Intrapartum and neonatal mortality in primary midwife-led and secondary obstetrician-led care in the Amsterdam region of the Netherlands: A retrospective cohort study.

OBJECTIVE: To compare intrapartum- and neonatal mortality and intervention rates in term women starting labour in primary midwife-led versus secondary obstetrician-led care. DESIGN: Retrospective cohort study. SETTING: Amsterdam region of the Netherlands. PARTICIPANTS: Women with singleton pregnancies who gave birth beyond 37+0 weeks gestation in the years 2005 up to 2008 and lived in the catchment area of the neonatal intensive care units of both academic hospitals in Amsterdam. Women with a primary caesarean section or a pregnancy complicated by antepartum death or major congenital anomalies were excluded. For women in the midwife-led care group, a home or hospital birth could be planned. MEASUREMENTS: Analysis of linked data from the national perinatal register, and hospital- and midwifery record data. We assessed (unadjusted) relative risks with confidence intervals. Main outcome measures were incidences of intrapartum and neonatal (<28 days) mortality. Secondary outcomes included incidences of caesarean section and vaginal instrumental delivery. FINDINGS: 53,123 women started labour in primary care and 30,166 women in secondary care. Intrapartum and neonatal mortality rates were 37/53,123 (0.70‰) in the primary care group and 24/30,166 (0.80‰) in the secondary care group (relative risk 0.88; 95% CI 0.52-1.46). Women in the primary care group were less likely to deliver by secondary caesarean section (5% versus 16%; RR 0.31; 95% CI 0.30-0.32) or by instrumental delivery (10% versus 13%; RR 0.76; 95% CI 0.73-0.79). KEY CONCLUSIONS: We found a low absolute risk of intrapartum and neonatal mortality, with a comparable risk for women who started labour in primary versus secondary care. The intervention rate was significantly lower in women who started labour in primary care. IMPLICATIONS FOR PRACTICE: These findings suggest that it is possible to identify a group of women at low risk of complications that can start labour in primary care and have low rates of medical interventions whereas perinatal mortality is low.

Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour.

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).

Involving women in personalised decision-making on mode of delivery after caesarean section: the development and pilot testing of a patient decision aid.

OBJECTIVE: To develop a patient decision aid (PtDA) for mode of delivery after caesarean section that integrates personalised prediction of vaginal birth after caesarean (VBAC) with the elicitation of patient preferences and evidence-based information. DESIGN: A PtDA was developed and pilot tested using the International Patients Decision Aid Standards (IPDAS) criteria. SETTING: Obstetric health care in the Netherlands. POPULATION: A multidisciplinary steering group, an expert panel, and 25 future users of the PtDA, i.e. women with a previous caesarean section. METHODS: The development consisted of a construction phase (definition of scope and purpose, and selection of content, framework, and format) and a pilot testing phase by interview. The process was supervised by a multidisciplinary steering group. MAIN OUTCOME MEASURES: Usability, clarity, and relevance. RESULTS: The construction phase resulted in a booklet including unbiased balanced information on mode of birth after caesarean section, a preference elicitation exercise, and tailored risk information, including a prediction model for successful VBAC. During pilot testing, visualisation of risks and clarity formed the main basis for revisions. Pilot testing showed the availability of tailored structured information to be the main factor involving women in decision-making. The PtDA meets 39 out of 50 IPDAS criteria (78%): 23 out of 23 criteria for content (100%) and 16 out of 20 criteria for the development process (80%). Criteria for effectiveness (n = 7) were not evaluated. CONCLUSIONS: An evidence-based PtDA was developed, with the probability of successful VBAC and the availability of structured information as key items. It is likely that the PtDA enhances the quality of decision-making on mode of birth after caesarean section.

A clinical prediction model to assess the risk of operative delivery.

OBJECTIVE: To predict instrumental vaginal delivery or caesarean section for suspected fetal distress or failure to progress. DESIGN: Secondary analysis of a randomised trial. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: 5667 labouring women with a singleton term pregnancy in cephalic presentation. METHODS: We developed multinomial prediction models to assess the risk of operative delivery using both antepartum (model 1) and antepartum plus intrapartum characteristics (model 2). The models were validated by bootstrapping techniques and adjusted for overfitting. Predictive performance was assessed by calibration and discrimination (area under the receiver operating characteristic), and easy-to-use nomograms were developed. MAIN OUTCOME MEASURES: Incidence of instrumental vaginal delivery or caesarean section for fetal distress or failure to progress with respect to a spontaneous vaginal delivery (reference). RESULTS: 375 (6.6%) and 212 (3.6%) women had an instrumental vaginal delivery or caesarean section due to fetal distress, and 433 (7.6%) and 571 (10.1%) due to failure to progress, respectively. Predictors were age, parity, previous caesarean section, diabetes, gestational age, gender, estimated birthweight (model 1) and induction of labour, oxytocin augmentation, intrapartum fever, prolonged rupture of membranes, meconium stained amniotic fluid, epidural anaesthesia, and use of ST-analysis (model 2). Both models showed excellent calibration and the receiver operating characteristics areas were 0.70-0.78 and 0.73-0.81, respectively. CONCLUSION: In Dutch women with a singleton term pregnancy in cephalic presentation, antepartum and intrapartum characteristics can assist in the prediction of the need for an instrumental vaginal delivery or caesarean section for fetal distress or failure to progress.

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

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

Comparative analysis of recommendations in local Dutch guidelines on 'Hypertension and pregnancy'.

OBJECTIVE: Hypertensive disorders in pregnancy remain the most prevalent cause of maternal and fetal morbidity and mortality. We hypothesise that incompleteness of local protocols 'Hypertension during pregnancy' might be associated with adverse obstetric outcome. Therefore, we analyzed the contents of the local Dutch protocols. STUDY DESIGN: We analyzed local Dutch protocols on 'Hypertension during pregnancy' using qualitative methods to score the completeness using the national guideline as standard. Indicators were designed using key recommendation from the national Dutch guideline 'Hypertension during pregnancy' (n=83 indicators), 22 of these indicators were classified as crucial indicators. Deficiencies in the local Dutch protocols, differences between the protocols and differences between the protocols of academically affiliated hospitals, teaching non-academic hospitals and non-teaching hospitals were analyzed using ANOVA test. RESULTS: The median total score of the local protocols is 32.5 (max 83, range from 2 to 55). Thirteen indicators were described in less than 10% of the local protocols. We found more indicators lacking in the non-teaching hospitals protocols compared to academically affiliated hospitals and teaching non-academically hospitals protocols. (Six of the crucial indicators were described in less than 50% of the local protocols.) CONCLUSIONS: The data from this review imply incompleteness of the local Dutch protocols. Improvement of the protocols can result in improvement of implementation and subsequent improvement of quality care for pregnant women with hypertension finally resulting in better outcome of mother and child.

[Prevention of neonatal infection with group B streptococci: what the best strategy is remains unclear]. / Preventie van neonatale infectie met groep B-streptokokken: onduidelijk welke strategie de beste is.

Early-onset group B streptococcal disease (GBS disease) is an important cause of morbidity and mortality in newborn infants. There is no international agreement on the best strategy for selecting pregnant women for antibiotic prophylaxis during delivery in order to reduce the incidence of this disease. A cost-effectiveness study of 4 strategies using a theoretical model showed that the risk strategy (antibiotics for women at risk) and combination strategy (antibiotics for GBS-positive women at risk) seemed more cost-effective than the current Dutch strategy (antibiotics for women at risk ifGBS positive) and the screening strategy (antibiotics for GBS-positive women). Balancing the possible effects, costs, unwanted side effects, and limitations of the implementation of either strategy in the Netherlands, the combination strategy may be a reasonable option. The possibly favourable introduction of PCR screening techniques and vaginal chlorhexidine flushing in Dutch obstetric practice deserves further scientific attention.

[Thrombophilia and the prevention of thromboembolic complications during pregnancy and the puerperium]. / Trombofilie en preventie van trombo-embolische complicaties tijdens zwangerschap en kraambed.

Deep vein thrombosis is one of the main causes of maternal death in the Western world, pulmonary embolism, as a complication, being the immediate cause of death in most cases. Deep vein thrombosis is the end result of several, partly interrelated, inherited and acquired risk factors. Thrombophilia is the overall name for a number of specific abnormalities resulting in an increased tendency towards haemocoagulation. In order to reduce the morbidity and mortality caused by thromboembolic complications in pregnant women, all women who want to become pregnant should be screened for risk factors in order to assess the a priori risk of venous thrombosis. Based on the individual thrombosis history and the presence of thrombophilia, a prophylactic policy can be determined for every pregnant woman. Currently, there are no data available from prospective and randomised trials assessing the effects of anticoagulants in pregnant women with thrombophilia.

[Malacoplakia of the female genital tract in a woman with postmenopausal bleeding]. / Malacoplakie van de tractus genitalis bij een vrouw met postmenopauzaal bloedverlies.

A 74-year-old woman had vaginal bleeding for 6 months with no other complaints. A suspected tumour was visible on the cervix and the endometrium was slightly thickened. Histological examination revealed Michaelis-Gutmann bodies. Following antibiotic treatment, the tumour and the bleeding disappeared. Malacoplakia is a chronic inflammation which usually arises in the urinary tract of older women and, rarely, in the female genital tract. The abnormality often appears to be a malignancy, although histologically it is an inflammatory condition. Histological examination is necessary to establish the diagnosis. Treatment usually consists of antibiotics and surgical excision.

[Preconception counseling: evaluation of an outpatient clinic at a university hospital]. / Preconceptionele advisering: evaluatie van een polikliniek in een academisch ziekenhuis.

OBJECTIVE: To provide an overview of the outcomes from an outpatients' clinic for preconceptional counselling in the Netherlands and to assess its activities in terms of referrals, referral indications, supplementary investigations, treatment policy and a possible future pregnancy. DESIGN: Retrospective, descriptive. METHOD: Data were collected from the medical records of women who were seen at the outpatients' clinic for preconceptional counselling, University Medical Centre St Radboud, Nijmegen, the Netherlands, during the period 1 January 1996-6 July 2000. RESULTS: Of the 484 women studied, medical records were available for 459 (95%); their median age was 31 years (range: 19-44). Most of the women with one or more risk factors were referred by gynaecologists (65%), followed by general practitioners (17%) and other specialists (14%). The main categories of referral were previous complicated obstetric history, previous fetal abnormality, and chronic maternal disease. Half of the women were subjected to supplementary investigations on the basis of an indication; hyperhomocysteinaemia was diagnosed in 24%, other form of thrombophilia (coagulopathy) in 21% and vitamin deficiency in 18%. The most frequent preconceptional interventions were the correction of hyperhomocysteinaemia by means of administering folic acid or other vitamin supplements and a change of therapy or cessation of therapy for potentially teratogenic medications. CONCLUSION: The outpatients' clinic for preconceptional counselling helped to minimise risk factors for adverse pregnancy outcome amongst high-risk women by providing extensive advice as well as by means of the early detection and treatment of diagnosed abnormalities.

Conditions at conception in women with recurrent miscarriage.

In order to evaluate the role of conditions at conception in the risk of miscarriage, we sent 234 women with at least two consecutive miscarriages after conceptions from the same partner a short questionnaire asking for the birth dates of their mothers and their live or stillborn siblings and the occurrence of any maternal miscarriages. Complete information was provided by 186 respondents. Using matched logistic regression, we investigated whether these women were born more often than their siblings (total n = 578) to young (< or = 19 years) or relatively old (> or = 40 years) mothers or shortly after a preceding pregnancy (born within 1 year). We also evaluated whether they showed a different month-of-birth distribution. No increased odds ratios were found for young or advanced maternal age, or for short preceding birth intervals. However, relative to their siblings, cases showed a deviant month-of-birth distribution (p = 0.08) with a peak in (late) winter. These results indicate that low and high maternal age and short preceding birth intervals are not determinants of the risk of miscarriage in the daughter. They also suggest that there may be seasonally varying factors that prenatally influence the risk of miscarriage.

Hyperhomocysteinemia: a risk factor for placental abruption or infarction.

OBJECTIVE: To establish the prevalence of hyperhomocysteinemia in women with placental abruption or infarction. DESIGN: Forty-six women with normal pregnancy outcome (controls) and 84 women with placental abruption or infarction (study group) were selected, and studied in the non-pregnant state. Homocysteine metabolism was investigated by a standardized oral methionine loading test. Hyperhomocysteinemia was defined as a concentration of fasting and/or postmethionine plasma homocysteine exceeding the estimated 97.5 percentile level of the controls. In the fasting state, the vitamin status was investigated by the measurement of serum and red cell folate, serum vitamin B12, and whole blood pyridoxal-5'-phosphate (PLP, an active form of vitamin B6). RESULTS: Hyperhomocysteinemia was diagnosed in four controls (9%) and 26 women of the study group (31%, P < 0.05). The median concentrations of the vitamins studied were significantly lower in women of the study group as compared to the controls, except for red cell folate, where the median concentration was comparable in both groups. The median concentration of fasting plasma homocysteine, unlike post-methionine plasma homocysteine, was significantly higher in women who experienced placental abruption or infarction in their first pregnancy than in women who had the same event after one or more uncomplicated pregnancies. CONCLUSION: Hyperhomocysteinemia is associated with placental abruption or infarction.

Plasma homocysteine and menopausal status.

The aim of the study was to measure the concentrations of plasma homocysteine in premenopausal and postmenopausal women, and to examine a possible relationship between plasma homocysteine and oestrogen status. Homocysteine metabolism was studied by a standardized oral methionine loading test, and oestrogen status was assessed by the measurement of serum 17 beta-oestradiol. Forty-six premenopausal and 26 postmenopausal healthy women without a history of vascular disease or adverse pregnancy outcome were recruited by public advertisement. The main outcome measures were the concentrations of fasting and postmethionine plasma homocysteine, and serum 17 beta-oestradiol. Fasting plasma homocysteine concentrations (mean +/- SD) were significantly higher in postmenopausal women as compared to premenopausal women (12 +/- 4 mumol L-1 and 10 +/- 3 mumol L-1, respectively) as well as postmethionine plasma homocysteine concentrations (46 +/- 16 mumol L-1 and 32 +/- 9 mumol L-1, respectively). In premenopausal women, postmethionine plasma homocysteine was negatively and significantly correlated to serum 17 beta-oestradiol (r = -0.34). It is concluded that plasma homocysteine concentrations, both fasting and after methionine loading, are significantly higher in postmenopausal women than in premenopausal women. In premenopausal women, the higher concentrations of serum 17 beta-oestradiol may account in part for the lower concentrations of postmethionine plasma homocysteine.

Maternal hyperhomocysteinemia: a risk factor for neural-tube defects?

The maternal vitamin status, especially of folate, is involved in the pathogenesis of neural-tube defects (NTDs). Maternal folate administration can prevent these malformations. The precise metabolic mechanism of the beneficial effect of folate is unclear. In this study we focus on homocysteine accumulation, which may derive from abnormalities of metabolism of folate, vitamin B12, and vitamin B6. We studied nonpregnant women, 41 of whom had given birth to infants with NTDs and 50 control women who previously had normal offspring. The determinations included the plasma total homocysteine both in the fasting state and 6 hours after the ingestion of a methionine load. In addition, we measured the fasting blood levels of folate, vitamin B12, and vitamin B6. The mean values for both basal homocysteine and homocysteine following a methionine load were significantly increased in the group of women who previously had infants with NTDs. In nine of these subjects and two controls, the values after methionine ingestion exceeded the mean control by more than 2 standard deviations. Cystathionine synthase levels in skin fibroblasts derived from these methionine-intolerant women were within the normal range. Our findings suggest a disorder in the remethylation of homocysteine to methionine due to an acquired (ie, nutritional) or inherited derangement of folate or vitamin B12 metabolism. Increased homocysteine levels can be normalized by administration of vitamin B6 or folate. Therefore, we suggest that the prevention of NTDs by periconceptional folate administration may effectively correct a mild to moderate hyperhomocysteinemia.

Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women.

In a prospective study we investigated the possible changes in fasting serum total homocysteine concentrations during continuous micronized 17 beta-oestradiol, 2 mg daily, in combination with cyclic dydrogesterone, 10 mg daily during the first 14 days of each 28 day cycle, in 21 healthy non-hysterectomized postmenopausal women. During the first six cycles mean serum homocysteine decreased by 10.9% (P = 0.013), after which no further significant changes were found during the 2 years of treatment. A 16.9% decrease (P = 0.017; n = 8) was found in women with high homocysteine concentrations, while in women with low homocysteine concentrations (n = 13) no significant changes were observed. The observed decrease in high homocysteine concentrations in postmenopausal women may in part contribute to the decreased risk of developing cardiovascular disease during hormone replacement therapy.

Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss.

OBJECTIVE: To establish the prevalence of hyperhomocysteinemia in women with unexplained recurrent early pregnancy loss. DESIGN: In a patient-control study, the methionine-homocysteine metabolism was investigated by a standardized oral methionine-loading test. SETTING: Gynecologic outpatient department of university hospital. PATIENTS: One-hundred and two women who had been referred to the hospital because they suffered from at least two consecutive unexplained spontaneous abortions (study group) as well as 41 controls who were recruited by public advertisement were selected. INTERVENTIONS: Blood samples were collected just before and 6 hours after oral methionine administration to determine plasma total homocysteine concentrations. MAIN OUTCOME MEASURE: Plasma total homocysteine concentrations 6 hours after methionine loading. Hyperhomocysteinemia was defined as total homocysteine concentration at 6 hours exceeding the 97.5 percentile level of the controls. RESULTS: Hyperhomocysteinemia was diagnosed in 21 women of the study group (21%). In the parous women of the study group, the prevalence of hyperhomocysteinemia was more than two times greater compared with the nulliparous subjects (33% and 14%, respectively). CONCLUSION: Hyperhomocysteinemia is a risk factor in women with unexplained recurrent early pregnancy loss.

Disturbed reproductive performance in extreme folic acid deficient golden hamsters.

We studied the effects of folic acid-deficient diets on maternal red blood cell folate level and reproductive performance in golden hamsters (Mesocricetus auratus, Waterhouse). Animals on the same day of oestrous cycle were put together and finally divided into three groups. Each group comprised at least 12 mature female hamsters. The animals were given three different diets, which were commenced before mating. The feeding regimens comprised a standard diet (group 1), or a folic acid-deficient diet which started either 2 weeks (group 2) or 16 weeks (group 3) prior to mating. The regimens were continued until sacrifice of the animals on day 9 of pregnancy. Pregnancy was realized by caging a male with a selected female during the night of ovulation. Just prior to sacrifice, blood samples were drawn to measure maternal folic acid levels in red blood cells. The pregnant uteri were removed and the embryonic sacs were carefully dissected away from the uterus. The number of sacs per pregnant animal was noted. Extreme folic acid deficiencies were confirmed in the pregnant golden hamsters on a folic acid-deficient diet which started 16 weeks prior to mating as compared to those on a standard diet and on a folic acid-deficient diet which started 2 weeks prior to mating. This deficiency appears to interfere with normal reproductive performance. It caused early embryonic loss several days after mating and resulted, finally, in restoration of the oestrous cycle.