Noninvasive fetal RHD genotyping to guide targeted anti-D prophylaxis-an external quality assessment workshop.

BACKGROUND AND OBJECTIVES: Fetal RHD genotyping of cell-free fetal DNA from RhD-negative pregnant women can be used to guide targeted antenatal and postnatal anti-D prophylaxis for the prevention of RhD immunization. To assure the quality of clinical testing, we conducted an external quality assessment workshop with the participation of 28 laboratories. MATERIALS AND METHODS: Aliquots of pooled maternal plasma were sent to each laboratory. One sample was positive, and the second sample was negative for fetal RHD, verified by pre-workshop testing using quantitative real-time PCR (qPCR) analysis of RHD exons 4, 5, 7 and 10. Plasma samples were shipped at room temperature. A reporting scheme was supplied for data collection, including questions regarding the methodological setup, results and clinical recommendations. Different methodological approaches were used, all employing qPCR with a total of eight different combinations of RHD exon targets. The samples were tested blindly. RESULTS: Fetal RHD genotyping was performed with no false-negative and no false-positive results. One inconclusive result was reported for the RHD-positive sample, and four inconclusive results were reported for the RHD-negative sample. All clinical conclusions were satisfactory. CONCLUSION: This external quality assessment workshop demonstrates that despite the different approaches taken to perform the clinical assays, fetal RHD genotyping is a reliable laboratory assay to guide targeted use of Rh prophylaxis in a clinical setting.

Cytomegalovirus Screening in Pregnancy: A Cost-Effectiveness and Threshold Analysis.

OBJECTIVE: To determine threshold cytomegalovirus (CMV) infectious rates and treatment effectiveness to make universal prenatal CMV screening cost-effective. STUDY DESIGN: Decision analysis comparing cost-effectiveness of two strategies for the prevention and treatment of congenital CMV: universal prenatal serum screening and routine, risk-based screening. The base case assumptions were a probability of primary CMV of 1% in seronegative women, hyperimmune globulin (HIG) effectiveness of 0%, and behavioral intervention effectiveness of 85%. Screen-positive women received monthly HIG and screen-negative women received behavioral counseling to decrease CMV seroconversion. The primary outcome was the cost per maternal quality-adjusted life year (QALY) gained with a willingness to pay of $100,000 per QALY. RESULTS: In the base case, universal screening is cost-effective, costing $84,773 per maternal QALY gained. In sensitivity analyses, universal screening is cost-effective only at a primary CMV incidence of more than 0.89% and behavioral intervention effectiveness of more than 75%. If HIG is 30% effective, primary CMV incidence can be 0.82% for universal screening to be cost-effective. CONCLUSION: The cost-effectiveness of universal maternal screening for CMV is highly dependent on the incidence of primary CMV in pregnancy. If efficacious, HIG and behavioral counseling allow universal screening to be cost-effective at lower primary CMV rates.

Mycophenolate fetal toxicity and risk evaluation and mitigation strategies.

The mycophenolic acid (MPA) preparations are one of the most commonly used immunosuppressants in the United States. However, these agents carry a black box warning regarding their use during pregnancy due to an association with increased risk of miscarriage and congenital defects. To ensure that the benefits of MPA outweigh the risks, the Food and Drug Administration (FDA) required all manufacturers of MPA products to propose risk evaluation and mitigation strategies (REMS). Four years after initially calling for proposals, the FDA approved a single shared REMS system in September 2012. The elements of the MPA REMS include a medication guide and elements to assure safe use (ETASU). The medication guide, which was previously FDA-approved in 2008, should continue to be distributed to patients, and the ETASU requires physicians to complete training and obtain patient signatures on the "Patient-Prescriber Acknowledgement Form." A single, national, voluntary pregnancy registry is available, and pregnant patients should be encouraged to participate. Although the impact of the MPA REMS on clinical practice is not clear, it is a step toward increasing the understanding of fetal risks with MPA products among patients and possibly practitioners.

A framework for strategic investments in research to reduce the global burden of preterm birth.

Preterm birth and stillbirth are among the greatest health burdens associated with pregnancy and childbirth. Fifteen million babies are born preterm each year, causing about 1 million deaths annually and lifelong problems for many survivors; 3 million stillbirths also occur annually. Worldwide, the number of women and children who die during pregnancy and childbirth exceeds the total number of births in the United States. New approaches could provide a greater understanding of prematurity, stillbirth, and maternal complications of pregnancy and childbirth. Integrated multidisciplinary investigations of the mother, fetus, and newborn in different contexts and populations could elucidate the biological pathways that result in adverse outcomes and how to prevent them. Descriptive research can determine the burden of disease, while more mechanistic discovery research could explore the physiology and pathophysiology of pregnancy and childbirth. Together, this research can lead to the development and delivery of new and much more effective interventions, even in low-resource settings. Recent surveys of researchers and funders reveal a striking lack of consensus regarding priority areas for research and the development of interventions. While researchers enumerate unanswered questions about pregnancy and childbirth, they lack consensus on priorities. Funders are equally uncertain about research and development projects that need to be undertaken, and many are hard-pressed to support research on the complex problems of pregnancy and childbirth given competing priorities. This lack of consensus provides an opportunity to engage with funders and researchers to recognize the importance of understanding healthy pregnancies and the consequences of adverse pregnancy outcomes. A strategic alliance of funders, researchers, nongovernmental organizations, the private sector, and others could organize a set of grand challenges centered on pregnancy and childbirth that could yield a substantial improvement in reproductive health.

The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system.

BACKGROUND: Preventing fetal exposure to isotretinoin is widely acknowledged as an important safety issue. The iPLEDGE program is the latest in a series of Food and Drug Administration-mandated risk management programs designed to prevent pregnancies in female patients of childbearing potential (FCBP) taking isotretinoin. OBJECTIVE: We sought to evaluate the effect of iPLEDGE relative to the prior risk management program (system to manage Accutane-related teratogenicity [SMART]) on the risk of isotretinoin fetal exposure in FCBP in a managed care setting. METHODS: All FCBP at Kaiser Permanente Southern and Northern California who filled at least one prescription for isotretinoin during a 4-year period (March 1, 2004, to February 29, 2008) were included in this retrospective cohort study (n = 8344). Chart review was performed to confirm fetal exposures and outcomes. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals. RESULTS: There were a total of 29 fetal exposures and 9912 isotretinoin treatment courses. After iPLEDGE was implemented, the unadjusted rate of fetal exposure decreased from 3.11 to 2.67 per 1000 treatment courses (P = .69). The hazard ratio = 0.76 (95% confidence interval 0.36-1.61) for fetal exposures to isotretinoin during treatment courses filled after iPLEDGE implementation compared with SMART. LIMITATIONS: Limitations include limited generalizability of results, small sample size (n = 29 total documented fetal exposures), and potential uncontrolled confounders. CONCLUSION: Evaluating the impact of iPLEDGE on isotretinoin fetal exposures is important in understanding the full risks and benefits of isotretinoin treatment. We found no evidence that iPLEDGE significantly decreased the risk of fetal exposure in FCBP compared to the SMART program.

Alcohol use and pregnancy consensus clinical guidelines.

OBJECTIVE: to establish national standards of care for the screening and recording of alcohol use and counselling on alcohol use of women of child-bearing age and pregnant women based on the most up-to-date evidence. EVIDENCE: published literature was retrieved through searches of PubMed, CINAHL, and the Cochrane Library in May 2009 using appropriate controlled vocabulary (e.g., pregnancy complications, alcohol drinking, prenatal care) and key words (e.g., pregnancy, alcohol consumption, risk reduction). Results were restricted to literature published in the last five years with the following research designs: systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment (HTA) and HTA-related agencies, national and international medical specialty societies, clinical practice guideline collections, and clinical trial registries. Each article was screened for relevance and the full text acquired if determined to be relevant. The evidence obtained was reviewed and evaluated by the members of the Expert Workgroup established by the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. VALUES: the quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR: the Public Health Agency of Canada and the Society of Obstetricians and Gynaecologists of Canada. ENDORSEMENT: these consensus guidelines have been endorsed by the Association of Obstetricians and Gynecologists of Quebec; the Canadian Association of Midwives; the Canadian Association of Perinatal, Women's Health and Neonatal Nurses (CAPWHN); the College of Family Physicians of Canada; the Federation of Medical Women of Canada; the Society of Rural Physicians of Canada; and Motherisk. SUMMARY STATEMENTS: 1. There is evidence that alcohol consumption in pregnancy can cause fetal harm. (II-2) There is insufficient evidence regarding fetal safety or harm at low levels of alcohol consumption in pregnancy. (III) 2. There is insufficient evidence to define any threshold for low-level drinking in pregnancy. (III) 3. Abstinence is the prudent choice for a woman who is or might become pregnant. (III) 4. Intensive culture-, gender-, and family-appropriate interventions need to be available and accessible for women with problematic drinking and/or alcohol dependence. (II-2). RECOMMENDATIONS: 1. Universal screening for alcohol consumption should be done periodically for all pregnant women and women of child-bearing age. Ideally, at-risk drinking could be identified before pregnancy, allowing for change. (II-2B) 2. Health care providers should create a safe environment for women to report alcohol consumption. (III-A) 3. The public should be informed that alcohol screening and support for women at risk is part of routine women's health care. (III-A) 4. Health care providers should be aware of the risk factors associated with alcohol use in women of reproductive age. (III-B) 5. Brief interventions are effective and should be provided by health care providers for women with at-risk drinking. (II-2B) 6. If a woman continues to use alcohol during pregnancy, harm reduction/treatment strategies should be encouraged. (II-2B) 7. Pregnant women should be given priority access to withdrawal management and treatment. (III-A) 8. Health care providers should advise women that low-level consumption of alcohol in early pregnancy is not an indication for termination of pregnancy. (II-2A).

[Smoking and exposure to tobacco smoke among pregnant women in Ecuador]. / Consumo y exposición al humo de tabaco en mujeres embarazadas de Ecuador.

OBJECTIVES: To determine the frequency of smoking and second-hand smoke exposure among pregnant women in Ecuador and to describe the sociodemographic profiles associated with these perinatal risk factors. METHODS: A cross-sectional descriptive study using a survey of women 18-46 years of age who were more than three months pregnant and attended follow-up consultations in seven maternity clinics in six cities in Ecuador between October 2004 and September 2005. Demographics and environmental exposure (independent variables) data and their relationship to cigarette smoking and secondhand-smoke exposure were analyzed. RESULTS: Of the 746 women studied, 53.3% had smoked occasionally, and 4.3%, regularly; of these, 75% had quit smoking before or during pregnancy. Of the respondents, 12.9% were frequently or always exposed to secondhand smoke indoors. Having more education (11 or more years), being in the middle or upper socioeconomic classes, being Caucasian, and it being considered acceptable for women in the community to smoke were significantly and directly associated with cigarette smoking (P<0.001). Overall, 12.9% of women were being exposed to secondhand smoke and this was significantly associated with being single and cohabiting with smokers or employees connected to the tobacco industry (P<0.001). CONCLUSIONS: Specific measures must be designed and implemented to not only encourage smoking cessation during pregnancy, but also to prevent women of reproductive age from taking up smoking and to limit smoking in the home environment.

Consumo y exposición al humo de tabaco en mujeres embarazadas de Ecuador / Smoking and exposure to tobacco smoke among pregnant women in Ecuador

OBJETIVOS: Determinar la frecuencia de tabaquismo y exposición ambiental al humo de tabaco en mujeres embarazadas de Ecuador y describir los perfiles sociodemográficos asociados con esos factores de riesgo perinatal. MÉTODOS: Estudio descriptivo transversal mediante una encuesta aplicada a mujeres de 18 a 46 años con más de 3 meses de embarazo que asistieron entre octubre de 2004 y septiembre de 2005 a sus consultas de seguimiento en siete servicios de maternidad de seis ciudades de Ecuador. Se analizaron los datos demográficos y de exposición medioambiental (variables independientes) y su relación con el hábito de fumar cigarrillos y la exposición ambiental al humo de tabaco. RESULTADOS: De las 746 mujeres analizadas, 53,3 por ciento había fumado ocasionalmente y 4,3 por ciento había fumado habitualmente; de estas, 75,0 por ciento había dejado de fumar antes o durante el embarazo. De las encuestadas, 12,9 por ciento estuvo expuesta con frecuencia o siempre al humo de tabaco en ambientes cerrados. Tener mayor educación (11 años o más) y un nivel socioeconómico medio o alto, ser caucásica y considerar aceptable que las mujeres de su comunidad fumen se asoció significativa y directamente con el hábito de fumar cigarrillos (P < 0,001). En general, 12,9 por ciento de las mujeres estuvo expuesta al humo de tabaco y esto se asoció significativamente con ser soltera y cohabitar con fumadores o trabajadores vinculados con la industria del tabaco (P < 0,001). CONCLUSIONES: Se deben diseñar e implementar medidas específicas dirigidas no solo a estimular el abandono de este hábito en las embarazadas, sino también a prevenir que las mujeres en edad reproductiva comiencen a fumar y controlar el entorno fumador en el hogar.

OBJECTIVES: To determine the frequency of smoking and second-hand smoke exposure among pregnant women in Ecuador and to describe the sociodemographic profiles associated with these perinatal risk factors. METHODS: A cross-sectional descriptive study using a survey of women 18-46 years of age who were more than three months pregnant and attended follow-up consultations in seven maternity clinics in six cities in Ecuador between October 2004 and September 2005. Demographics and environmental exposure (independent variables) data and their relationship to cigarette smoking and secondhand-smoke exposure were analyzed. RESULTS: Of the 746 women studied, 53.3 percent had smoked occasionally, and 4.3 percent, regularly; of these, 75 percent had quit smoking before or during pregnancy. Of the respondents, 12.9 percent were frequently or always exposed to secondhand smoke indoors. Having more education (11 or more years), being in the middle or upper socioeconomic classes, being Caucasian, and it being considered acceptable for women in the community to smoke were significantly and directly associated with cigarette smoking (P < 0.001). Overall, 12.9 percent of women were being exposed to secondhand smoke and this was significantly associated with being single and cohabiting with smokers or employees connected to the tobacco industry (P < 0.001). CONCLUSIONS: Specific measures must be designed and implemented to not only encourage smoking cessation during pregnancy, but also to prevent women of reproductive age from taking up smoking and to limit smoking in the home environment.

[Prevention of complications in twin gestations and pregnancies after assisted reproduction]. / Risikoprävention bei Geminigraviditäten und Schwangerschaften nach assistierter Reproduktion.

BACKGROUND: Twin pregnancies and gestations after assisted reproductive therapy (ART) are of special obstetric significance with regard to their associated risks. However, little is known about preventive approaches specifically evaluated for these constellations. METHODS: A selective literature search was conducted to examine possible preventive approaches for complications such as hypertensive disorders, anaemia, gestational diabetes, prematurity, and others, seen significantly more often in twin gestations and pregnancies after ART. RESULTS: For both constellations, preventive approaches are not specifically evaluated for the majority of complications. For some preventive methods a possible detrimental effect cannot even be ruled out. CONCLUSIONS: The knowledge about specific preventive approaches against complications in twin pregnancies and gestations after ART is scarce. More prospective trials are urgently needed to assess the risks and benefits of prophylactic approaches for these risk constellations.

[Monochorionic twin pregnancy and the following problems]. / Die monochoriale Zwillingsgravidität und ihre Problematik.

Monochorionic twin pregnancies have an increased risk of intrauterine and postnatal complications because of the present placental vascular anastomoses. The main problems are the development of twin-to-twin transfusion syndrome,selective intrauterine growth restriction, monoamniotic twins and single intrauterine death on the one hand and congenital abnormalities like twin reversed-arterial perfusion and conjoined twins on the other hand. Fetoscopic laser therapy with selective coagulation of placental intertwin anastomoses is the best option in the treatment of twin-to-twin transfusion syndrome. The risk of preterm delivery, cerebral injury and abnormalities of long-term neurodevelopmental outcome are increased. Perinatal management of monochorionic twin pregnancies should be performed in specialized tertiar centers.

On the nature, assessment, and treatment of fetal pain: neurobiological bases, pragmatic issues, and ethical concerns.

Over the past 2 decades, the issue of fetal pain and stress has attracted considerable attention and has become the focus of ongoing debate in light of advances in medical diagnostics and technology that allow invasive prenatal medical intervention(s), and an enhanced understanding of fetal neurophysiology, together with a broadened appreciation for the relationship of brain and consciousness. In this essay, we explore the issue of fetal pain based upon knowledge of both the ontogeny and function of the nervous system and the interaction of brain, mind, and pain. We posit that contemporary understanding of neurological development fortifies appreciation that pain sensation and perception occurs during (later) fetal life and that this pain warrants clinical consideration during the conduct of invasive prenatal procedures. We present differing perspectives on this issue, discuss the relative merits and difficulties of these positions, and ultimately describe the fundamental basis for a consideration of fetal pain and address this consideration with regard to pragmatic and ethical benefits, burdens, and risks. We adopt a neurocentric, yet consilient approach that entails both scientific and philosophical orientations. By attempting to reveal inherent limitations in our contemporary appreciation and approach(es) to fetal pain, we hope to illustrate the need for and posit potential venues toward resolving these limitations and dilemmas.

First trimester ultrasound screening for fetal aneuploidy and middle cerebral artery Doppler assessment for fetal alloimmunization.

PURPOSE OF REVIEW: Traditional methods of fetal evaluation require invasive procedures (e.g. amniocentesis) with an inherent, albeit low, risk of complications and pregnancy loss. As medical knowledge and ultrasound technology have advanced, noninvasive modes of fetal evaluation have become increasingly used. Two disorders in which this has been most applied are fetal aneuploidy and alloimmunization to red blood cell antigens. RECENT FINDINGS: First-trimester screening protocols for fetal aneuploidy combine ultrasound measurement of the fetal nuchal translucency with the measurement of two maternal serum hormones, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. This combination detects approximately 85% of women pregnant with fetuses with trisomy 21. An increase in the velocity of fetal middle cerebral artery blood flow occurs in the setting of moderate to severe fetal anemia and can be measured with Doppler ultrasound. Middle cerebral artery evaluation is equally sensitive in the prediction of anemia as amniocentesis for bilirubin breakdown products and has less associated risk. It has an additional benefit because it can also be applied to causes of anemia other than hemolysis. SUMMARY: Noninvasive methods of fetal assessment are becoming increasingly commonplace. There has been a dramatic decrease in the use of prenatal diagnostic services as screening strategies have become available. Doppler assessment of the velocity of blood flow through the fetal middle cerebral artery will allow for more judicious application of invasive procedures to pregnancies at significant risk for anemia.

The cost effectiveness of empiric intravenous immunoglobulin for the antepartum treatment of fetal and neonatal alloimmune thrombocytopenia.

OBJECTIVE: The purpose of this study was to compare the cost effectiveness of empiric intravenous immunoglobulin (IVIG) with that of fetal blood sampling-indicated treatment for the antepartum care of fetal and neonatal alloimmune thrombocytopenia. STUDY DESIGN: We developed a decision analysis model to compare the cost effectiveness of 2 strategies for treatment of pregnancies in women with a history of fetal and neonatal alloimmune thrombocytopenia and an at-risk fetus: 1) IVIG and corticosteroids as indicated by fetal platelet levels determined by fetal blood sampling (FBS); and 2) empiric IVIG. In the first strategy, FBS is used to measure fetal platelets at 24 weeks of gestation and repeated 6 weeks later to guide pharmacotherapy. In the second strategy, weekly IVIG is empirically administered from 24 weeks' to 37 weeks' gestation. The main outcome measure was the marginal cost per quality-adjusted life years (QALY) gained. RESULTS: For every 1000 women with a fetus at risk for recurrent alloimmune thrombocytopenia, empiric therapy, compared with FBS-indicated treatment, decreases perinatal deaths from 31.7 to 11.8 while increasing the number of infants with long-term neurologic deficits from 6.1 to 9.6. These health outcomes translate to 382 QALYs gained with empiric therapy and a cost effectiveness ratio of dollar 32,747 per QALY favoring empiric therapy. In the sensitivity analysis, empiric therapy was not cost effective when the rate of perinatal ICH exceeded 28%. CONCLUSION: Empiric IVIG therapy is a cost-effective strategy for the treatment of women at risk for fetal and neonatal alloimmune thrombocytopenia when the rate of perinatal ICH is less than 28%.

Exposure of Arctic populations to methylmercury from consumption of marine food: an updated risk-benefit assessment.

Recent and powerful epidemiological studies have been used as a basis for revising international and domestic guidelines for human exposure to mercury. Long-range transport of mercury into the Arctic makes some Arctic peoples consuming traditional marine foods, especially newborns, children and pregnant women, very vulnerable to harmful exposures. The WHO, the USEPA and Health Canada have all recently revised their mercury intake guidelines as a result of neurological effects reported in children exposed in utero and adults. Guidance values are equivalent to 0.23 microg/kg-bw/d, 0.1 microg/kg-bw/d and 0.2 microg/kg-bw/d respectively. Differences between the numbers represent slight differences in the uncertainty factors applied, rather than in toxicological interpretation. More recent findings suggest that mercury may also be a factor in ischemic heart disease, which could lower guidance values in the future. Considering the benefits of marine fatty acids (n-3 fatty acids) and guidance that populations consume 300-400g fish/week, consumers face a reality that most open ocean and relatively 'unpolluted' fish species contain levels of mercury that would lead to exposures at current guidance levels. Clearly, there is no more room for further mercury pollution and there is an urgent need for international action to reduce mercury emissions. Concomitantly, while there may be a need for public health authorities to provide consumption advisories to some highly exposed populations, such as in the Arctic, there remains a need to better understand the interactions and benefits associated with marine foods that may reduce health risks associated with low-level mercury exposure.