver operating characteristic curve was 58.9% (95% CI: 45.1 - 72.7). Using relevant risk-thresholds, the model created groups that were only moderately different in terms of their average risk of recurrent preeclampsia (Table 1)., Conclusion: Compared to an AUC of 65% in the development cohort, the discriminate ability of the model was diminished. It had inadequate performance to classify women into clinically relevant risk groups., (Copyright © 2013. Published by Elsevier B.V.)

Preterm labor (PTL) is an important cause of preterm delivery. The trigger initiating the process toward overt labor and parturition is poorly understood and the molecular basis remains an enigma. It recently emerged that the overall occurrence of PTL in pregnant women with congenital heart disease (CHD) is increased. In this review, we present data on pregnancy in women with CHD and the opportunities this provides for research on the initiating mechanisms of inappropriately premature contractions. This may provide means for early detection of women at high risk of PTL in the general population, with models using cervical length, novel biomarkers, and maternal factors. We discuss human embryonic development of the heart and the uterus and the molecular pathways shared by the cardio- and uteromyocytes. We propose 2 hypotheses for the co-occurrence of maternal CHD and PTL; one based on a shared genetic origin and the other on a shared epigenetic origin.

Objective: To assess the association between first-trimester crown-rump length (CRL) and the risk of spontaneous preterm birth before 32 weeks' gestation., Methods: We performed a matched case-control study of 129 women with spontaneous preterm birth at < 32 weeks' gestation (cases) and 129 women with term deliveries (controls) using data stored in the ultrasound and obstetric databases of our tertiary referral center. Cases and controls were individually matched based on maternal age, parity, history of preterm birth and medical indication for antenatal care. Fetal CRL measured between 8 + 0 and 13 + 6 weeks was expressed as multiples of the median (MoM) expected CRL, based on last menstrual period. We investigated the association between CRL-MoM and spontaneous preterm birth using logistic regression analysis., Results: CRL-MoM was not associated with spontaneous preterm birth: odds ratio (OR) 1.10 (95% CI, 0.89-1.36) per 0.10 MoM increase in CRL. Timing of measurement did not influence the model (P = 0.59). This was confirmed when restricting the analysis to the 93 pairs with CRL measurements made between 10 + 0 and 13 + 6 weeks: OR for preterm birth 1.07 (95% CI, 0.83-1.37) per 0.10 MoM increase in CRL., Conclusion: A short CRL in the first trimester is not associated with spontaneous preterm birth before 32 weeks' gestation, thus short CRL cannot be used to identify women at increased risk of preterm birth., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Background: The prevalence of asymptomatic bacteriuria (ASB) in pregnancy is 2-10% and is associated with both maternal and neonatal adverse outcomes as pyelonephritis and preterm delivery. Antibiotic treatment is reported to decrease these adverse outcomes although the existing evidence is of poor quality., Methods/design: We plan a combined screen and treat study in women with a singleton pregnancy. We will screen women between 16 and 22 weeks of gestation for ASB using the urine dipslide technique. The dipslide is considered positive when colony concentration ≥105 colony forming units (CFU)/mL of a single microorganism or two different colonies but one ≥105 CFU/mL is found, or when Group B Streptococcus bacteriuria is found in any colony concentration. Women with a positive dipslide will be randomly allocated to receive nitrofurantoin or placebo 100 mg twice a day for 5 consecutive days (double blind). Primary outcomes of this trial are maternal pyelonephritis and/or preterm delivery before 34 weeks. Secondary outcomes are neonatal and maternal morbidity, neonatal weight, time to delivery, preterm delivery rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal admission days and costs., Discussion: This trial will provide evidence for the benefit and cost-effectiveness of dipslide screening for ASB among low risk women at 16-22 weeks of pregnancy and subsequent nitrofurantoin treatment., Trial Registration: Dutch trial registry: NTR-3068.

Background: Women with a short cervical length in mid-trimester pregnancy have a higher risk of preterm birth and therefore a higher rate of neonatal mortality and morbidity. Progesterone can potentially decrease the number of preterm births and lower neonatal mortality and morbidity. Previous studies showed good results of progesterone in women with either a history of preterm birth or a short cervix. However, it is unknown whether screening for a short cervix and subsequent treatment in mid trimester pregnancy is effective in low risk women., Methods/design: We plan a combined screen and treat study among women with a singleton pregnancy without a previous preterm birth. In these women, we will measure cervical length at the standard anomaly scan performed between 18 and 22 weeks. Women with cervical length ≤ 30 mm at two independent measurements will be randomly allocated to receive either vaginal progesterone tablets or placebo between 22 and 34 weeks. The primary outcome of this trial is adverse neonatal condition, defined as a composite outcome of neonatal mortality and severe morbidity. Secondary outcomes are time to delivery, preterm birth rate before 32, 34 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We will assess growth, physical condition and neurodevelopmental outcome of the children at two years of age., Discussion: This study will provide evidence for the usefulness and cost-effectiveness of screening for short cervical length at the 18-22 weeks and subsequent progesterone treatment among low risk women., Trial Registration: Netherlands Trial Register (NTR): NTR207.

Background: Gestational hypertension (GH) and pre-eclampsia (PE) can result in severe complications such as eclampsia, placental abruption, syndrome of Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) and ultimately even neonatal or maternal death. We recently showed that in women with GH or mild PE at term induction of labour reduces both high risk situations for mothers as well as the caesarean section rate. In view of this knowledge, one can raise the question whether women with severe hypertension, pre-eclampsia or deterioration chronic hypertension between 34 and 37 weeks of gestation should be delivered or monitored expectantly. Induction of labour might prevent maternal complications. However, induction of labour in late pre-term pregnancy might increase neonatal morbidity and mortality compared with delivery at term., Methods/design: Pregnant women with severe gestational hypertension, mild pre-eclampsia or deteriorating chronic hypertension at a gestational age between 34+0 and 36+6 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant monitoring. In the expectant monitoring arm, women will be induced only when the maternal or fetal condition detoriates or at 37+0 weeks of gestation. The primary outcome measure is a composite endpoint of maternal mortality, severe maternal complications (eclampsia, HELLP syndrome, pulmonary oedema and thromboembolic disease) and progression to severe pre-eclampsia. Secondary outcomes measures are respiratory distress syndrome (RDS), neonatal morbidity and mortality, caesarean section and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be intention to treat. The power calculation is based on an expectant reduction of the maternal composite endpoint from 5% to 1% for an expected increase in neonatal RDS from 1% at 37 weeks to 10% at 34 weeks. This implies that 680 women have to be randomised., Discussion: This trial will provide insight as to whether in women with hypertensive disorders late pre-term, induction of labour is an effective treatment to prevent severe maternal complications without compromising the neonatal morbidity., Trial Registration: NTR1792 CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl.

Randomized trials on the clinical utility of fetal fibronectin in women with symptoms of preterm labor have thus far failed to demonstrate benefits. We systematically reviewed the methodology of these trials to assess if these negative results may be related to their study designs. We searched the literature for randomized trials that evaluated fibronectin testing in women with symptoms of preterm labor. Study results were evaluated and five methodological criteria were assessed: (1) randomization of discordant test results, (2) use of a fixed management protocol, (3) description of interventions in relation to the test result, (4) evaluation of a learning curve, and (5) sample size calculation in agreement with the prevalence of the test results. We detected four randomized trials that met inclusion criteria. All trials allocated women to a strategy with or without availability of fibronectin results without using a discordancy design or a fixed management protocol. One study reported the given treatment in relation to the test results. Learning curves were evaluated in one study. Two studies used transport sample size calculations. The negative results of randomized trials on fetal fibronectin may be due to particular choices in their study design., (© Thieme Medical Publishers.)

Antiphospholipid syndrome (APS) had been previously diagnosed in three pregnant women aged 32, 27 and 36 years, respectively. All three of them were using low-molecular weight heparin for the prevention of thromboembolic complications. The first two women were admitted because of foetal growth retardation. In the first patient, either HELLP syndrome or exacerbation of APS was suspected. A caesarean section was performed due to foetal distress. The patient's condition deteriorated further postoperatively. Multiple infarctions in liver and placenta were identified. Catastrophic antiphospholipid syndrome (CAPS) was diagnosed. Despite intensive medical treatment including anticoagulation the patient died of massive pulmonary embolism. The second patient suffered from thrombocytopaenia, disturbances in hepatic function and epigastric pain. CAPS was diagnosed. The condition improved after treatment with glucocorticoids, but because of a poor foetal prognosis, delivery was induced and a lifeless son was born. The third woman was admitted due to pyelonephritis. Shortly thereafter, symptoms of HELLP syndrome developed and she was administered glucocorticoids. Hepatic infarcts and petechiae developed, indicating CAPS. Delivery was induced and a girl was born. Glucocorticoid treatment was resumed and combined with immunoglobulins and plasmapheresis. The patient recovered and was discharged together with her daughter. CAPS is a life-threatening variation of APS. It is characterised by multiple thromboses and rapidly progressive multi-organ failure. Mortality is high, but seems to diminish with treatment by immunosuppressive therapy. In pregnancy, clinical signs of CAPS are similar to those of HELLP syndrome. Since the treatment for HELLP syndrome is different from CAPS, a correct diagnosis is essential. Because of the rarity of this condition in combination with high rates of perinatal and maternal mortality, care for pregnant patients with APS should be centralised in academic centres and close cooperation between obstetricians and internal medicine is necessary.

In complicated labor, neonatal outcome may depend not only on the extent of fetal asphyxia and acidosis but also on the effects on the fetal cardiovascular system of reactive oxygen species (ROS) generated during the ischemia-reperfusion (I/R) associated with repeated compressions of the umbilical cord. This study tested the hypothesis that maternal treatment with clinical doses of the antioxidant allopurinol in the setting of fetal asphyxia would reduce oxidative stress in the fetal cardiovascular system. The hypothesis was tested in chronically instrumented fetal sheep in late gestation by investigating the effects of maternal treatment with therapeutic doses of allopurinol or vehicle on the fetal cardiovascular system during and after episodes of I/R. The latter were produced by repeated, measured compressions of the umbilical cord. The data show that maternal treatment with allopurinol helped maintain umbilical blood flow and it reduced fetal cardiac oxidative stress after I/R of the type associated with clinically relevant acidemia and repetitive fetal heart rate decelerations. The data support the hypothesis tested and suggest that maternal treatment with allopurinol may offer plausible clinical intervention in the management of perinatal asphyxia in complicated labor.

Background: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy., Methods/design: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis., Discussion: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia., Trial Registration Number: Clinical Trials, protocol registration system: NCT00189007.

Objectives: Fetal heart block is a rare and irreversible condition associated with structural heart defects or maternal autoantibodies (SS-A/Ro and SS-B/La) resulting in permanent damage of the atrioventricular (AV) node. This is the first report of 4 cases with a transient fetal heart block in structurally normal hearts without maternal autoantibodies., Methods: A report on 4 patients seen within a 14-year period at one center with fetal heart block without intracardiac abnormalities or maternal autoantibodies., Results: Three patients were referred to our center with a fetal bradycardia (heart rate 70-85 bpm), between 20 and 33 weeks' gestational age, and 1 for a 'triple' test at 16 weeks' gestational age. Echocardiography showed a complete heart block in 2 fetuses, and a second-degree AV block in the other 2. Heart block had completely resolved at all following visits. Postnatal ECG recordings showed normal sinus rhythm in all patients. Echocardiographic evaluation at presentation and follow-up showed normal cardiac anatomy, without signs of hydrops or cardiac decompensation in all patients. All mothers tested negative on SS-A/Ro and SS-B/La autoantibodies., Conclusions: Fetal heart block can occur in the absence of structural heart defects and maternal autoantibodies to SS-A/Ro and SS-B/La. The origin of such heart block is unknown, but its course seems benign: none of the patients ever showed ventricular heart rates <55 bpm, signs of congestive heart failure or fetal hydrops. Heart block resolved spontaneously in all patients., (Copyright (c) 2005 S. Karger AG, Basel.)

Objective: Fetal tachycardia is a condition associated with congestive heart failure and development of fetal hydrops, which may result in neurological morbidity and mortality. The aim of this study was to investigate the long-term outcome of hydropic fetuses., Methods: This was a retrospective study on cognitive and neurological functioning of 11 infants, aged 6 months to 12 years, who experienced fetal tachycardia complicated by hydrops., Results: Seven fetuses had supraventricular tachycardia (SVT), three had atrial flutter (AF) and one had ventricular tachycardia (VT). Nine fetuses converted to sinus rhythm within a mean time of 8.2 days of presentation; resolution of hydrops was achieved in six of these patients in a mean time of 8.8 days. Mean gestational age (GA) at birth was 35 + 4 weeks. Neonatal cranial ultrasound was normal in seven infants and all but one of these were normal at follow-up: one infant who initially had no abnormalities developed multiple cerebral lesions as a result of a malignant long QT syndrome (LQTS) and died at the age of 2 years. Three infants had periventricular echogenicity (PVE) on neonatal cranial ultrasound, associated with a pseudocyst in one infant. The remaining infant showed a parenchymal hemorrhage of antenatal onset, seen as a porencephalic cyst at birth. One of these infants was normal at follow-up, one died 2 days after birth and two infants had neurological abnormalities at follow-up, consisting of mild hemiplegia with normal cognitive function in one, and a cognitive developmental delay in the other., Conclusions: In this study, neurological outcome was good in eight out of 11 infants. Initiation of therapy should not be withheld or delayed on the assumption of poor neurological outcome., (Copyright 2004 ISUOG)

Background: The morphology of the fetal ECG complex provides information on the fetal condition during labour, such as the ST segment and T-wave configuration. We hypothesised that the intrapartum fetal QT interval may provide additional information on the condition of the fetus, as it is known that the QT interval reacts to situations of stress and exercise., Design: Retrospective study., Setting: Data were substracted from a European community multicentre trial., Methods: The intrapartum QT interval was measured in 68 fetuses who were acidemic at birth (pH <7.05 and BD (ecf) >12 mmol/L) and in a control group of similar size. All of these cases were monitored by STAN S21. Measurements were performed at the start of the recording at baseline heart rate, during variable decelerations and at the end of the recording. The QTc was calculated using Bazett's formula: QT/ radical RR. The intervals were compared using the Wilcoxon signed ranks test., Main Outcome Measures: Fetal QT interval, and the corrected QT interval: QTc., Results: In the acidemic fetuses, there was a significant shortening of the QTc interval at the end of the recording compared with the start of the recording (397 ms at the end vs 359.3 ms at start; P < 0.001), in association with a significantly lowered heart rate (136.3 vs 110.9 bpm, P < 0.001). Measurements of QT and QTc during variable decelerations at the start and end of the recording also showed a shortening of the QT interval (301.9 vs 273.3 ms, P< or = 0.001) and QTc interval (381.6 vs 340.3, P < 0.001), and this was not dependent on heart rate. In the control cases, no differences in FHR, QT and QTc intervals were present., Conclusions: In intrapartum hypoxia, resulting in metabolic acidosis, a significant shortening of the fetal QT and QTc is present, irrespective of changes in heart rate. In control cases, this shortening does not occur. The intrapartum fetal QT interval may therefore provide additional information on the condition of the fetus.

Objectives: The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of sotalol in the treatment of fetal tachycardia., Background: Maternally administered, intrauterine therapy of fetal tachycardia is dependent on the transplacental passage of the antiarrhythmic agent., Methods: In a prospective study of patients treated for fetal tachycardia with sotalol, concentrations of sotalol were determined in maternal and umbilical blood and in amniotic fluid, and the relationship between these concentrations and the occurrence of conversion to sinus rhythm was investigated., Results: Eighteen fetal patients were studied, nine with atrial flutter and nine with supraventricular tachycardia. Fourteen were treated with sotalol; 13 converted to sinus rhythm, of whom 2 relapsed. There was one intrauterine death. Four patients were treated with sotalol and digoxin, of whom two were treated successfully. Mean birth weight was 3,266 g. The daily maternal sotalol dose was linearly related to the maternal plasma concentration. The mean fetal/maternal sotalol plasma concentration was 1.1 (range 0.67 to 2.87, SD 0.63), and the mean amniotic fluid/fetal blood ratio of sotalol was 3.2 (range 1.28 to 5.8, SD 1.4). The effectiveness of sotalol therapy could not be extrapolated from maternal blood levels., Conclusions: Sotalol is a potent antiarrhythmic agent in the treatment of fetal tachycardia. The placental transfer is excellent. Sotalol accumulates in amniotic fluid but not in the fetus itself. Therefore it seems that renal excretion in the fetus is efficient and greater than the oral absorption by fetal swallowing. The maternal blood level is not a reliable predictor of the chances of success of therapy. Sotalol is not associated with fetal growth restriction.

Background: Persistent junctional reciprocating tachycardia (PJRT) tends to be a persistent arrhythmia and requires aggressive therapeutic management. Diagnosis and management of this infrequently occurring tachycardia in the fetus at an early stage is of importance for the prevention of congestive heart failure (CHF)., Methods: A retrospective study of four fetuses with supraventricular tachycardia (SVT) of the PJRT type was performed., Results: All had sustained SVT (mean of 228 beats/min) at a mean gestational age of 34 + 5 weeks, with CHF present in two. Three fetuses had prenatal characteristics of PJRT on M-mode echocardiography with a ventriculoatrial (VA)/atrioventricular ratio of > 1 on M-mode echocardiography suggesting a slow conducting accessory pathway. All four fetuses had postnatal confirmation of the diagnosis. Transplacental treatment with flecainide was effective in one patient; sotalol as a single drug or in combination with digoxin was partially effective in the remaining three. Two developed sinus rhythm, with short intermittent periods of tachycardia and decreasing signs of CHF; one case showed a minimal decrease in heart rate. Oral propranolol therapy converted two patients postnatally; in the remaining two patients radiofrequency ablation was performed at the age of 5 months and 6 years., Conclusions: The characteristics of our prenatal PJRT cases included a sustained heart rate not exceeding 240 beats/min with a long VA interval, the presence of CHF and therapy resistance. Transplacental treatment should be initiated, possibly with a combination of sotalol and digoxin in non-hydropic cases, or flecainide, especially in case of fetal hydrops. Pharmacological therapy is to be preferred postnatally, but radiofrequency ablation seems to be indicated in therapy-resistant cases with CHF, even in the first months of life.

Objective: To determine the contribution of the prenatal ultrasound diagnosis of structural congenital heart defects to the care of patients requiring surgery for their condition in the neonatal period., Design: Retrospective., Method: During the period January 1991-June 1999, data were collected from two groups of children. One group had a structural heart defect diagnosed prenatally and the other underwent a neonatal operation due to a heart defect. In the prenatal group, the management and follow-up were analysed, whilst in the surgery group, the extent to which ultrasound investigation had been performed and whether there was a relationship between prenatal diagnosis and the severity of acidosis were analysed., Results: A structural heart defect was found through prenatal ultrasound in 170 children and 64% of these prenatally diagnosed patients died before or immediately after birth, or the pregnancy was aborted. 14% underwent surgery within 31 days post partum. This last category formed an overlap with the surgery group. The surgery group contained 191 patients, who required surgery in the neonatal period, including 24 from the prenatal group. In total, 87% had no prenatal diagnosis. In the group with a prenatal diagnosis pre-operative lactate values were significantly lower., Conclusion: The heart defect was only diagnosed prenatally in 13% of the patients from the surgery group, although this would have been technically feasible in 46%. Better prenatal diagnosis of heart disease could contribute to a better counselling of parents in their choice between abortion, conservative treatment or emergency surgery. In the case of emergency surgery, prenatal detection might lead to a decrease in morbidity and mortality.

The pharmacological treatment of fetal tachycardia (FT) has been described in various publications. We present a study reviewing the necessity for treatment of FT, the regimens of drugs used in the last two decades and their mode of administration. The absence of reliable predictors of fetal hydrops (FH) has led most centers to initiate treatment as soon as the diagnosis of FT has been established, although a small minority advocate nonintervention. As the primary form of pharmacological intervention, oral maternal transplacental therapy is generally preferred. Digoxin is the most common drug used to treat FT; however, effectiveness remains a point of discussion. After digoxin, sotalol seems to be the most promising agent, specifically in atrial flutter and nonhydropic supraventricular tachycardia (SVT). Flecainide is a very effective drug in the treatment of fetal SVT, although concerns about possible pro-arrhythmic effects have limited its use. Amiodarone has been described favorably, but is frequently excluded due to its poor tolerability. Verapamil is contraindicated as it may increase mortality. Conclusions on other less frequently used drugs cannot be drawn. In severely hydropic fetuses and/or therapy-resistant FT, direct fetal therapy is sometimes initiated. To minimize the number of invasive procedures, fetal intramuscular or intraperitoneal injections that provide a more sustained release are preferred. Based on these data we propose a drug protocol of sotalol 160 mg twice daily orally, increased to a maximum of 480 mg daily. Whenever sinus rhythm is not achieved, the addition of digoxin 0.25 mg three times daily is recommended, increased to a maximum of 0.5 mg three times daily. Only in SVT complicated by FH, either maternal digoxin 1 to 2mg IV in 24 hours, and subsequently 0.5 to 1 mg/day IV, or flecainide 200 to 400 mg/day orally is proposed. Initiating direct fetal therapy may follow failure of transplacental therapy.

The protocols mentioned are used by Utrecht University Hospital for the treatment of foetal supraventricular tachycardias. In the case of atrial flutters the pregnant woman is treated with sotalol administered orally and, if no sinus rhythm is obtained nor a reduced ventricular rhythm occurs, subsequently with digoxin. If there is no hydrops foetalis then this is also the treatment regimen for other forms of foetal supraventricular tachycardia. In the case of hydrops foetalis the treatment is more aggressive: digoxin intravenously or flecanide orally; if the rhythm does not convert into a sinus rhythm nor a reduced ventricular rhythm occurs then both of these medications are administered; if that also proves to be insufficient then direct foetal therapy can be considered.

Background: Fetal tachycardia may cause hydrops fetalis and lead to fetal death. No unanimity of opinion exists regarding the optimum treatment. This study evaluates our experience with transplacental sotalol therapy to treat fetal tachycardias in terms of safety and efficacy., Methods and Results: The charts of 21 patients who were treated with sotalol for fetal tachycardia were reviewed. Ten fetuses had atrial flutter (AF), 10 had supraventricular tachycardia (SVT), and 1 had VT. Hydrops fetalis was present in 9 fetuses. Drug treatment was successful in establishing sinus rhythm in 8 of 10 fetuses with AF and in 6 of 10 fetuses with SVT. The mortality rate in this study was 19% (4 of 21 fetuses; 3 had SVT and 1 had AF); 3 deaths occurred just days after the initiation of sotalol therapy, and 1 occurred after a dosage increase. At birth, tachycardia was present in 6 infants. Two patients who converted to sinus rhythm in utero suffered from neurologic pathology postnatally., Conclusions: Fetal tachycardia is a serious condition in which treatment should be initiated, especially in the presence of hydrops fetalis. The high success rate in fetuses with AF suggests that sotalol should be considered a drug of first choice to treat fetal AF. The low conversion rate and the fact that 3 of the 4 deaths in this study occurred in fetuses with SVT indicate that the risks of sotalol therapy outweigh the benefits in this group and that sotalol should, therefore, be limited in the treatment of fetal SVT.