Anjoke J. M. Huisjes

Corticosteroids, pregnancy, and HELLP syndrome: a review.

Corticosteroids are potent antiinflammatory and immunosuppressive drugs, which are used in the treatment of a wide range of medical disorders. During pregnancy, several corticosteroids are administered for maternal as well as fetal reasons. Prednisone and prednisolone show limited transplacental passage and are thus used for treatment of maternal disease. Dexamethasone and betamethasone, drugs that can easily cross the placenta, are more suitable for fetal indications. During the last decade, administration of corticosteroids was introduced in the treatment of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), a severe form of preeclampsia unique to human pregnancy. Several randomized, controlled trials as well as other prospective and retrospective studies have been performed to investigate this beneficial effect of corticosteroids on biochemical measures and clinical signs. This review discusses the characteristics of corticosteroids in humans and details the use of corticosteroids during pregnancy. A review of literature on the effect of corticosteroids on HELLP syndrome is given and possible mechanisms of action are discussed. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to compare the relative strength of the commercially available steroids, to outline the pharmacologic characteristics of glucocorticoids in humans, to compare the anti-inflammatory characteristics of corticosteroids, to explain the changes in glucocorticoid metabolism during pregnancy, and to list the effects of corticosteroids on the fetus.

HELLP syndrome is associated with an increased inflammatory response, which may be inhibited by administration of prednisolone.

Objective. To investigate the effect of prednisolone on HELLP syndrome by assessing several markers of the inflammatory response and hepatic damage associated with HELLP syndrome. Design. Prospective study. Setting. Single-center, tertiary obstetric care facility at the University Medical Centre Utrecht, The Netherlands. Population. Study subjects included normal controls, patients with non-HELLP preeclampsia, and patients with preeclampsia and HELLP syndrome. Methods. HELLP syndrome was defined by hemolysis (serum lactate dehydrogenase [LDH] >600 IU/L and/or haptoglobin ≤0.3 g/L), elevated liver enzymes (serum aspartate aminotransferase [AST] >70 U/L and/or serum alanine aminotransferase [ALT] >70 U/L), and a low platelet count (<100 × 109/L). Blood samples from patients with HELLP syndrome who were receiving either prednisolone or placebo were obtained before, during, and after a HELLP exacerbation in the antepartum period. Plasma levels of CRP, IL-1RA, IL-6, sIL-6R, IL-8, IL-10, TNF-α, and GSTA1-1 were determined. Samples from women with preeclampsia but without HELLP syndrome and from healthy pregnant women were included as controls. Main Outcome Measures. Plasma levels of CRP, IL-1RA, IL-6, sIL-6R, IL-8, IL-10, TNF-α, and GSTA1-1. Results. During a HELLP exacerbation CRP, IL-6, IL-1Ra, and GSTA1-1 levels are significantly increased (p < 0.01). In the group of patients treated with prednisolone, significantly lower IL-6 levels were observed during a HELLP exacerbation, compared with patients who did not receive prednisolone (p < 0.01). Conclusion.HELLP syndrome is associated with an increased inflammatory response. Circulating IL-6 levels in HELLP syndrome are reduced during prednisolone administration, suggesting a stabilizing effect on the inflammatory endothelial process.

Induction of labour versus expectant monitoring in women with pregnancy induced hypertension or mild preeclampsia at term: the HYPITAT trial

BackgroundHypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates.Methods/DesignWomen with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%.DiscussionThis trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications.Trial RegistrationThe protocol is registered in the clinical trial register number ISRCTN08132825.

Disproportionate Intrauterine Growth Intervention Trial At Term: DIGITAT

BackgroundAround 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term.Methods/designThe proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm.DiscussionThis trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term.Trial registrationDutch Trial Register and ISRCTN-Register: ISRCTN10363217.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial

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.

External validation of prognostic models to predict risk of gestational diabetes mellitus in one Dutch cohort: prospective multicentre cohort study

Objective To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first trimester of pregnancy. Design External validation of all published prognostic models in large scale, prospective, multicentre cohort study. Setting 31 independent midwifery practices and six hospitals in the Netherlands. Participants Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded. Main outcome measures Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots. Results 3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit. Conclusions In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact.

Management of fetal death after 20 weeks of gestation complicated by placenta previa

Fetal death after 20 weeks of gestation in combination with complete placenta previa is rarely seen. A search in PubMed and EMBASE (1966–2006; search terms: ‘placenta previa’ and ‘fetal death’) revealed only one case report [1]. There is limited experience with these cases and management is controversial. An inquiry among the eight University Hospitals in the Netherlands revealed only three cases in the period of 1990 through 2005. These cases, in which three different policies were followed, are presented below. The first woman was a 33-year-old gravida 7 para 4, with a well-controlled diabetes mellitus. She had had four uncomplicated deliveries and two miscarriages. The pregnancy in question, in 1990, was complicated by complete placenta previa. Fetal death occurred unexpectedly at 33 weeks. There was no bleeding. Five days later labor induction was initiated using prostaglandins (intravenous sulprostone, intramuscular carboprost and intracervical dinoprostone, respectively). After eight days and a total administration of 17 000 mg prostaglandins, attempts to induce labor were discontinued because of minimal cervical response. Expectant management was now agreed upon. Nineteen days after the diagnosis of stillbirth, the woman was readmitted because of fever and ruptured membranes. Coagulation tests and hemoglobin were normal and bleeding was still minimal. Antibiotics and oxytocin were started intravenously. Fourteen hours after admission the patient gave birth to a stillborn son with a birth weight of 1070 g (55 percentile). The placenta had to be extracted manually and weighed 130 g (510 percentile). A central placental rupture was present, suggesting that the fetus was born through the placenta. Total blood loss was 50 mL and the postpartum period was uneventful. The second case was a 33-year-old woman, who was gravida 5 para 2. Her two previous children were born by cesarean section because of cephalopelvic disproportion. In 1998 at 26þ5 weeks she complained of painless vaginal bleeding. Ultrasound examination showed complete placenta previa with partial placental abruption and fetal death in transverse lie. Blood loss was moderate and coagulation tests and hemoglobin were normal. Contractions started and ultrasound examination showed cervical dilation of 1 cm. After ample consideration it was decided to perform a repeat cesarean section, because of the risk of uterine rupture and the explicit request of the mother who wished to try for another child in the future. A stillborn boy of 680 g (10–50 percentile) was delivered. The placenta weighed 165 g (510 percentile). The cesarean section was complicated by a hemorrhage of 1500 mL for which two units of packed cells, two units of fresh frozen plasma and sulprostone were administered intravenously. The postoperative period was uneventful with normal coagulation tests. The third woman was a 37-year-old gravida 4 para 2. Her obstetric history revealed two uncomplicated pregnancies and one spontaneous abortion. In 2000 at 20 weeks of gestation, she was referred because of moderate painless vaginal bleeding. Ultrasound The Journal of Maternal-Fetal and Neonatal Medicine, March 2007; 20(3): 267–269

Is there a diurnal pattern in the clinical symptoms of HELLP syndrome

Objective. To determine if there is a diurnal pattern in the clinical symptoms of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome. Study design. A retrospective study was performed in 134 pregnancies complicated by HELLP syndrome. The medical records were reviewed to describe each HELLP episode. Time of day was divided into three periods, day, evening, and night. The following parameters were categorized according to the time of day: onset of symptoms, consultation by the doctor, initial blood sampling, diagnosis and decrease of symptoms. Biochemical parameters at clinical presentation and consecutive changes within 24 h were recorded. Results. In 65 pregnancies 77 HELLP episodes were well documented. Times of onset of symptoms and consultation by the doctor were significantly higher during the evening and night (p < 0.001), whereas times of diagnosis and decrease of symptoms occurred significantly more during the day (p < 0.001). In only 49.3% of the cases were diagnostic laboratory criteria met at clinical presentation. This was mainly due to platelet values in excess of 100 × 109/l. Several hours later (median 8 h, range 2–23) the decrease in platelets occurred. Conclusions. A diurnal pattern exists in the clinical symptoms of HELLP syndrome that is characterized by an exacerbation during the night and recovery during the day. There is a considerable delay between the onset of symptoms and the fulfilment of diagnostic laboratory criteria.

SIMPLE: implementation of recommendations from international evidence-based guidelines on caesarean sections in the Netherlands. Protocol for a controlled before and after study

BackgroundCaesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently.Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives).MethodsAn independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs.DiscussionThis study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child.Trial registrationhttp://www.clinicaltrials.gov: NCT01261676

Development and Measurement of Guidelines-Based Quality Indicators of Caesarean Section Care in the Netherlands: A RAND-Modified Delphi Procedure and Retrospective Medical Chart Review

Background There is an ongoing discussion on the rising CS rate worldwide. Suboptimal guideline adherence may be an important contributor to this rise. Before improvement of care can be established, optimal CS care in different settings has to be defined. This study aimed to develop and measure quality indicators to determine guideline adherence and identify target groups for improvement of care with direct effect on caesarean section (CS) rates. Method Eighteen obstetricians and midwives participated in an expert panel for systematic CS quality indicator development according to the RAND-modified Delphi method. A multi-center study was performed and medical charts of 1024 women with a CS and a stratified and weighted randomly selected group of 1036 women with a vaginal delivery were analysed. Quality indicator frequency and adherence were scored in 2060 women with a CS or vaginal delivery. Results The expert panel developed 16 indicators on planned CS and 11 indicators on unplanned CS. Indicator adherence was calculated, defined as the number of women in a specific obstetrical situation in which care was performed as recommended in both planned and unplanned CS settings. The most frequently occurring obstetrical situations with low indicator adherence were: 1) suspected fetal distress (frequency 17%, adherence 46%), 2) non-progressive labour (frequency 12%, CS performed too early in over 75%), 3) continuous support during labour (frequency 88%, adherence 37%) and 4) previous CS (frequency 12%), with adequate counselling in 15%. Conclusions We identified four concrete target groups for improvement of obstetrical care, which can be used as a starting point to reduce CS rates worldwide.