Unplanned cesarean sections in advanced maternal age: A predictive model.

INTRODUCTION: As maternal age during pregnancy is rising all over the world, there is a growing need for prognostic factors that determine maternal and perinatal outcomes in older women. MATERIAL AND METHODS: This study is a retrospective cohort study of women aged 40 years or older at the time of delivery in four Santeon hospitals across the Netherlands between January 2016 and December 2019. Outcomes were compared between women of 40-44 years (advanced maternal age) and 45 years and older (very advanced maternal age). Primary outcome was unplanned cesarean section, secondary outcomes included postpartum hemorrhage and neonatal outcomes. Multivariate regression analysis was performed to analyze predictive factors for unplanned cesarean sections in women who attempted vaginal delivery. Subsequently, a predictive model and risk scores were constructed to predict unplanned cesarean section. RESULTS: A cohort of 1660 women was analyzed; mean maternal age was 41.4 years, 4.8% of the women were 45 years and older. In both groups, more than half of the women had not delivered vaginally before. Unplanned cesarean sections were performed in 21.1% of the deliveries in advanced maternal age and in 29.1% in very advanced maternal age. Four predictive factors were significantly correlated with unplanned cesarean sections: higher body mass index (BMI), no previous vaginal delivery, spontaneous start of delivery and number of days needed for cervical priming. A predictive model was constructed from these factors with an area under the curve of 0.75 (95% confidence interval 0.72-0.78). A sensitivity analysis in nulliparous women proved that BMI, days of cervical priming, age, and gestational age were risk factors, whereas spontaneous start of delivery and induction were protective factors. There was one occurrence of neonatal death. CONCLUSIONS: Women of advanced maternal age and those of very advanced maternal age have a higher chance of having an unplanned cesarean section compared to the general obstetric population in the Netherlands. Unplanned cesarean sections can be predicted through use of our predictive model. Risk increases with higher BMI, no previous vaginal delivery, and increasing number of days needed for cervical priming, whereas spontaneous start of labor lowers the risk. In nulliparous women, age and gestational age also increase risk, but induction lowers the risk of having an unplanned cesarean section.

[Skin-to-skin caesarean section: better patient care]. / De huid-op-huidsectio: betere patiëntenzorg.

Five years ago, we described the skin-to-skin caesarean section, a procedure in which parental participation, slow delivery and direct skin-to-skin contact are important aspects. By multiple research, the skin-to-skin CS has been shown to have positive outcomes for the child and parents, as long as there is attention for neonatal thermal regulation. These outcomes should lead to cost reduction, versus the extra personnel costs for the nurse. However, a proper cost-effectiveness analysis has not yet been described. There are still many local differences in availability and performance of the skin-to-skin CS in the Netherlands, often caused by logistical challenges. In the meanwhile the protocol has been further optimized. In our opinion, the skin-to-skin caesarean section is better care for parents and their child, and should be available anywhere anytime, as long as the fetal and maternal condition permits this.

Pregnancy outcomes in women with gestational diabetes mellitus diagnosed according to the WHO-2013 and WHO-1999 diagnostic criteria: a multicentre retrospective cohort study.

BACKGROUND: The World Health Organization (WHO) adopted more stringent diagnostic criteria for GDM in 2013, to improve pregnancy outcomes. However, there is no global consensus on these new diagnostic criteria, because of limited evidence. The objective of the study was to evaluate maternal characteristics and pregnancy outcomes in two cohorts in the Netherlands applying different diagnostic criteria for GDM i.e. WHO-2013 and WHO-1999. METHODS: A multicenter retrospective study involving singleton GDM pregnancies in two regions, between 2011 and 2016. Women were diagnosed according to the WHO-2013 criteria in the Deventer region (WHO-2013-cohort) and according to the WHO-1999 criteria in the Groningen region (WHO-1999-cohort). After GDM diagnosis, all women were treated equally based on the national guideline. Maternal characteristics and pregnancy outcomes were compared between the two groups. RESULTS: In total 1386 women with GDM were included in the study. Women in the WHO-2013-cohort were older and had a higher pre-gestational body mass index. They were diagnosed earlier (24.9 [IQR 23.3-29.0] versus 27.7 [IQR 25.9-30.7] weeks, p = < 0.001) and less women were treated with additional insulin therapy (15.6% versus 43.4%, p = < 0.001). Rate of spontaneous delivery was higher in the WHO-2013-cohort (73.1% versus 67.4%, p = 0.032). The percentage large-for-gestational-age (LGA) neonates (birth weight > 90th percentile, corrected for sex, ethnicity, parity, and gestational age) was lower in the WHO-2013- cohort, but not statistical significant (16.5% versus 18.5%, p = 0.379). There were no differences between the cohorts regarding stillbirth, birth trauma, low Apgar score, and preeclampsia. CONCLUSIONS: Using the new WHO-2013 criteria resulted in an earlier GDM diagnosis, less women needed insulin treatment and more spontaneous deliveries occurred when compared to the cohort diagnosed with WHO-1999 criteria. No differences were found in adverse pregnancy outcomes.

New diagnostic criteria for gestational diabetes mellitus and their impact on the number of diagnoses and pregnancy outcomes.

AIMS/HYPOTHESIS: Detection and management of gestational diabetes mellitus (GDM) are crucial to reduce the risk of pregnancy-related complications for both mother and child. In 2013, the WHO adopted new diagnostic criteria for GDM to improve pregnancy outcomes. However, the evidence supporting these criteria is limited. Consequently, these new criteria have not yet been endorsed in the Netherlands. The aim of this study was to determine the impact of these criteria on the number of GDM diagnoses and pregnancy outcomes. METHODS: Data were available from 10,642 women who underwent a 75 g OGTT because of risk factors or signs suggestive of GDM. Women were treated if diagnosed with GDM according to the WHO 1999 criteria. Data on pregnancy outcomes were obtained from extensive chart reviews from 4,431 women and were compared between women with normal glucose tolerance (NGT) and women classified into the following groups: (1) GDM according to WHO 1999 criteria; (2) GDM according to WHO 2013 criteria; (3) GDM according to WHO 2013 fasting glucose threshold, but not WHO 1999 criteria; and (4) GDM according to WHO 1999 2 h plasma glucose threshold (2HG), but not WHO 2013 criteria. RESULTS: Applying the new WHO 2013 criteria would have increased the number of diagnoses by 45% (32% vs 22%) in this population of women at higher risk for GDM. In comparison with women with NGT, women classified as having GDM based only on the WHO 2013 threshold for fasting glucose, who were not treated for GDM, were more likely to have been obese (46.1% vs 28.1%, p < 0.001) and hypertensive (3.3% vs 1.2%, p < 0.001) before pregnancy, and to have had higher rates of gestational hypertension (7.8% vs 4.9%, p = 0.003), planned Caesarean section (10.3% vs 6.5%, p = 0.001) and induction of labour (34.8% vs 28.0%, p = 0.001). In addition, their neonates were more likely to have had an Apgar score <7 at 5 min (4.4% vs 2.6%, p = 0.015) and to have been admitted to the Neonatology Department (15.0% vs 11.1%, p = 0.004). The number of large for gestational age (LGA) neonates was not significantly different between the two groups. Women potentially missed owing to the higher 2HG threshold set by WHO 2013 had similar pregnancy outcomes to women with NGT. These women were all treated for GDM with diet and 20.5% received additional insulin. CONCLUSIONS/INTERPRETATION: Applying the WHO 2013 criteria will have a major impact on the number of GDM diagnoses. Using the fasting glucose threshold set by WHO 2013 identifies a group of women with an increased risk of adverse outcomes compared with women with NGT. We therefore support the use of a lower fasting glucose threshold in the Dutch national guideline for GDM diagnosis. However, adopting the WHO 2013 criteria with a higher 2HG threshold would exclude women in whom treatment for GDM seems to be effective.

Risks and benefits of the skin-to-skin cesarean section - a retrospective cohort study.

OBJECTIVE: Comparing maternal and neonatal outcomes after conventional cesarean section (CS) versus a "natural" or "skin-to-skin" cesarean section (SSCS). METHODS: Retrospective cohort of women who underwent a SSCS (01-2013 until 12-2013) compared to conventional CS (08-2011 to 08-2012). CS before 37 weeks, under general anesthesia and in case of fetal distress were excluded. Main outcome measures were maternal blood loss, post-operative infection and admission; neonatal infection and admission; procedural outcomes. RESULTS: We analyzed 285 (44%) women in the SSCS-group and 365 (56%) in the conventional CS-group. There were no significant differences in surgical site infection (2.1% versus 1.6%; RR 1.1; 95%CI 0.64-2.0), or other maternal outcomes. Fewer neonates born after SSCS were admitted to the pediatric ward (9.5% versus 18%; RR 0.58; 95%CI 0.41-0.80) and fewer neonates had a suspected neonatal infection (2.0% versus 7.3%; RR 0.40; 95%CI 0.19-0.83). No differences were observed for other outcomes. Mean operation time was 4m42s longer in the SSCS-group compared to the conventional CS-group (58m versus 53m; 95%CI 2m44s-6m40s). Mean recovery time was 14m46s shorter (114m versus 129m; 95%CI 3m20s-26m). CONCLUSION: Adverse maternal and neonatal outcomes were not increased after skin-to-skin cesarean compared to conventional cesarean delivery.

Evaluation of an international educational programme for health care professionals on best practice in the management of a perinatal death: IMproving Perinatal mortality Review and Outcomes Via Education (IMPROVE).

BACKGROUND: Stillbirths and neonatal deaths are devastating events for both parents and clinicians and are global public health concerns. Careful clinical management after these deaths is required, including appropriate investigation and assessment to determine cause (s) to prevent future losses, and to improve bereavement care for families. An educational programme for health care professionals working in maternal and child health has been designed to address these needs according to the Perinatal Society of Australia and New Zealand Guideline for Perinatal Mortality: IMproving Perinatal mortality Review and Outcomes Via Education (IMPROVE). The programme has a major focus on stillbirth and is delivered as six interactive skills-based stations. We aimed to determine participants' pre- and post-programme knowledge of and confidence in the management of perinatal deaths, along with satisfaction with the programme. We also aimed to determine suitability for international use. METHODS: The IMPROVE programme was delivered to health professionals in maternity hospitals in all seven Australian states and territories and modified for use internationally with piloting in Vietnam, Fiji, and the Netherlands (with the assistance of the International Stillbirth Alliance, ISA). Modifications were made to programme materials in consultation with local teams and included translation for the Vietnam programme. Participants completed pre- and post-programme evaluation questionnaires on knowledge and confidence on six key components of perinatal death management as well as a satisfaction questionnaire. RESULTS: Over the period May 2012 to May 2015, 30 IMPROVE workshops were conducted, including 26 with 758 participants in Australia and four with 136 participants internationally. Evaluations showed a significant improvement between pre- and post-programme knowledge and confidence in all six stations and overall, and a high degree of satisfaction in all settings. CONCLUSIONS: The IMPROVE programme has been well received in Australia and in three different international settings and is now being made available through ISA. Future research is required to determine whether the immediate improvements in knowledge are sustained with less causes of death being classified as unknown, changes in clinical practice and improvement in parents' experiences with care. The suitability for this programme in low-income countries also needs to be established.

Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study.

BACKGROUND: To evaluate the neonatal and obstetric outcomes of pregnancies complicated by gestational diabetes mellitus (GDM). Screening and treatment - diet-only versus additional insulin therapy - were based on the 2010 national Dutch guidelines. METHODS: Retrospective study of the electronic medical files of 820 singleton GDM pregnancies treated between January 2011 and September 2014 in a university and non-university hospital. Pregnancy outcomes were compared between regular care treatment regimens -diet-only versus additional insulin therapy- and pregnancy outcomes of the Northern region of the Netherlands served as a reference population. RESULTS: A total of 460 women (56 %) met glycaemic control on diet-only and 360 women (44 %) required additional insulin therapy. Between the groups, there were no differences in perinatal complications (mortality, birth trauma, hyperbilirubinaemia, hypoglycaemia), small for gestational age, large for gestational age (LGA), neonate weighing >4200 g, neonate weighing ≥4500 g, Apgar score <7 at 5 min, respiratory support, preterm delivery, and admission to the neonatology department. Neonates born in the insulin-group had a lower birth weight compared with the diet-group (3364 vs. 3467 g, p = 0.005) and a lower gestational age at birth (p = 0.001). However, birth weight was not different between the groups when expressed in percentiles, adjusted for gestational age, gender, parity, and ethnicity. The occurrence of preeclampsia and gestational hypertension was comparable between the groups. In the insulin-group, labour was more often induced and more planned caesarean sections were performed (p = 0.001). Compared with the general obstetric population, the percentage of LGA neonates was higher in the GDM population (11.0 % vs.19.9 %, p = <0.001). CONCLUSIONS: Neonatal and obstetric outcomes were comparable either with diet-only or additional insulin therapy. However, compared with the general obstetric population, the incidence of LGA neonates was significantly increased in this GDM cohort.

Characteristics of a global classification system for perinatal deaths: a Delphi consensus study.

BACKGROUND: Despite the global burden of perinatal deaths, there is currently no single, globally-acceptable classification system for perinatal deaths. Instead, multiple, disparate systems are in use world-wide. This inconsistency hinders accurate estimates of causes of death and impedes effective prevention strategies. The World Health Organisation (WHO) is developing a globally-acceptable classification approach for perinatal deaths. To inform this work, we sought to establish a consensus on the important characteristics of such a system. METHODS: A group of international experts in the classification of perinatal deaths were identified and invited to join an expert panel to develop a list of important characteristics of a quality global classification system for perinatal death. A Delphi consensus methodology was used to reach agreement. Three rounds of consultation were undertaken using a purpose built on-line survey. Round one sought suggested characteristics for subsequent scoring and selection in rounds two and three. RESULTS: The panel of experts agreed on a total of 17 important characteristics for a globally-acceptable perinatal death classification system. Of these, 10 relate to the structural design of the system and 7 relate to the functional aspects and use of the system. CONCLUSION: This study serves as formative work towards the development of a globally-acceptable approach for the classification of the causes of perinatal deaths. The list of functional and structural characteristics identified should be taken into consideration when designing and developing such a system.

Thyroid function testing in women who had a stillbirth.

CONTEXT: Thyroid dysfunction is thought to be associated with stillbirth. Therefore, thyroid function is often recommended in the diagnostic investigations for stillbirth. OBJECTIVE: We aimed to evaluate the added value of thyroid function testing in the diagnostic investigations for stillbirth. DESIGN AND PATIENTS: A nationwide multicentre prospective cohort study in 1025 women who suffered stillbirth >20 weeks of gestation performed between 2002 and 2008. In each woman, an extensive diagnostic work-up was performed, including placental examination and autopsy. TSH and FT4 values below the 2·5th percentile or above the 97·5th percentile according local laboratory reference values were regarded as abnormal. Women with a history of thyroid disease were evaluated separately. MAIN OUTCOME MEASURES: Thyroid function abnormalities in women with stillbirth. RESULTS: Of 1025 included women, 21 had a history of thyroid disease (2%). In the 875 with TSH and FT4 results and no history of thyroid disease, 10% had hypothyroxinemia, 4·6% subclinical hypothyroidism, 1·6% overt hypothyroidism and 1·5% subclinical hyperthyroidism. Women with a subclinical hyperthyroidism more often had a foetal death caused by foetal hydrops: 23% vs 2·9% (adjusted OR 10·3, 95% CI 2·5-42). CONCLUSIONS: Women with a stillbirth had a slightly higher prevalence of overt hypothyroidism, subclinical hypothyroidism and hypothyroxinaemia compared to previous studies on thyroid dysfunction in pregnant women. Given the absence of a strong associations with the cause of stillbirth, and no demonstrated beneficial effects of treating thyroid dysfunction in these women, routine screening after stillbirth is not justified.

Classification of substandard factors in perinatal care: development and multidisciplinary inter-rater agreement of the Groningen-system.

BACKGROUND: Perinatal audit is an established method for improving the quality of perinatal care. In audit meetings substandard factors (SSF) are identified in cases of perinatal mortality and morbidity. To our knowledge there is no classification system specifically designed for the classification of substandard factors. Such a classification may help to standardise allocation of substandard factors to categories. This will help to prioritise, guide and implement actions in quality improvement programs. METHODS: A classification system of 284 substandard factors (SSF) identified in perinatal audit meetings between 2007 and 2011 was drawn up using the WHO Conceptual Framework for the International Classification for Patient Safety as a starting point. Discussions were held on inter-rater disagreements, inclusion of items, format and organisation and definitions of the main- and subcategories. A guideline was developed. An independent multidisciplinary group tested the classification. Independent of inter-rater agreement the allocations to categories were counted. For the counts in the subcategories one and two, we used the allocations in the main category as reference. The chance corrected agreement between classifiers was tested with Cohen's kappa statistic. RESULTS: The classification consists of 9 main categories with one or two subcategories. The main categories are (1) Equipment and Materials, (2) Medication, (3) Additional tests/ investigations, (4) Transportation , (5) Documentation, (6) Communication, (7) Medical practice, (8) Other and (9) non classifiable. Of 3663 allocations by 13 classifiers 1452 SSF's were allocated (40%) to 'medical practice' and 1247 (34%) to 'documentation'. 118 (3%) times SSF's were not classifiable, mainly due to unclear phrasing of the SSF. The chance corrected agreement of 284 substandard factors in the main category was 0.68 (95% CI 0.66-0.70) and 0.57 (95% CI 0.54-0.59) for the CDG and the IGD respectively. CONCLUSIONS: Classifying substandard factors has given insight into problem area's in perinatal care and can give direction to medical, political and financial quality improvement measures. The Groningen-system has well defined categories and subcategories and the guidelines and examples are clear. The multidisciplinary inter-rater agreement is moderate to good. Improvement of the phrasing of the substandard factors is expected to improve inter-rater agreement.

Evaluation of 1025 fetal deaths: proposed diagnostic workup.

OBJECTIVE: We sought to evaluate the contribution of different diagnostic tests for determining cause of fetal death. Our goal was to propose a workup guideline. STUDY DESIGN: In a multicenter prospective cohort study from 2002 through 2008, for 1025 couples with fetal death ≥20 weeks' gestation, an extensive nonselective diagnostic workup was performed. A panel classified cause and determined contribution of diagnostics for allocating cause. RESULTS: A Kleihauer-Betke, autopsy, placental examination, and cytogenetic analysis were abnormal in 11.9% (95% confidence interval [CI], 9.8-14.2), 51.5% (95% CI, 47.4-55.2), 89.2% (95% CI, 87.2-91.1), and 11.9% (95% CI, 8.7-15.7), respectively. The most valuable tests for determination of cause were placental examination (95.7%; 95% CI, 94.2-96.8), autopsy (72.6%; 95% CI, 69.2-75.9), and cytogenetic analysis (29.0%; 95% CI, 24.4-34.0). CONCLUSION: Autopsy, placental examination, cytogenetic analysis, and testing for fetal maternal hemorrhage are basic tests for workup after fetal death. Based on the results of these tests or on specific clinical characteristics, further sequential testing is indicated.

Prevalence of parental thrombophilic defects after fetal death and relation to cause.

OBJECTIVE: To estimate whether parental thrombophilic defects after fetal death, either acquired or inherited, were more prevalent than in the normal population and to estimate associations between these thrombophilic defects and different fetal death causes. METHODS: In a multicenter, prospective cohort study of 750 fetal deaths, we tested couples for antithrombin, protein C, total and free protein S, and von Willebrand factor (vWF) plasma levels. Mothers' values were compared with reference values in gestational age-matched healthy pregnant women, and fathers were compared with healthy men. Prevalence of factor V Leiden, prothrombin G20210A mutation, and lupus anticoagulant were compared with the normal population. A panel classified death cause. RESULTS: More women with fetal death had decreased antithrombin (16.8%, P<.001) and protein C (4.0%, P=.03) and increased vWF (15.5%, P<.001) plasma levels than healthy pregnant women (2.5%). However, compared with normal ranges in the nonpregnant population, we only observed more women with increased vWF (12.4%, P<.001). More fathers had decreased free protein S (6.3%, P<.001) and elevated vWF (12.1%, P<.001) than healthy men (2.5%). Prevalence of inherited thrombophilias was not higher in couples with fetal death than in the population. Neither inherited nor acquired maternal or paternal thrombophilic defects were associated with the main cause of death. Of placental causes, abruption and infarction were associated with acquired maternal defects. CONCLUSION: Except for vWF and paternal free protein S, acquired and inherited thrombophilic defects were not more prevalent after fetal death. Routine thrombophilia testing after fetal death is not advised. LEVEL OF EVIDENCE: II.

Diverse placental pathologies as the main causes of fetal death.

OBJECTIVE: To estimate the occurrence of placental causes of fetal death in relation to different gestational ages and their clinical manifestations during pregnancy. METHODS: In a prospective cohort study conducted from 2002 to 2006, we studied 750 couples with singleton intrauterine fetal death after 20 weeks of gestation. Cause of death was classified according to the Dutch Tulip cause of death classification for perinatal mortality. Differences between groups for categorical data were evaluated by the Fisher exact test or chi test. RESULTS: The main causes were placental pathology (64.9%), congenital anomaly (5.3%), infection (1.9%), other (4.8%), and unknown (23.1%). The contribution of causes differed over gestational age periods. At lower gestational age, placental and unknown were the most dominant causes of death (34.8% and 41.7%, respectively); at higher gestational age, the relative importance of an unknown cause decreased and a placental cause increased (16.5% and 77.6%) (P<.001). Placental bed pathology was observed in 33.6% of all fetal deaths, with the highest occurrence between 24 0/7 and 31 6/7 weeks and a strong decline after 32 weeks. In contrast, contribution of developmental placental pathology (17.6%) increased after 32 weeks of gestation (P<.001), as did umbilical cord complications (5.2%) and combined placental pathology (5.4%). Solitary placental parenchyma pathology was less frequent (3.1%). Hypertension-related disease was observed in 16.1% (95% confidence interval [CI] 13.6-19.0) of the cohort, small for gestational age fetuses in 37.9% (95% CI 34.1-41.7), and diabetes-related disease in 4.1% (95% CI 2.8-5.8). CONCLUSION: Most fetal deaths were caused by a variety of placental pathologies. These were related to gestational age, and their clinical manifestations varied during pregnancy. LEVEL OF EVIDENCE: II.

A multilayered approach for the analysis of perinatal mortality using different classification systems.

Many classification systems for perinatal mortality are available, all with their own strengths and weaknesses: none of them has been universally accepted. We present a systematic multilayered approach for the analysis of perinatal mortality based on information related to the moment of death, the conditions associated with death and the underlying cause of death, using a combination of representatives of existing classification systems. We compared the existing classification systems regarding their definition of the perinatal period, level of complexity, inclusion of maternal, foetal and/or placental factors and whether they focus at a clinical or pathological viewpoint. Furthermore, we allocated the classification systems to one of three categories: 'when', 'what' or 'why', dependent on whether the allocation of the individual cases of perinatal mortality is based on the moment of death ('when'), the clinical conditions associated with death ('what'), or the underlying cause of death ('why'). A multilayered approach for the analysis and classification of perinatal mortality is possible by using combinations of existing systems; for example the Wigglesworth or Nordic Baltic ('when'), ReCoDe ('what') and Tulip ('why') classification systems. This approach is useful not only for in depth analysis of perinatal mortality in the developed world but also for analysis of perinatal mortality in the developing countries, where resources to investigate death are often limited.

Cytogenetic analysis after evaluation of 750 fetal deaths: proposal for diagnostic workup.

OBJECTIVE: To estimate success rates for cytogenetic analysis in different tissues after intrauterine fetal death, and study selection criteria and value of cytogenetic testing in determining cause of death. METHODS: Cytogenetic analyses and the value of this test in determining cause by a multidisciplinary panel were studied in 750 fetal deaths. Morphologic abnormalities, small for gestational age (SGA), advanced maternal age (older than 35 years) and maceration were studied as selection criteria. RESULTS: Chromosomal abnormalities were observed in 13% of fetal deaths. Cytogenetic success rates were significantly higher for invasive testing (85%) than for postpartum tissue analysis (28%, P<.001). There were more abnormal chromosomes (38%) in fetal deaths with morphologic abnormalities than in those without (5%, P<.001). This was not observed for SGA (16% compared with 9.2%, P=.22) or for advanced maternal age (16.7% compared with 12.0%, P=.37). The posterior probability of a chromosomal abnormality in the absence of morphologic abnormalities was still 4.6%. Cytogenetic analysis was successful in 35% of severely macerated fetuses. We do not advise using these selection criteria, because the failure rate was high on postpartum tissues. Cytogenetic analysis was valuable in determining the cause in 19% of the fetal deaths. CONCLUSION: Parents should be counseled on aspects of cytogenetic analysis after fetal death. We advise performing nonselective invasive testing after fetal death and before labor for all fetal deaths.

High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects.

Pregnancy is associated with an increased risk of venous thromboembolism, which probably varies according to the presence of single or multiple thrombophilic defects. This retrospective family cohort study assessed the risk of venous thromboembolism during pregnancy and puerperium, and the contribution of concomitant thrombophilic defects in families with hereditary antithrombin, protein C or protein S deficiencies. Probands were excluded. Of 222 female relatives, 101 were deficient and 121 non-deficient. Annual incidences of venous thromboembolism were 1.76% in deficient women versus 0.19% in non-deficient women [adjusted relative risk (RR) 11.9; 95% confidence interval (CI), 3.9-36.2]. Other single and multiple thrombophilic defects increased the risk in deficient women from 1.55% to 2.14% and 2.92%, and in non-deficient women from 0.16% to 0.09% and 0.54% respectively. Deficient women were at lower risk (1.37%; 0.80-2.19) than deficient women that had never been pregnant (2.96%; 1.53-5.18); RR 0.5 (0.2-0.99). This difference was due to the predominance of events related to oral contraceptives in deficient women that had never been pregnant (75%), while 71% of events in deficient women that had had at least one pregnancy were pregnancy-related. In conclusion, women with hereditary deficiencies of antithrombin, protein C or protein S are at high risk of pregnancy-related venous thromboembolism. This risk is increased by multiple additional thrombophilic defects.

Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women.

Hereditary thrombophilia is associated with an increased risk of fetal loss. Assuming that fetal loss is due to placental thrombosis, anticoagulant treatment might improve pregnancy outcome. In an observational family cohort study, we prospectively assessed the effects of anticoagulant drugs on fetal loss rates in women with hereditary deficiencies of antithrombin, protein C or protein S. The cohort contained 376 women (50 probands and 326 deficient or non-deficient relatives). Probands were consecutive deficient patients with venous tromboembolism. Thromboprophylaxis during pregnancy was recommended in deficient women, irrespective of prior venous thromboembolism, and in non-deficient women with prior venous thromboembolism. Outcome of first pregnancy was analysed in 55 eligible women. Of 37 deficient women, 26 (70%) received thromboprophylaxis during pregnancy, compared with three of 18 (17%) non-deficient women. Fetal loss rates were 0% in deficient women with thromboprophylaxis versus 45% in deficient women without (P = 0.001) and 7% in non-deficient women without thromboprophylaxis (P = 0.37). The adjusted relative risk of fetal loss in women who received thromboprophylaxis versus women who did not was 0.07 (95% confidence interval 0.001-0.7; P = 0.02). Our data suggest that anticoagulant treatment during pregnancy reduces the high fetal loss rate in women with hereditary deficiencies of antithrombin, protein C or protein S.