Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts.

Folic acid (FA) food fortification in Australia has resulted in a higher-than-expected intake of FA during pregnancy. High FA intake is associated with increased insulin resistance and gestational diabetes. We aimed to establish whether maternal one-carbon metabolism and hormones that regulate glucose homeostasis change in healthy pregnancies post-FA food fortification. Circulating folate, B12, homocysteine, prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy maternal blood in women with uncomplicated pregnancies prior to (SCOPE: N = 604) and post (STOP: N = 711)-FA food fortification. FA food fortification resulted in 63% higher maternal folate. STOP women had lower hPL (33%) and GH2 (43%) after 10 weeks of gestation, but they had higher PRL (29%) and hPL (28%) after 16 weeks. FA supplementation during pregnancy increased maternal folate and reduced homocysteine but only in the SCOPE group, and it was associated with 54% higher PRL in SCOPE but 28% lower PRL in STOP. FA food fortification increased maternal folate status, but supplements no longer had an effect, thereby calling into question their utility. An altered secretion of hormones that regulate glucose homeostasis in pregnancy could place women post-fortification at an increased risk of insulin resistance and gestational diabetes, particularly for older women and those with obesity.

The cost-effectiveness of using a prognosis-tailored strategy model to triage couples with idiopathic infertility for assisted reproduction technology.

OBJECTIVES: To evaluate whether a prognosis-tailored triage of ART for couples with idiopathic infertility by using the Hunault prognostic model can decrease the cost of treatment without compromising the chance of live birth. STUDY DESIGN: This is a retrospective study conducted in an Australian fertility clinic. Couples seeking infertility consultation who were subsequently found to have idiopathic infertility after evaluation were included. We compared the costs per conception leading to live birth of the prognosis-tailored strategy with the immediate ART strategy, which generally reflects the current practice in Australian fertility clinics, over a 24-month period. In the prognosis-tailored strategy, for each couple, the prognosis for natural conception was assessed using the well-established Hunault model. Total cost of treatments were calculated as the sum of typical out-of-pocket and Australian Medicare cost (Australian national insurance scheme). RESULTS: We studied 261 couples. In the prognosis-tailored strategy, the total cost was $2,766,781 and the live birth rate was 63.9%. In contrast, the immediate ART strategy yielded a live birth rate of 64.4% with a total cost of $3,176,845. Implementing the prognosis-tailored strategy using the Hunault model saved $410,064 in total and $1,571 per couple. The incremental cost-effectiveness ratio (ICER) was $341,720 per live birth. CONCLUSION: In couples with idiopathic infertility, assessment of prognosis for natural conception using the Hunault model and delaying ART for 12 months in couples with favourable prognoses can considerably reduce costs without significantly compromising live birth rates.

Live birth is not the only relevant outcome in research assessing assisted reproductive technology.

In assisted reproductive technology (ART) research, live birth has been generally accepted as an important outcome, if not the most important one. However, it has been reported inconsistently in the literature and solely focusing on live birth can lead to misinterpretation of research findings. In this review, we provide an overview on the definitions of live birth, including various denominators and numerators use. We present a series of real clinical examples in ART research to demonstrate the impact of variations in live birth on research findings and the importance of other outcomes, including multiple pregnancy, pregnancy loss, time to pregnancy leading to live birth, other short and long term maternal and offspring health outcomes and cost effectiveness measures. We suggest that outcome choices in ART research should be tailored for the research questions. A holistic outcome assessment beyond live birth would provide a full picture to address research questions in ART in terms of effectiveness and safety, and thus facilitate evidence-based decision making.

Preterm Infant Outcomes Following COVID-19 Lockdowns in Melbourne, Australia.

Background Community lockdowns during the coronavirus disease 2019 (COVID-19) pandemic may influence preterm birth rates, but mechanisms are unclear. Methods We compared neonatal outcomes of preterm infants born to mothers exposed to community lockdowns in 2020 (exposed group) to those born in 2019 (control group). Main outcome studied was composite of significant neonatal morbidity or death. Results Median gestational age was 35 + 4 weeks (295 infants, exposed group) vs. 35 + 0 weeks (347 infants, control group) (p = 0.108). The main outcome occurred in 36/295 (12.2%) infants in exposed group vs. 46/347 (13.3%) in control group (p = 0.69). Continuous positive airway pressure (CPAP) use, jaundice requiring phototherapy, hypoglycaemia requiring treatment, early neonatal white cell and neutrophil counts were significantly reduced in the exposed group. Conclusions COVID-19 community lockdowns did not alter composite neonatal outcomes in preterm infants, but reduced rates of some common outcomes as well as early neonatal inflammatory markers.

Effect of an individualised nutritional intervention on gestational diabetes mellitus prevention in a high-risk population screened by a prediction model: study protocol for a multicentre randomised controlled trial.

BACKGROUND: The ability of a preventive nutritional intervention to reduce the morbidity of gestational diabetes mellitus (GDM) remains controversial. We aim to assess whether GDM can be prevented by an individualised nutritional intervention in pregnant women who are at high risk for the disease based on a prediction model. METHODS/DESIGN: A multicentre randomised controlled trial was designed to assess the efficacy of an individualised nutritional intervention for the prevention of GDM in a high-risk population screened by a novel prediction model in the first trimester. Pregnant women evaluated to be at high risk for GDM by the prediction model at less than 14 gestational weeks will be included. Women with pre-existing chronic diseases, including pregestational diabetes, or who are currently prescribed medicines that affect glucose values will be excluded. Allocation to intervention/control at a ratio of 1:1 will be conducted by a computerized randomisation system. The intervention group will complete 3-day food records and receive 3 individualised nutritional consultations with professional dieticians before the oral glucose tolerance test. The primary intention of the intervention is to promote a long-term healthy dietary pattern and prevent excessive gestational weight gain throughout pregnancy. The control group will complete 3-day food records at designated gestational weeks and receive standard antenatal care according to local health care provisions. The primary outcome is the incidence of GDM according to the criteria of the International Association of Diabetes and Pregnancy Study Group (IADPSG). A sample of 464 participants will provide 80% power to detect a 30% reduction in GDM incidence (α = 0.05 two tailed, 10% dropout). A total of 500 participants will be recruited. DISCUSSION: To date, this is the first randomised controlled trial aimed to evaluate the protective effect of an individualised nutritional intervention against GDM based on a logistic regression prediction model. Eligibility is not limited to obese women or singleton pregnancies, as in previous studies. This pragmatic trial is expected to provide valuable information on early screening and effective GDM prevention methods. TRIAL REGISTRATION NUMBER: ChiCTR, ChiCTR1900026963 . Registered 27 October 2019.

Safety of oil-based contrast medium for hysterosalpingography: a systematic review.

Recent meta-analyses have shown that a hysterosalpingography (HSG) with oil-based contrast increases pregnancy rates in subfertile women. However, the frequency of complications during or after an HSG with oil-based contrast in subfertile women and/or their offspring is still unclear. This systematic review and meta-analysis, without restrictions on language, publication date or study design, was performed to fill this knowledge gap. The results show that the most frequently reported complication was intravasation of contrast, which occurred in 2.7% with the use of oil-based contrast (31 cohort studies and randomized controlled trials [RCT], 95% CI 1.7-3.8, absolute event rate 664/19,339), compared with 2.0% with the use of water-based contrast (8 cohort studies and RCT, 95% CI 1.2-3.0, absolute event rate 18/1006). In the cohort studies and RCT there were 18 women with an oil embolism (18/19,339 HSG), all without serious lasting consequences. Four cases with serious consequences of an oil embolism were described (retinal oil embolism [n = 1] and cerebral complaints [n = 3]); these reports did not describe the use of adequate fluoroscopy guidance during HSG. In conclusion, the most frequently reported complication after an HSG with oil-based contrast is intravasation occurring in 2.7%. In total four cases with serious consequences of oil embolisms in subfertile women were published.

Vitamin D supplementation prior to in vitro fertilisation in women with polycystic ovary syndrome: a protocol of a multicentre randomised, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the leading causes of female infertility, affecting around 5% of women of childbearing age in China. Vitamin D insufficiency is common in women with PCOS and is associated with lower live birth rates. However, evidence regarding the effectiveness of vitamin D supplementation in women with PCOS is inconclusive. This multicentre randomised, double-blinded, placebo-controlled trial aims to evaluate the effectiveness of vitamin D supplementation prior to in vitro fertilisation (IVF) on the live birth rate in women with PCOS. METHODS AND ANALYSIS: We plan to enrol women with PCOS scheduled for IVF. After informed consent, eligible participants will be randomised in a 1:1 ratio to receive oral capsules of 4000 IU vitamin D per day or placebo for around 12 weeks until the day of triggering. All IVF procedures will be carried out routinely in each centre. The primary outcome is live birth after the first embryo transfer. The primary analysis will be by intention-to-treat analysis. To demonstrate or refute that treatment with vitamin D results in a 10% higher live birth rate than treatment with placebo, we need to recruit 860 women (48% vs 38% difference, anticipating 10% loss to follow-up and non-compliance, significance level 0.05 and power 80%). ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee in Women's Hospital of Zhejiang University on 2 March 2020 (reference number: IRB-20200035-R). All participants will provide written informed consent before randomisation. The results of the study will be submitted to scientific conferences and a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04082650.

A double-blind randomised placebo-controlled trial of melatonin as an adjuvant agent in induction of labour (MILO): a study protocol.

INTRODUCTION: Induction of labour (IOL) is a common practice. In Australia, up to 40% of women undergoing labour induction will ultimately have a caesarean section. As a biological role for melatonin in the onset and progress of labour has been demonstrated, we aim to test the hypothesis that addition of melatonin will reduce the need for caesarean section. METHODS AND ANALYSIS: This is a double-blind, randomised, placebo-controlled trial in women undergoing IOL at term. We plan to randomise 722 women (1:1 ratio) to receive either melatonin (four doses of 10 mg melatonin: first dose-in the evening at the time of cervical balloon or Dinoprostone PGE2 vaginal pessary insertion, second dose-at time of oxytocin infusion commencement, third dose-6 hours after the second dose, fourth dose-6 hours after the third dose) or placebo (same dosing regime). Participants who are having artificial rupture of the membranes only as the primary means of labour induction will receive up to three doses of the trial intervention. The primary outcome measure will be the requirement for a caesarean section. Secondary outcomes will include duration of each stage of labour and time from induction to birth, total dose of oxytocin administration, epidural rate, indication for caesarean section, rate of instrumental deliveries, birth within 24 hours of induction commencement, estimated blood loss, Apgar score at 5 min, neonatal intensive care unit admissions and participant satisfaction. Maternal melatonin levels will be measured immediately before commencement of the oxytocin intravenous infusion and 3 hours after and at the time of birth in order to determine any differences between the two trial arms. ETHICS AND DISSEMINATION: The study is conducted in accordance with the conditions of Monash Health HREC (RES-17-0000-168A). Findings from the trial will be disseminated through peer-reviewed publications and conference presentations. PROTOCOL VERSION: V.7.0, 30 July 2019. TRIAL REGISTRATION NUMBER: ACTRN12616000311459, Universal trial number: (UTN) U1111-1195-3515.

Intrapartum and neonatal mortality in low-risk term women in midwife-led care and obstetrician-led care at the onset of labor: A national matched cohort study.

INTRODUCTION: Midwife-led models of care have been the subject of debate for many years. We conducted a study to compare intrapartum and neonatal mortality rates in midwife-led (primary) vs obstetrician-led (secondary) care at the onset of labor in low-risk term women. MATERIAL AND METHODS: We performed an unmatched and a propensity score matched cohort study using data from the national perinatal audit registry (PAN) and from the national perinatal registry (PERINED) of the Netherlands. We included women with singleton pregnancies (without congenital anomalies or antepartum fetal death) who gave birth at term between 2010 and 2012. We excluded the following major risk factors: non-vertex position of the fetus, previous cesarean birth, hypertension, diabetes mellitus, prolonged rupture of membranes (≥24 hours), vaginal bleeding in the second half of pregnancy, nonspontaneous start of labor and post-term pregnancy (≥42 weeks). The primary outcome was intrapartum or neonatal mortality up to 28 days after birth. Secondary outcome measures were mode of delivery and a 5-minute Apgar score <7. RESULTS: We included 259 211 women. There were 100/206 642 (0.48‰) intrapartum and neonatal deaths in the midwife group and 23/52 569 (0.44‰) in the obstetrician group (odds ratio [OR] 1.11, 95% CI 0.70-1.74). Propensity score matched analysis showed mortality rates of 0.49‰ (26/52 569) among women in midwife-led care and 0.44‰ (23/52 569) for women in obstetrician-led care (OR 1.13, 95% CI 0.65-1.98). In the midwife group there were significantly lower rates of vaginal instrumental deliveries (8.4% vs 13.0%; matched OR 0.65, 95% CI 0.62-0.67) and intrapartum cesarean sections (2.6% vs 8.2%; matched OR 0.32, 95% CI 0.30-0.34), and fewer neonates with low Apgar scores (<7 after 5 minutes) (0.69% vs 1.11%; matched OR 0.61, 95% CI 0.53-0.69). CONCLUSIONS: Among low-risk term women, there were comparable intrapartum and neonatal mortality rates for women starting labor in midwife-led vs obstetrician-led care, with lower intervention rates and fewer low Apgar scores in the midwife group.

Evidence-Based Prevention of Preeclampsia: Commonly Asked Questions in Clinical Practice.

In this review, we discuss the recent literature regarding the prevention of preeclampsia and aim to answer common questions that arise in the routine antenatal care of pregnant women. Prescription of low-dose aspirin for high-risk patients has been shown to reduce the risk of preeclampsia (PE). A daily dose between 100 and 150 mg taken in the evening should be initiated prior to 16 weeks of gestation and can be continued until delivery. Calcium supplementation seems to be advantageous but currently it is only considered for patients with poor dietary intake and high risk for PE. Recent data about heparin are still conflicting, and therefore, heparin can currently not be recommended in the prevention of PE.

The IVF-LUBE trial - a randomized trial to assess Lipiodol® uterine bathing effect in women with endometriosis or repeat implantation failure undergoing IVF.

RESEARCH QUESTION: Does pre-IVF Lipiodol® increase the success of IVF treatment in women with endometriosis or repeat implantation failure (RIF) compared with IVF alone? DESIGN: Lipiodol is known to enhance natural fertility, especially amongst women with endometriosis. The effect of Lipiodol may accrue through an impact on the endometrium that enhances receptivity to implantation. A randomized controlled trial (RCT) was carried out on 70 women due to undergo IVF. Women with endometriosis or RIF in previous IVF treatments, recruited from IVF clinics in New Zealand and in Pune, India, received either Lipiodol by hysterosalpingogram or no intervention prior to IVF treatment. RESULTS: Between May 2009 and January 2014, 33 women were randomized to Lipiodol plus IVF and 37 to IVF alone. When pregnancies resulting from fresh embryo transfer from the IVF cycle under study were considered, live birth rates were 8/33 (24%) in the pre-IVF Lipiodol group and 11/37 (30%) in the IVF only group (relative risk [RR] 0.81; 95% confidence interval [CI] 0.37 to 1.8). Live birth rates from pregnancies within 6 months were 11/33 (33%) and 12/37 (32%) in these respective groups (RR 1.03; 95% CI, 0.53 to 2.0). The trial was underpowered to detect smaller differences between treatment and control groups. CONCLUSIONS: No evidence was found of benefit of Lipiodol prior to fresh embryo transfer in women with endometriosis or RIF. It is suggested that this treatment should not be undertaken purely as an adjuvant in IVF other than in the context of a further well-designed RCT.

Determinants of successful lifestyle change during a 6-month preconception lifestyle intervention in women with obesity and infertility.

PURPOSE: To identify demographic, (bio)physical, behavioral, and psychological determinants of successful lifestyle change and program completion by performing a secondary analysis of the intervention arm of a randomized-controlled trial, investigating a preconception lifestyle intervention. METHODS: The 6-month lifestyle intervention consisted of dietary counseling, physical activity, and behavioral modification, and was aimed at 5-10% weight loss. We operationalized successful lifestyle change as successful weight loss (≥ 5% weight/BMI ≤ 29 kg/m2), weight loss in kilograms, a reduction in energy intake, and an increase in physical activity during the intervention program. We performed logistic and mixed-effect regression analyses to identify baseline factors that were associated with successful change or program completion. RESULTS: Women with higher external eating behavior scores had higher odds of successful weight loss (OR 1.10, 95% CI 1.05-1.16). Women with the previous dietetic support lost 0.94 kg less during the intervention period (95% CI 0.01-1.87 kg). Women with higher self-efficacy reduced energy intake more than women with lower self-efficacy (p < 0.01). Women with an older partner had an increased energy intake (6 kcal/year older, 95% CI 3-13). A high stage of change towards physical activity was associated with a higher number of daily steps (p = 0.03). A high stage of change towards weight loss was associated with completion of the intervention (p = 0.04). CONCLUSIONS: Determinants of lifestyle change and program completion were: higher external eating behavior, not having received previous dietetic support, high stage of change. This knowledge can be used to identify women likely to benefit from lifestyle interventions and develop new interventions for women requiring alternative support. TRIAL REGISTRATION: The LIFEstyle study was registered at the Dutch trial registry (NTR 1530; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530 ).

Oil-based or water-based contrast for hysterosalpingography in infertile women: a cost-effectiveness analysis of a randomized controlled trial.

OBJECTIVE: To determine the cost effectiveness of the use of oil-based versus water-based contrast in infertile women undergoing hysterosalpingography (HSG). DESIGN: Economic evaluation alongside a multicenter randomized trial. SETTING: Hospitals. PATIENT(S): Infertile women with an ovulatory cycle, 18-39 years of age, low risk of tubal pathology. INTERVENTION(S): Use of oil-based versus water-based contrast during HSG. MAIN OUTCOME MEASURE(S): Costs per additional ongoing pregnancy and per live birth within 6 months of randomization, incremental cost-effective ratios (ICERs). RESULT(S): A total of 1,119 women were randomized to HSG (oil-based contrast, n = 557; water-based contrast, n = 562). After HSG, most women had no additional treatment; a minority had IUI or IVF. In the oil group, 39.7% women had an ongoing pregnancy within 6 months of randomization versus 29.1% women in the water group. There was a 10.7% increase in the live birth rate in the oil group. For ongoing pregnancy, the mean costs per couple were US$2,014 in the oil group and US$1,144 in the water group, with a corresponding ICER of US$8,198 per additional ongoing pregnancy. For live birth, the mean costs per couple were US$11,532 in the oil group and US$8,310 in the water group, with a corresponding ICER of US$30,112 per additional live birth. CONCLUSION(S): Hysterosalpingography with oil-based contrast results in higher 6-month ongoing pregnancy and live birth rate. If society is willing to pay US$8,198 for an additional ongoing pregnancy, HSG with oil-based contrast is a cost-effective strategy compared with HSG with water-based contrast for infertile, ovulatory women at low risk for tubal pathology. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Register, NTR 6577 (www.trialregister.nl).

Intrapartum and neonatal mortality among low-risk women in midwife-led versus obstetrician-led care in the Amsterdam region of the Netherlands: a propensity score matched study.

OBJECTIVE: To compare intrapartum and neonatal mortality in low-risk term women starting labour in midwife-led versus obstetrician-led care. STUDY DESIGN: We performed a propensity score matched study using data from our national perinatal register, completed with data from medical files. We studied women without major risk factors with singleton pregnancies who gave birth at term between 2005 and 2008 in the Amsterdam region of the Netherlands. Major risk factors comprised non-vertex position of the fetus, previous Caesarean birth, hypertension, (gestational) diabetes mellitus, post-term pregnancy (≥42 weeks), prolonged rupture of membranes (>24 hours), vaginal bleeding in the second half of pregnancy or induced labour. Groups were devided by midwife-led versus obstetrician-led care at the onset of labour. The primary outcome was intrapartum and neonatal (<28 days) mortality. Secondary outcomes included obstetric interventions, 5 min Apgar scores<7 and neonatal intensive care admittance for >24 hours. RESULTS: We studied 57 396 women. Perinatal mortality occurred in 30 of 46 764 (0.64‰) women in midwife-led care and in 2 of 10 632 (0.19‰) women in obstetrician-led care (OR 3.4, 95% CI 0.82 to 14.3). A propensity score matched analysis in a 1:1 ratio with 10 632 women per group revealed an OR for perinatal mortality of 4.0 (95% CI 0.85 to 18.9). CONCLUSION: Among low-risk women, midwife-led care at the onset of labour was associated with a statistically non-significant higher mortality rate.

Risk indicators for referral during labor from community midwife to gynecologist: a prospective cohort study.

OBJECTIVE: To identify risk indicators for referral during labor from community midwife to a gynecologist in a prospective cohort of women with a singleton term pregnancy, starting labor with a community midwife between 2000 and 2007, registered in the Dutch national perinatal registry. MAIN OUTCOME MEASURES: Referral from community midwife to a gynecologist during labor, because of fetal distress, failure to progress in second stage of labor, meconium stained amniotic fluid, failure to progress in first stage of labor, wish for pain relief, a combination of other less urgent reasons or no referral (reference). RESULTS: A total of 241 595 (32%) were referred from community midwife to a gynecologist during labor, because of fetal distress (FD;5%), failure to progress in second stage of labor (FTP2;14%), meconium stained amniotic fluid (MSAF;24%), failure to progress in first stage of labor (FTP1;17%), wish for pain relief (WFPR;7%) or a combination of other less urgent reasons, for example, malpresentation (e.g. breech) or other nonspecified problems (OTHER;33%). The strongest overall risk indicators were gestational age (lower risk of referral because of FD, FTP2, MSAF, FTP1 and WFPR and a higher risk of referral because of OTHER at a gestational age between 37(+0) and 37(+)(6) weeks, and higher risks of referral for all reasons at a gestational age ≥41(+)(0) when compared to a gestational age between 38 (+)(0) and 40 (+)(6) weeks and no referral), the intended place of delivery (higher risk of all types of referral compared to no referral when the intended place of delivery was either at a midwife-led birth center or a hospital instead of at home) and birth history (higher risk of all types of referral compared to no referral when women had a history of instrumental vaginal delivery or when they were nulliparous instead of being multiparous without a history of an instrument vaginal delivery). Risk indicators associated with specific reasons of referral were maternal age, ethnicity, degree of urbanization, social economic status, neonatal gender and birth weight. CONCLUSIONS: Among low-risk pregnant women, a referral during labor is associated with readily available risk indicators. These risk indicators may be used to increase referral risk awareness and to counsel women for the intended place to start labor.

Randomized comparison of nifedipine and placebo in fibronectin-negative women with symptoms of preterm labor and a short cervix (APOSTEL-I Trial).

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.

Prediction and primary prevention of pre-eclampsia.

Pre-eclampsia is associated with increased maternal and perinatal mortality and morbidity. Early recognition of women at risk of pre-eclampsia will enable the identification of high-risk women who may benefit from enhanced surveillance and prophylaxis. In this chapter, we summarise the accuracy of various tests used to predict the onset of pre-eclampsia and the effectiveness of preventative treatment. The tests used to predict pre-eclampsia include clinical history, examination findings, laboratory and haemodynamic tests. In general, tests in early pregnancy for predicting later development of pre-eclampsia have better specificity than sensitivity, as Body Mass Index greater than 34, alpha-fetoprotein, fibronectin and uterine artery Doppler (bilateral notching) all have specificities above 90%. Only uterine artery Doppler resistance index and combinations of indices have a sensitivity of over 60%. Test such as kallikreinuria not used in clinical practice, has shown high sensitivity above 80%, without compromising specificity, and require further investigation. None of the tests are sufficiently accurate to recommend them for routine use in clinical practice. The various treatment options for preventing pre-eclampsia include pharmacological agents, dietary supplementation and lifestyle modification. Antiplatelet agents, primarily low-dose aspirin, reduce the risk of pre-eclampsia by 10% (RR 0.90, 95% CI 0.84 to 0.97). Calcium effectively prevents pre-eclampsia (RR 0.45, 95% CI 0.31 to 0.65); the beneficial effect being observed in the high-risk group (RR 0.22; 95% CI 0.12 to 0.42) and in the group with low nutritional calcium intake (RR 0.36, 95% CI 0.20 to 0.65). Pharmacological agents, such as low molecular weight heparin, progesterone, nitric oxide donors, anti-hypertensive medication and diuretics are not effective in preventing pre-eclampsia. Dietary supplements, such as magnesium, anti-oxidants, marine oils and folic acid, do not reduce the incidence of pre-eclampsia. Evidence is lacking to support lifestyle preventative interventions for pre-eclampsia, such as rest, exercise and reduced dietary salt intake.

Indications and results of labour induction in nulliparous women: an interview among obstetricians, residents and clinical midwives.

OBJECTIVE: To investigate which clinical factors are important in management decisions that clinicians make in the process of labour induction, and which clinical factors they estimate as predictive of labour outcome after induction. STUDY DESIGN: A written interview was conducted among obstetricians, residents and clinical midwives in five teaching hospitals in the south of the Netherlands. Sixteen fictive vignettes were constructed of pregnant nulliparous women who were candidates for induction of labour. The vignettes differed on eight clinical variables: maternal age, BMI, gestational age, indication for induction (maternal request vs mild pre-eclampsia), dilation, position, consistency and effacement of the cervix. For each case presentation, the inclination to induce labour was calculated for the three groups, and their estimates of the probability of a spontaneous vaginal delivery or a caesarean delivery were analyzed. RESULTS: Of the 80 questionnaires sent, 60 (75%) were completed. Mild pre-eclampsia and post-term pregnancy were the most important clinical factors for the decision to induce or not in all three groups. Gestational age, effacement and dilation of the cervix were considered as the most important predictors of labour outcome after induction. CONCLUSIONS: In this interview, obstetricians, residents and clinical midwives based their decision-making whether or not to induce labour predominantly on medical indications. Outcome of labour after induction was estimated to depend on gestational age and cervical status at the start of induction.

The METEX study: methotrexate versus expectant management in women with ectopic pregnancy: a randomised controlled trial.

BACKGROUND: Patients with ectopic pregnancy (EP) and low serum hCG concentrations and women with a pregnancy of unknown location (PUL) and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX). However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs. METHODS/DESIGN: A multicentre randomised controlled trial in The Netherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration < 1,500 IU/L or with a persisting PUL with plateauing serum hCG concentrations < 2,000 IU/L are eligible for the trial. Patients with a viable EP, signs of tubal rupture/abdominal bleeding, or a contra-indication for MTX will not be included. Expectant management is compared with systemic MTX in a single dose intramuscular regimen (1 mg/kg) in an outpatient setting. Serum hCG levels are monitored weekly; in case of inadequately declining, systemic MTX is installed or continued. In case of hemodynamic instability and/or signs of tubal rupture, surgery is performed. The primary outcome measure is an uneventful decline of serum hCG to an undetectable level by the initial intervention. Secondary outcomes are (re)interventions (additional systemic MTX injections and/or surgery), treatment complications, health related quality of life, financial costs, and future fertility. Analysis is performed according to the intention to treat principle. Quality of life is assessed by questionnaires before and at three time points after randomisation. Costs are expressed as direct costs with data on costs and used resources in the participating centres. Fertility is assessed by questionnaires after 6, 12, 18 and 24 months. Patients' preferences will be assessed using a discrete choice experiment. DISCUSSION: This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 48210491.