Type of deliveries supported by Dutch clinical midwives.

OBJECTIVE: The number of clinical midwives in the Netherlands has substantially increased over the last twenty years, but their role in obstetric care is not clearly defined. Our aim was to identify the type of deliveries that are usually supported by clinical midwives and whether these changed over time. DESIGN, SETTING, AND PARTICIPANTS: National data from the Netherlands Perinatal Registry from the years 2000 to 2016 (n = 2.999.411 deliveries) were used to divide all deliveries into classes using latent class analyses based on delivery characteristics. In the primary analyses, the identified classes, type of hospital, and year of cohort were used to predict deliveries supported by a clinical midwife. In secondary analyses, the same analyses were repeated where the classes were replaced by individual level characteristics of deliveries and stratified by referral during birth. MEASUREMENTS AND FINDINGS: The latent class analyses identified three classes: I. referral during birth; II. Induction of labour; and III. Planned caesarian section. The primary analyses indicated that women in both class I and II were frequently supported by clinical midwives and those in the third class almost never. Therefore, only data from deliveries assigned to class I and II were used in the secondary analyses. The secondary analyses showed that clinical midwives supported deliveries with a great variety in characteristics, such as pain relief and preterm birth. Although the frequency of clinical midwives being involved in the second stage of labour increased over the years, we did not find noticeable changes in their involvement. KEY CONCLUSION AND IMPLICATIONS FOR PRACTICE: Clinical midwives care for women with various types of deliveries with varying degrees of pathology and complexity during second stage of labour. Additional training, taking previously acquired skills and competences into account, is necessary to deal with this complexity for which clinical midwives are not always trained.

Development of a Blueprint for Integrated Care for Vulnerable Pregnant Women.

PURPOSE: There has been increasing awareness of perinatal health and organisation of maternal and child health care in the Netherlands as a result of poor perinatal outcomes. Vulnerable women have a higher risk of these poor perinatal outcomes and also have a higher chance of receiving less adequate care. Therefore, within a consortium, embracing 100 organisations among professionals, educators, researchers, and policymakers, a joint aim was defined to support maternal and child health care professionals and social care professionals in providing adequate, integrated care for vulnerable pregnant women. DESCRIPTION: Within the consortium, vulnerability is defined as the presence of psychopathology, psychosocial problems, and/or substance use, combined with a lack of individual and/or social resources. Three studies focussing on population characteristics, organisation of care and knowledge, skills, and attitudes of professionals regarding vulnerable pregnant women, were carried out. Outcomes were discussed in three field consultations. ASSESSMENT: The outcomes of the studies, followed by the field consultations, resulted in a blueprint that was subsequently adapted to local operational care pathways in seven obstetric collaborations (organisational structures that consist of obstetricians of a single hospital and collaborating midwifery practices) and their collaborative partners. We conducted 12 interviews to evaluate the adaptation of the blueprint to local operational care pathways and its' embedding into the obstetric collaborations. CONCLUSION: Practice-based research resulted in a blueprint tailored to the needs of maternal and child health care professionals and social care professionals and providing structure and uniformity to integrated care provision for vulnerable pregnant women.

Defining and describing birth centres in the Netherlands - a component study of the Dutch Birth Centre Study.

BACKGROUND: During the last decade, a rapid increase of birth locations for low-risk births, other than conventional obstetric units, has been seen in the Netherlands. Internationally some of such locations are called birth centres. The varying international definitions for birth centres are not directly applicable for use within the Dutch obstetric system. A standard definition for a birth centre in the Netherlands is lacking. This study aimed to develop a definition of birth centres for use in the Netherlands, to identify these centres and to describe their characteristics. METHODS: International definitions of birth centres were analysed to find common descriptions. In July 2013 the Dutch Birth Centre Questionnaire was sent to 46 selected Dutch birth locations that might qualify as birth centre. Questions included: location, reason for establishment, women served, philosophies, facilities that support physiological birth, hotel-facilities, management, environment and transfer procedures in case of referral. Birth centres were visited to confirm the findings from the Dutch Birth Centre Questionnaire and to measure distance and time in case of referral to obstetric care. RESULTS: From all 46 birth locations the questionnaires were received. Based on this information a Dutch definition of a birth centre was constructed. This definition reads: "Birth centres are midwifery-managed locations that offer care to low risk women during labour and birth. They have a homelike environment and provide facilities to support physiological birth. Community midwives take primary professional responsibility for care. In case of referral the obstetric caregiver takes over the professional responsibility of care." Of the 46 selected birth locations 23 fulfilled this definition. Three types of birth centres were distinguished based on their location in relation to the nearest obstetric unit: freestanding (n = 3), alongside (n = 14) and on-site (n = 6). Transfer in case of referral was necessary for all freestanding and alongside birth centres. Birth centres varied in their reason for establishment and their characteristics. CONCLUSIONS: Twenty-three Dutch birth centres were identified and divided into three different types based on location according to the situation in September 2013. Birth centres differed in their reason for establishment, facilities, philosophies, staffing and service delivery.

First trimester size charts of embryonic brain structures.

STUDY QUESTION: Can reliable size charts of human embryonic brain structures be created from three-dimensional ultrasound (3D-US) visualizations? SUMMARY ANSWER: Reliable size charts of human embryonic brain structures can be created from high-quality images. WHAT IS KNOWN ALREADY: Previous studies on the visualization of both the cavities and the walls of the brain compartments were performed using 2D-US, 3D-US or invasive intrauterine sonography. However, the walls of the diencephalon, mesencephalon and telencephalon have not been measured non-invasively before. Last-decade improvements in transvaginal ultrasound techniques allow a better visualization and offer the tools to measure these human embryonic brain structures with precision. STUDY DESIGN, SIZE, DURATION: This study is embedded in a prospective periconceptional cohort study. A total of 141 pregnancies were included before the sixth week of gestation and were monitored until delivery to assess complications and adverse outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: For the analysis of embryonic growth, 596 3D-US scans encompassing the entire embryo were obtained from 106 singleton non-malformed live birth pregnancies between 7(+0) and 12(+6) weeks' gestational age (GA). Using 4D View (3D software) the measured embryonic brain structures comprised thickness of the diencephalon, mesencephalon and telencephalon, and the total diameter of the diencephalon and mesencephalon. MAIN RESULTS AND THE ROLE OF CHANCE: Of 596 3D scans, 161 (27%) high-quality scans of 79 pregnancies were eligible for analysis. The reliability of all embryonic brain structure measurements, based on the intra-class correlation coefficients (ICCs) (all above 0.98), was excellent. Bland-Altman plots showed moderate agreement for measurements of the telencephalon, but for all other measurements the agreement was good. Size charts were constructed according to crown-rump length (CRL). LIMITATIONS, REASONS FOR CAUTION: The percentage of high-quality scans suitable for analysis of these brain structures was low (27%). WIDER IMPLICATIONS OF THE FINDINGS:  The size charts of human embryonic brain structures can be used to study normal and abnormal development of brain development in future. Also, the effects of periconceptional maternal exposures, such as folic acid supplement use and smoking, on human embryonic brain development can be a topic of future research. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Obstetrics and Gynaecology of the Erasmus University Medical Center. M.G. was supported by an additional grant from the Sophia Foundation for Medical Research (SSWO grant number 644). No competing interests are declared.

Bridging between professionals in perinatal care: towards shared care in the Netherlands.

Relatively high perinatal mortality rates in the Netherlands have required a critical assessment of the national obstetric system. Policy evaluations emphasized the need for organizational improvement, in particular closer collaboration between community midwives and obstetric caregivers in hospitals. The leveled care system that is currently in place, in which professionals in midwifery and obstetrics work autonomously, does not fully meet the needs of pregnant women, especially women with an accumulation of non-medical risk factors. This article provides an overview of the advantages of greater interdisciplinary collaboration and the current policy developments in obstetric care in the Netherlands. In line with these developments we present a model for shared care embedded in local 'obstetric collaborations'. These collaborations are formed by obstetric caregivers of a single hospital and all surrounding community midwives. Through a broad literature search, practical elements from shared care approaches in other fields of medicine that would suit the Dutch obstetric system were selected. These elements, focusing on continuity of care, patient centeredness and interprofessional teamwork form a comprehensive model for a shared care approach. By means of this overview paper and the presented model, we add direction to the current policy debate on the development of obstetrics in the Netherlands. This model will be used as a starting point for the pilot-implementation of a shared care approach in the 'obstetric collaborations', using feedback from the field to further improve it.

A newly developed scavenging system for administration of nitrous oxide during labour: safe occupational use.

OBJECTIVE: Nitrous oxide (N(2) O) is routinely used as an analgesic in obstetrics during labour. Epidemiological studies have linked chronic occupational exposure to N(2) O to specific health problems, including reproductive risks. Occupational exposure limits (OELs) allow the use of N(2) O once appropriate preventive and safety measures have been taken. We assessed the effectiveness of a scavenger system (Anevac P-system®, Medicvent Heinen & Löwestein Benelux, Barneveld, the Netherlands) applied in N(2) O administration during labour in a midwifery-led birthing centre in the Netherlands. METHODS: After informed consent, non-pregnant midwives were trained to administer N(2) O. N(2) O was delivered as a 50 : 50 mixture with oxygen and was self administered by the patient. The scavenging device, containing a double mask and a chin mask, was connected to the local evacuation system vented outside the building. Data on the 8-h time-weighted average (8-h TWA) as well as the 15-min TWA (15-min TWA) were obtained. RESULTS: Thirteen patients were included. Six patients were included in the first study period. In this period the 8-h TWA was not exceeded, however, in all patients, the 15-min TWA occasionally exceeded the OELs. After four additional measures, seven patients were included. After implementation of these measures, the 8-h TWA and 15-min TWA never exceeded the OELs. System leakage was not observed during both study periods. CONCLUSION: The Anevac P-scavenging system during N(2) O analgesia in labour prevents exceeding OELs in professional workers. The scavenging system appeared acceptable and effective, and can be considered in hospital settings that use N(2) O as analgesic during labour.

OS036. Ethnic differences in blood pressure and hypertensivecomplications during pregnancy; the generation R Study.

INTRODUCTION: Blood pressure levels during pregnancy are important risk factors for gestational hypertensive disorders. Non-pregnant women from ethnic minority groups are found to have higher blood pressure levels compared to white women. Little is known about variation in blood pressure development during pregnancy across different ethnic groups. OBJECTIVES: To investigate ethnic differences in blood pressure levels in each trimester of pregnancy and the risk of gestational hypertensive disorders and the degree to which such differences can be explained by education and lifestyle related factors. METHODS: The study included 6215 women participating in a population-based prospective cohort study from early pregnancy onwards in Rotterdam, The Netherlands. Ethnicity was assessed at enrolment. Blood pressure was measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Lifestyle factors included smoking, alcohol, caffeine intake, folic acid supplementation, sodium and energy intake, body mass index and maternal stress. Associations and explanatory pathways were investigated using linear and logistic regression analysis. RESULTS: Dutch pregnant women had higher systolic blood pressure levels as compared to women in other ethnic groups in each trimester of pregnancy. Compared to Dutch women, Turkish and Moroccan women had lower diastolic blood pressure levels in each trimester. These differences remained after adjusting for education and lifestyle factors. Turkish and Moroccan women had a lower risk of gestational hypertension as compared to Dutch women (OR 0.32; 95% CI: 0.18, 0.58 and OR 0.28; 95% CI: 0.14, 0.58) and Cape Verdean women had an elevated risk of preeclampsia (OR 2.22; 95% CI: 1.22, 4.07). Differences could not be explained by education or lifestyle. CONCLUSION: Substantial ethnic differences were observed in blood pressure levels in each trimester of pregnancy and risk of gestational hypertensive disorders. A wide range of potential explanatory variables could not explain these differences.

Explaining differences in birth outcomes in relation to maternal age: the Generation R Study.

OBJECTIVE: To examine the association between maternal age and birth outcomes, and to investigate the role of sociodemographic and lifestyle-related determinants. DESIGN: Population-based prospective cohort study from early pregnancy onwards. SETTING: Rotterdam, the Netherlands. POPULATION: A cohort of 8568 mothers and their children. METHODS: Maternal age was assessed at enrolment. Information about sociodemographic (height, weight, educational level, ethnicity, parity) and lifestyle-related determinants (alcohol consumption, smoking habits, folic acid supplement use, caffeine intake, daily energy intake) and birth outcomes was obtained from questionnaires and hospital records. Multivariate linear and logistic regression analyses were used. MAIN OUTCOMES MEASURES: Birthweight, preterm delivery, small-for-gestational-age, and large-for-gestational-age. RESULTS: As compared with mothers aged 30-34.9 years, no differences in risk of preterm delivery were found. Mothers younger than 20 years had the highest risk of delivering small-for-gestational-age babies(OR 1.6, 95% CI: 1.1-2.5); however, this increased risk disappeared after adjustment for sociodemographic and lifestyle-related determinants. Mothers older than 40 years had the highest risk of delivering large-for-gestational-age babies (OR 1.3, 95% CI: 0.8-2.4). The associations of maternal age with the risks of delivering large-for-gestational-age babies could not be explained by sociodemographic and lifestyle-related determinants. CONCLUSIONS: As compared with mothers aged 30-34.9 years, younger mothers have an increased risk of small-for-gestational-age babies, whereas older mothers have an increased risk of large-for-gestational-age babies. Sociodemographic and lifestyle-related determinants cannot fully explain these differences.

Folic acid is positively associated with uteroplacental vascular resistance: the Generation R study.

BACKGROUND AND AIMS: Periconception folic acid supplementation may influence early placentation processes and thereby the occurrence of hypertensive pregnancy disorders. For this reason we examined the associations between periconception folic acid supplementation and uteroplacental vascular resistance, blood pressure, and the risks of gestational hypertension and preeclampsia, in 5993 pregnant women, participating in a population-based cohort study. METHODS AND RESULTS: Folic acid supplementation was assessed by questionnaire. Mean pulsatility index (PI) and resistance index (RI) of the uterine (UtA) and umbilical arteries (UmA) were measured by Doppler ultrasound in mid- and late pregnancy. Systolic and diastolic blood pressures (SBP, DBP) were measured in early, mid- and late pregnancy. Compared to women who did not use folic acid, preconception folic acid users had a slightly lower UtA-RI in mid-pregnancy [ß -0.02, 95% confidence interval (CI) -0.03, -0.01] and late pregnancy [ß -0.02, 95% CI -0.03, -0.001], a lower UtA-PI in mid-pregnancy [ß -0.06, 95% CI -0.1, -0.03] and late pregnancy [ß -0.03, 95% CI -0.05, -0.01], as well as tendencies towards a lower UmA-PI in mid-pregnancy [ß -0.02, 95% CI -0.04, -0.001] and late pregnancy [ß -0.01, 95% CI -0.02, 0.01]. Additionally, these women had slightly higher SBP and DBP throughout pregnancy. Neither the patterns of blood-pressure change during pregnancy, nor the risk of gestational hypertension and preeclampsia differed between the folic acid categories. CONCLUSION: Periconception folic acid supplementation is associated with lower uteroplacental vascular resistance and higher blood pressures during pregnancy. The effects are small and within physiologic ranges and seem not associated with the risk of hypertensive pregnancy disorders.

Explaining ethnic differences in late antenatal care entry by predisposing, enabling and need factors in The Netherlands. The Generation R Study.

Despite compulsory health insurance in Europe, ethnic differences in access to health care exist. The objective of this study is to investigate how ethnic differences between Dutch and non-Dutch women with respect to late entry into antenatal care provided by community midwifes can be explained by need, predisposing and enabling factors. Data were obtained from the Generation R Study. The Generation R Study is a multi-ethnic population-based prospective cohort study conducted in the city of Rotterdam. In total, 2,093 pregnant women with a Dutch, Moroccan, Turkish, Cape Verdean, Antillean, Surinamese Creole and Surinamese Hindustani background were included in this study. We examined whether ethnic differences in late antenatal care entry could be explained by need, predisposing and enabling factors. Subsequently, logistic regression analysis was used to assess the independent role of explanatory variables in the timing of antenatal care entry. The main outcome measure was late entry into antenatal care (gestational age at first visit after 14 weeks). With the exception of Surinamese-Hindustani women, the percentage of mothers entering antenatal care late was higher in all non-Dutch compared to Dutch mothers. We could explain differences between Turkish (OR = 0.95, CI: 0.57-1.58), Cape Verdean (OR = 1.65. CI: 0.96-2.82) and Dutch women. Other differences diminished but remained significant (Moroccan: OR = 1,74, CI: 1.07-2.85; Dutch Antillean OR 1.80, CI: 1.04-3.13). We found that non-Dutch mothers were more likely to enter antenatal care later than Dutch mothers. Because we are unable to explain fully the differences regarding Moroccan, Surinamese-Creole and Antillean women, future research should focus on differences between 1st and 2nd generation migrants, as well as on language barriers that may hinder access to adequate information about the Dutch obstetric system.

Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment.

BACKGROUND This study investigates whether dietary patterns, substantiated by biomarkers, are associated with semen quality. METHODS In 161 men of subfertile couples undergoing in vitro fertilization treatment in a tertiary referral clinic in Rotterdam, the Netherlands, we assessed nutrient intakes and performed principal component factor analysis to identify dietary patterns. Total homocysteine (tHcy), folate, vitamin B12 and B6 were measured in blood and seminal plasma. Semen quality was assessed by sperm volume, concentration, motility, morphology and DNA fragmentation index (DFI). Linear regression models analyzed associations between dietary patterns, biomarkers and sperm parameters, adjusted for age, body mass index (BMI), smoking, vitamins and varicocele. RESULTS The 'Health Conscious' dietary pattern shows high intakes of fruits, vegetables, fish and whole grains. The 'Traditional Dutch' dietary pattern is characterized by high intakes of meat, potatoes and whole grains and low intakes of beverages and sweets. The 'Health Conscious' diet was inversely correlated with tHcy in blood (beta = -0.07, P = 0.02) and seminal plasma (beta = -1.34, P = 0.02) and positively with vitamin B6 in blood (beta = 0.217, P = 0.01). An inverse association was demonstrated between the 'Health Conscious' diet and DFI (beta = -2.81, P = 0.05). The 'Traditional Dutch' diet was positively correlated with red blood cell folate (beta = 0.06, P = 0.04) and sperm concentration (beta = 13.25, P = 0.01). CONCLUSIONS The 'Health Conscious' and 'Traditional Dutch' dietary pattern seem to be associated with semen quality in men of subfertile couples.

High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring.

OBJECTIVE: To study associations between maternal dietary and supplement intake of antioxidants vitamin E, retinol and congenital heart defects (CHDs). DESIGN: Case-control study. SETTING: Erasmus MC, University Medical Center Rotterdam, the Netherlands. POPULATION: Participants were 276 case mothers of a child with CHD and 324 control mothers with their children. METHODS: Food frequency questionnaires covering the intake of the previous 4 weeks were filled out at 16 months after the index pregnancy. Data were compared between cases and controls using the Mann-Whitney U test. Risk estimates for the association between CHD and dietary intake of vitamin E and retinol were estimated in a multivariable logistic regression model. MAIN OUTCOME MEASURES: Medians (5-95th percentile) and odds ratios with 95% CI. RESULTS: Dietary vitamin E intake was higher in case mothers than in controls, 13.3 (8.1-20.4) and 12.6 (8.5-19.8) mg/day (P= 0.05). CHD risk increased with rising dietary vitamin E intakes (P-trend = 0.01). Periconception use of vitamin E supplements in addition to a high dietary vitamin E intake above 14.9 mg/day up to nine-fold increased CHD risk. Retinol intakes were not significantly different between the groups and not associated with CHD risk. CONCLUSIONS: High maternal vitamin E by diet and supplements is associated with an increased risk of CHD offspring.

Substandard care in maternal mortality due to hypertensive disease in pregnancy in the Netherlands.

OBJECTIVES: To review the standard of care in cases of maternal mortality due to hypertensive diseases in pregnancy and to make recommendations for its improvement. DESIGN: Care given to women with hypertensive disease in pregnancy was audited and substandard care factors identified. SETTING: Confidential enquiry by the Dutch Maternal Mortality Committee (MMC) from the Netherlands Society of Obstetrics and Gynaecology. POPULATION: All maternal deaths reported to the MMC due to hypertensive disease in pregnancy in the Netherlands during the years 2000-04. METHODS: Assessment for substandard care factors using a checklist based on the Dutch guideline of 'Hypertensive Disorders in Pregnancy'. MAIN OUTCOME MEASURES: Substandard care in cases of maternal mortality due to hypertensive diseases in pregnancy. RESULTS: A total of 27 cases of maternal death due to hypertensive disease in pregnancy were reported to the committee in the study period. In 26 cases (96%), substandard care factors were present, of which in 17 cases (63%), these were for more than five different items. In community midwifery care, the most frequent substandard care factor was no testing for proteinuria when clearly indicated (41%). In hospital care, the most frequent substandard care was related to insufficient diagnostic testing when indicated (41%), insufficient management of hypertension by obstetricians (85%), no use or inadequate use of magnesium sulphate (67%), inadequate stabilisation before transport to tertiary care centres and/or delivery (52%) and failure to consider timely delivery (44%). CONCLUSIONS: Education of pregnant women concerning danger signs of hypertensive disease should be improved. Training of midwives and obstetricians should be improved in the following areas: performing basic diagnostic tests, adequate management of hypertension and eclampsia, with more attention to treatment of systolic blood pressure. This training should be guided by clear local protocols. Delivery should not be delayed in serious cases of hypertensive disease in pregnancy, not only after 32-34 weeks but also in early-onset pre-eclampsia as maternal risks often outweigh possible fetal benefits of temporising management.

[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.

[Unfounded recommendations for vitamin D supplementation in pregnant and breastfeeding women ]. / Onterechte aanbeveling voor extra vitamine D bij zwangeren en zogenden.

In 2000, the Health Council of the Netherlands produced new dietary reference values for the intake of several vitamins, including vitamin D. These stated that pregnant and breast-feeding women without usual exposure to sunlight should consume at least 10 micrograms of vitamin D per day, while for women who were exposed to sunlight 7.5 micrograms daily would be sufficient. Because the mean intake through food is about 3 micrograms daily, the Health Council recommendations imply that all these women should take additional vitamin D. However, the recommendations are not evidence-based. Relevant clinical benefits of vitamin D supplementation in pregnant or breast-feeding women, such as increased bone mass and a reduced fracture risk for mother or child, have never been shown and, given the robust capacity of the skin to produce vitamin D under the influence of ultraviolet light, are rather improbable. Therefore, the intake of extra vitamin D by pregnant and breast-feeding women is unnecessary if they are regularly outside with at least their face and hands uncovered.

Longitudinal vitamin and homocysteine levels in normal pregnancy.

Evidence of the impact of maternal nutritional status on pregnancy outcome is increasing. However, reference values for vitamin and homocysteine concentrations in maternal blood during normal pregnancy are scarce, and are lacking for the preconceptional period and early pregnancy. Thus, in a longitudinal study we evaluated vitamin and homocysteine concentrations in 102 nulliparous women with an uneventful singleton pregnancy and normal outcome not using supplements. The physiological changes in vitamin and homocysteine concentrations in blood were determined from the preconceptional period throughout pregnancy until 6 weeks post-partum. The vitamins evaluated comprised retinol, thiamin, riboflavin, pyridoxal 5'-phosphate, folate in serum and erythrocytes, vitamin B12 and alpha-tocopherol. The plasma homocysteine concentration was also measured, considering the essential roles of folate, vitamin B6 and vitamin B12 in homocysteine metabolism. The concentrations of retinol, thiamin, pyridoxal 5'-phosphate serum folate and vitamin B12 decreased during pregnancy. In contrast, the concentrations of riboflavin, alpha-tocopherol, and folate in erythrocytes increased or showed only minor changes. Homocysteine concentrations also remained approximately constant during pregnancy. These observations emphasize the importance of preconceptional and post-partum concentrations of vitamins in the evaluation of pregnancy-induced changes. These data have provided valuable reference values for vitamins and homocysteine before, during and after pregnancy in order to contribute to better diagnosis of maternal deficiencies and to study further the relationship between maternal vitamin status and adverse course and outcome of pregnancy.

Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis.

OBJECTIVE: To quantify the risk of recurrent early pregnancy loss in the presence of elevated fasting or afterload homocysteine concentrations or homozygosity for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (T/T genotype). DESIGN: Case-control studies published between January 1992 and November 1999 were identified with a MEDLINE-search. These studies were combined with a recent case-control study performed by our own research group. SETTING: Academic research environment. PATIENT(S): Studies published in the English language, concerning two or more pregnancy losses before 16 weeks' menstrual age were included. INTERVENTION(S): Meta-analysis of all of the studies included. MAIN OUTCOME MEASURE(S): The number of subjects with and without hyperhomocysteinemia or with the T/T genotype were derived, if necessary the study was supplemented by personal communication with the original authors. RESULT(S): Pooled risk estimates of 2.7 (1.4 to 5.2) and 4.2 (2.0 to 8.8) were calculated for fasting and afterload plasma homocysteine concentrations, respectively. For the MTHFR T/T genotype a pooled risk estimate of 1.4 (1.0 to 2.0) was found. CONCLUSION(S): These data support hyperhomocysteinemia as a risk factor for recurrent early pregnancy loss. Further research should be focused on the pathophysiology of this relationship and on the clinical efficacy of B vitamin supplementation.

Peripheral natural killer cytotoxicity and CD56(pos)CD16(pos) cells increase during early pregnancy in women with a history of recurrent spontaneous abortion.

For diagnostic purposes we assessed peripheral natural killer (NK) cell cytotoxicity and NK and T cell numbers to assess their putative predictive value in recurrent spontaneous abortion (RSA). A total of 43 women with subsequent pregnancy, 37 healthy controls and 39 women successfully partaking in an in-vitro fertilization (IVF) procedure, were included in the study. We show that before pregnancy, levels of NK cytotoxicity and numbers of both single CD56(pos) and double CD56(pos)CD16(pos) cells were similar between RSA women and controls. But notably, within the RSA group, NK cell numbers of <12% were strongly associated with a subsequent pregnancy carried to term. Supplementation of folic acid led to an increase of single CD56(pos) cells, but cytotoxic function appeared unaffected. The expression pattern of killer inhibitory receptors on CD56(pos) cells was not different between patients and controls. A longitudinal study revealed that, compared with controls, in RSA women higher numbers of double CD56(pos)CD16(pos) cells were present during early pregnancy, paralleled by an increase in cytotoxic NK cell reactivity. The single CD56(pos) population decreased in number. In conclusion, the analysis of peripheral NK cell characteristics appears a suitable diagnostic tool in RSA. Immunomodulation aimed at NK cell function appears a promising therapeutic measure.

Polymorphisms in biotransformation enzymes and the risk for recurrent early pregnancy loss.

An imbalance between phase I drug metabolizing enzymes and phase II detoxification enzymes may contribute to the development of pre-eclampsia. Polymorphic variants in the phase I enzyme, cytochrome P450 genes may lead to increased toxification, whereas polymorphisms in the phase II enzyme, glutathione S-transferase genes may result in impaired detoxification. Most abundant in placenta and decidua is glutathione S-transferase P1-1, which may therefore be of particular importance in reproduction. We studied the frequencies of polymorphic variants in those enzymes in 187 women with recurrent early pregnancy loss and in 109 women with an uncomplicated obstetric history. DNA was extracted and subsequently polymerase chain reaction based genotyping assays were used. chi(2)-Analysis and Fisher's exact test were used for statistical evaluation. The glutathione S-transferase P1b-1b genotype was found significantly more often in women with recurrent early pregnancy loss than in controls (12% versus 5%, P = 0.03), in particular in those who consumed coffee (P = 0.02) or smoked cigarettes (P = 0.04). Polymorphisms in other glutathione S-transferase and cytochrome P450 genes occurred equally frequently in cases and controls. In conclusion, the occurrence of the glutathione S-transferase P1b-1b genotype, leading to lower glutathione S-transferase Pi enzyme activity and consequently to impaired placental detoxification, may represent a risk factor for recurrent early pregnancy loss.

Homocysteine and folate levels as risk factors for recurrent early pregnancy loss.

OBJECTIVE: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations. METHODS: In a case-control study, we measured homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5'-phosphate, and cobalamin concentrations in 123 women who had at least two consecutive spontaneous early pregnancy losses each and compared concentrations with those of 104 healthy controls. RESULTS: Women with recurrent early pregnancy losses had significantly lower serum folate concentrations than controls, whereas the other measurements were similar to those of controls. Elevated homocysteine, fasting greater than 18.3 micromol/L and afterload greater than 61.5 micromol/L, was a risk factor for recurrent early pregnancy loss, with odds ratios (ORs) and 95% confidence intervals (95% CIs) of 3.6 (1.2, 12.7) and 2.7 (0.9, 8.8) in the group with recurrent miscarriages: 6.4 (1.9, 24.3) and 4.3 (1. 2, 17.3) in primary aborters, and 4.2 (1.3, 15.4) and 3.4 (1.0, 12. 8) in those with three or more miscarriages. The ORs (95% CIs) in the same study populations for serum folate concentrations less than 8.4 nmol/L were 2.1 (0.9, 4.8), 2.7 (1.0, 7.8), and 3.2 (1.3, 8.1), respectively. A significant dose-response relationship between serum folate concentrations and risk of recurrent early pregnancy loss suggested a protective effect by high serum folate concentrations. CONCLUSION: Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.