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Hospital births, when compared to out-of-hospital births, have generally led to not only a significantly reduced maternal and perinatal mortality and morbidity but also an increase in certain interventions. A trend seems to be emerging, especially in the US where some women are requesting home births, which creates ethical challenges for obstetricians and the health care organizations and policy makers. In the developing world, a completely different reality exists. Home births constitute the majority of deliveries in the developing world. There are severe limitations in terms of facilities, health personnel and deeply entrenched cultural and socio-economic conditions militating against hospital births. As a consequence, maternal and perinatal mortality and morbidity remain the highest, especially in Sub-Saharan Africa (SSA). Midwife-assisted planned home birth therefore has a major role to play in increasing the safety of childbirth in SSA. The objective of this paper is to propose a model that can be used to improve the safety of childbirth in low resource countries and to outline why midwife assisted planned home birth with coordination of hospitals is the preferred alternative to unassisted or inadequately assisted planned home birth in SSA.

It should be apparent that determining the reproductive risks of an exposure during pregnancy or the cause of a child's congenital malformations is not a simple process. It involves a careful analysis of the medical and scientific literature pertaining to the reproductive toxic effects of exogenous agents in humans and animals, as well as an evaluation of the exposure and the biological plausibility of the concern of an increased risk or a causal connection between the exposure and a child's congenital malformations. It also involves having available a detailed physical examination of the malformed infant or child and a review of the scientific literature pertaining to genetic and environmental causes of the malformations in question. Abridged counseling on the basis of superficial and incomplete analyses is a disservice to the family. Experienced counselors understand that their primary task is to educate the pregnant women or family members concerning the risk of an environmental exposure. The counselor should advise them on the options available, but not on which option to select.

Background: The Apgar score is used worldwide to assess the newborn infant shortly after birth. Apgar scores, including mean scores and those with high cut-off scores, have been used to support claims that planned home birth is as safe as hospital birth. The purpose of this study was to determine the distribution of 5 min Apgar scores among different birth settings and providers in the USA. Methods: We obtained data from the National Center for Health Statistics of the US Centers for Disease Control birth certificate data for 2007–2010 for all singleton, term births of infants weighing ≥2500 g (n=13,830,531). Patients were then grouped into six categories by birth setting and birth attendant: hospital-based physician, hospital-based midwife, freestanding birth center with either certified nurse midwife and/or other midwife, and home-based delivery with either certified nurse midwife or other midwife. The distribution of each Apgar score from 0 to 10 was assessed for each group. Results: Newborns delivered by other midwives or certified nurse midwives (CNMs) in a birthing center or at home had a significantly higher likelihood of a 5 min maximum Apgar score of 10 than those delivered in a hospital [52.63% in birthing centers, odds ratio (OR) 29.19, 95% confidence interval (CI): 28.29–30.06, and 52.44% at home, OR 28.95, 95% CI: 28.40–29.50; CNMs: 16.43% in birthing centers, OR 5.16, 95% CI: 4.99–5.34, and 36.9% at home births, OR 15.29, 95% CI: 14.85–15.73]. Conclusions: Our study shows an inexplicable bias of high 5 min Apgar scores of 10 in home or birthing center deliveries. Midwives delivering at home or in birthing centers assigned a significantly higher proportion of Apgar scores of 10 when compared to midwives or physicians delivering in the hospital. Studies that have claimed the safety of out-of-hospital deliveries by using higher mean or high cut-off 5 min Apgar scores and reviews based on these studies should be treated with skepticism by obstetricians and midwives, by pregnant women, and by policy makers. The continued use of studies using higher mean or high cut-off 5 min Apgar scores, and a bias of high Apgar score, to advocate the safety of home births is inappropriate.

The challenges physician leaders confront today call to mind Odysseus' challenge to steer his fragile ship successfully between Scylla and Charybdis. The modern Scylla takes the form of ever-increasing pressures to provide more resources for professional liability, compliance, patient satisfaction, central administration, and a host of other demands. The modern Charybdis takes the form of ever-increasing pressures to procure resources when fewer are available and competition is continuously increasing the need for resources, including managed care, hospital administration, payers, employers, patients who are uninsured or underinsured, research funding, and philanthropy. This publication provides physician leaders with guidance for identifying and managing common leadership challenges on the basis of the professional responsibility model of physician leadership. This model is based on Plato's concept of leadership as a life of service and the professional medical ethics of Drs John Gregory and Thomas Percival. Four professional virtues should guide physician leaders: self-effacement, self-sacrifice, compassion, and integrity. These professional virtues direct physician leaders to treat colleagues as ends in themselves, to provide justice-based resource management, to use power constrained by medical professionalism, and to prevent and respond effectively to organizational dysfunction. The professional responsibility model guides physician leaders by proving an explicit "tool kit" to complement managerial skills.

Planned home birth is a paradigmatic case study of the importance of ethics and professionalism in contemporary perinatology. In this article we provide a summary of recent analyses of the Centers for Disease Control database on attendants and birth outcomes in the United States. This summary documents the increased risks of neonatal mortality and morbidity of planned home birth as well as bias in Apgar scoring. We then describe the professional responsibility model of obstetric ethics, which is based on the professional medical ethics of two major figures in the history of medical ethics, Drs. John Gregory of Scotland and Thomas Percival of England. This model emphasizes the identification and careful balancing of the perinatologist's ethical obligations to pregnant, fetal, and neonatal patients. This model stands in sharp contrast to one-dimensional maternal-rights-based reductionist model of obstetric ethics, which is based solely on the pregnant woman's rights. We then identify the implications of the professional responsibility model for the perinatologist's role in directive counseling of women who express an interest in or ask about planned home birth. Perinatologists should explain the evidence of the increased, preventable perinatal risks of planned home birth, recommend against it, and recommend planned hospital birth. Perinatologists have the professional responsibility to create and sustain a strong culture of safety committed to a home-birth-like experience in the hospital. By routinely fulfilling these professional responsibilities perinatologists can help to prevent the documented, increased risks planned home birth.

INTRODUCTION:Over the last decade, planned home births in the United States (US) have increased, and have been associated with increased neonatal mortality and other morbidities. In a previous study we reported that neonatal mortality is increased in planned home births but we did not perform an analysis for the presence of professional certification status. PURPOSE:The objective of this study therefore was to undertake an analysis to determine whether the professional certification status of midwives or the home birth setting are more closely associated with the increased neonatal mortality of planned midwife-attended home births in the United States. MATERIALS AND METHODS:This study is a secondary analysis of our prior study. The 2006-2009 period linked birth/infant deaths data set was analyzed to examine total neonatal deaths (deaths less than 28 days of life) in term singleton births (37+ weeks and newborn weight ≥ 2,500 grams) without documented congenital malformations by certification status of the midwife: certified nurse midwives (CNM), nurse midwives certified by the American Midwifery Certification Board, and "other" or uncertified midwives who are not certified by the American Midwifery Certification Board. RESULTS:Neonatal mortality rates in hospital births attended by certified midwives were significantly lower (3.2/10,000, RR 0.33 95% CI 0.21-0.53) than home births attended by certified midwives (NNM: 10.0/10,000; RR 1) and uncertified midwives (13.7/10,000; RR 1.41 [95% CI, 0.83-2.38]). The difference in neonatal mortality between certified and uncertified midwives at home births did not reach statistical levels (10.0/10,000 births versus 13.7/10,000 births p = 0.2). CONCLUSIONS:This study confirms that when compared to midwife-attended hospital births, neonatal mortality rates at home births are significantly increased. While NNM was increased in planned homebirths attended by uncertified midwives when compared to certified midwives, this difference was not statistically significant. Neonatal mortality rates at home births were not significantly different in relationship to professional certification status of the birth attendant, whether the delivery was by a certified or an uncertified birth attendant.

A risk analysis of in utero caffeine exposure is presented utilizing epidemiological studies and animal studies dealing with congenital malformation, pregnancy loss, and weight reduction. These effects are of interest to teratologists, because animal studies are useful in their evaluation. Many of the epidemiology studies did not evaluate the impact of the “pregnancy signal,” which identifies healthy pregnancies and permits investigators to identify subjects with low pregnancy risks. The spontaneous abortion epidemiology studies were inconsistent and the majority did not consider the confounding introduced by not considering the pregnancy signal. The animal studies do not support the concept that caffeine is an abortafacient for the wide range of human caffeine exposures. Almost all the congenital malformation epidemiology studies were negative. Animal pharmacokinetic studies indicate that the teratogenic plasma level of caffeine has to reach or exceed 60 µg/ml, which is not attainable from ingesting large amounts of caffeine in foods and beverages. No epidemiological study described the “caffeine teratogenic syndrome.” Six of the 17 recent epidemiology studies dealing with the risk of caffeine and fetal weight reduction were negative. Seven of the positive studies had growth reductions that were clinically insignificant and none of the studies cited the animal literature. Analysis of caffeine's reproductive toxicity considers reproducibility and plausibility of clinical, epidemiological, and animal data. Moderate or even high amounts of beverages and foods containing caffeine do not increase the risks of congenital malformations, miscarriage or growth retardation. Pharmacokinetic studies markedly improve the ability to perform the risk analyses. Birth Defects Res (Part B) 92:152–187, 2011. © 2011 Wiley-Liss, Inc.

Radiography of the chest, head, neck, teeth, or extremity exposes the embryo or ovary to insignificant exposures of radiation except when radionuclides are utilized. In some instances, there is no exposure at all. Pulmonologists are fortunate with regard to the specific studies they request to provide clinical care because most of the diagnostic tests do not directly expose the uterus (embryo) or ovary. This article discusses radiation risks and their evaluation and pregnancy-related issues in diagnostic radiological studies.

Objective To examine the occurrence of 5-minute Apgar scores of 0 and seizures or serious neurologic dysfunction for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, free-standing birth center midwife, and home midwife) in the United States from 2007-2010. Methods Data from the United States Centers for Disease Control's National Center for Health Statistics birth certificate data files were used to assess deliveries by physicians and midwives in and out of the hospital for the 4-year period from 2007-2010 for singleton term births (≥37 weeks' gestation) and ≥2500 g. Five-minute Apgar scores of 0 and neonatal seizures or serious neurologic dysfunction were analyzed for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, freestanding birth center midwife, and home midwife). Results Home births (relative risk [RR], 10.55) and births in free-standing birth centers (RR, 3.56) attended by midwives had a significantly higher risk of a 5-minute Apgar score of 0 ( P P Conclusion The increased risk of 5-minute Apgar score of 0 and seizures or serious neurologic dysfunction of out-of-hospital births should be disclosed by obstetric practitioners to women who express an interest in out-of-hospital birth. Physicians should address patients' motivations for out-of-hospital delivery by continuously improving safe and compassionate care of pregnant, fetal, and neonatal patients in the hospital setting.

On February 3, 2010, a “Letter of Concern from Bioethicists,” organized by fetaldex.org, was sent to report suspected violations of the ethics of human subjects research in the off-label use of dexamethasone during pregnancy by Dr. Maria New. Copies of this letter were submitted to the FDA Office of Pediatric Therapeutics, the Department of Health and Human Services (DHHS) Office for Human Research Protections, and three universities where Dr. New has held or holds appointments. We provide a critical appraisal of the Letter of Concern and show that it makes false claims, misrepresents scientific publications and websites, fails to meet standards of evidence-based reasoning, makes undocumented claims, treats as settled matters what are, instead, ongoing controversies, offers “mere opinion” as a substitute for argument, and makes contradictory claims. The Letter of Concern is a case study in unethical transgressive bioethics. We call on fetaldex.org to withdraw the letter and for co-signatories to withdraw ...

* Abbreviations: AAP — : American Academy of Pediatrics The American Academy of Pediatrics (AAP) has long and consistently championed the best interests of the child standard as the foundation of pediatric ethics.1 This standard obligates pediatricians to protect and promote the biopsychosocial interests of children who are patients, as these interests are determined in deliberative (evidence-based, rigorous, transparent, and accountable) clinical judgment and practice. The interests of parents do not play a direct role in the conceptualization of this standard, although the ability and willingness of parents to participate in the health care of their child can become ethically relevant considerations in some cases. It is worth noting that, in pediatric ethics, the best interests of the child standard generates the ethical obligation of parents to protect and promote the biopsychosocial interests of their children when their children are patients. The recent AAP statement, “Planned Home Birth,” endorses the ethical position of the American College of Obstetricians and Gynecologists in its statement on planned home birth2: “The American Academy of Pediatrics concurs with the recent statement of the American College of Obstetricians and Gynecologists affirming that hospitals and birthing centers are the safest settings for birth in the United States while respecting the right of women to make an informed decision about delivery.”3 The AAP statement also recommends that “there should be at least 1 person present at every delivery whose primary responsibility is the care of the newborn infant.”3 The AAP can take these positions only if they are consistent with the best interests of the child standard. The purpose of this article is to call into question whether the AAP statement is indeed consistent with this foundational standard of pediatric ethics. The resolution of this question depends directly on the preventable, increased perinatal risks of planned home birth. … Address correspondence to Frank A. Chervenak, MD, New York Presbyterian Hospital, 525 East 68th St, M-724, Box 122, New York, NY 10065. E-mail: fac2001{at}med.cornell.edu

Assessing the risk profiles of potentially sensitive populations requires a "tool chest" of methodological approaches to adequately characterize and evaluate these populations. At present, there is an extensive body of literature on methodologies that apply to the evaluation of the pediatric population. The Health and Environmental Sciences Institute Subcommittee on Risk Assessment of Sensitive Populations evaluated key references in the area of pediatric risk to identify a spectrum of methodological approaches. These approaches are considered in this article for their potential to be extrapolated for the identification and assessment of other sensitive populations. Recommendations as to future research needs and/or alternate methodological considerations are also made.

To predict important strategic issues in product safety during the next 10 years, the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute initiated a mapping exercise to evaluate which issues are likely to be of societal, scientific, and regulatory importance to regulatory authorities, the HESI membership, and the scientific community at large. Scientists representing government, academia, and industry participated in the exercise. Societal issues identified include sensitive populations, alternative therapies, public education on the precautionary principle, obesity, and aging world populations. Scientific issues identified include cancer testing, children's health, mixtures and co-exposures, sensitive populations, idiosyncratic reactions, "omics" or bioinformatics, and environmental toxicology. Regulatory issues identified include national and regional legislation on chemical safety, exposure inputs, new technologies, transitioning new science into regulations and guidelines, conservative default factors, data quality, and sensitive populations. Because some issues were identified as important in all three areas (e.g. sensitive populations), a comprehensive approach to assessment and management is needed to ensure consideration of societal, scientific, and regulatory implications. The resulting HESI Combined Challenges Map is not intended to offer a universal description of challenges in safety assessment, nor is it intended to address, advocate, or manage the prioritized issues. Rather, the map focuses on and predicts issues likely to be central to the strategic agendas of individual companies and regulatory authorities in the developed world. Many of these issues will become increasingly important in the future in rapidly developing economies, such as India and China. The scientific mapping exercise has particular value to the toxicology community because it represents the contributions of key scientists from around the world from government, academia, and industry.

Imaging studies that use ionizing radiation are an essential tool for the evaluation of many disorders of childhood. Ionizing radiation is used in radiography, fluoroscopy, angiography, and computed tomography scanning. Computed tomography is of particular interest because of its relatively high radiation dose and wide use. Consensus statements on radiation risk suggest that it is reasonable to act on the assumption that low-level radiation may have a small risk of causing cancer. The medical community should seek ways to decrease radiation exposure by using radiation doses as low as reasonably achievable and by performing these studies only when necessary. There is wide agreement that the benefits of an indicated computed tomography scan far outweigh the risks. Pediatric health care professionals’ roles in the use of computed tomography on children include deciding when a computed tomography scan is necessary and discussing the risk with patients and families. Radiologists should be a source of consultation when forming imaging strategies and should create specific protocols with scanning techniques optimized for pediatric patients. Families and patients should be encouraged to ask questions about the risks and benefits of computed tomography scanning. The information in this report is provided to aid in decision-making and discussions with the health care team, patients, and families.

Industry and government institutions need a credible approach for evaluating and responding to emerging public health issues. Representatives of industry, government, and academia met under the auspices of the International Life Sciences Institute's Health and Environmental Sciences Institute (HESI) to develop successful strategies for dealing with emerging issues based on historical case studies. The case studies chosen for evaluation were (1) tampon use and toxic shock syndrome; (2) hazardous waste and childhood cancer risk in Toms River, New Jersey; (3) fenfluramine and phentermine use and valvular heart disease; (4) silicone breast implants and cancer and auto-immune disease; and (5) progestational drugs and birth defects. We identified eight lessons from these case studies. Foremost, we recommend that public and private institutions not defer action until an issue is scientifically resolved and stress that cooperation among issue stakeholders is critical for effective issue resolution. We suggest establishing a research program as an effective way to assure that good science is included in resolution of the issue. We further recommend frequent and timely communication with all stakeholders, and the development of research approaches to fill gaps when the scientific data on an issue are limited.

There is no convincing evidence of germline mutation manifest as heritable disease in the offspring of humans attributable to ionizing radiation, yet radiation clearly induces mutations in microbes and somatic cells of rodents and humans. Doses to the embryo estimated to be in the range of 0.15-0.2 Gy during the pre-implantation and pre-somite stages may increase the risk of embryonic loss. However, an increased risk of congenital malformations or growth retardation has not been observed in the surviving embryos. These results are primarily derived from mammalian animal studies and are referred to as the "all-or-none phenomenon." The tissue reaction effects of ionizing radiation (previously referred to as deterministic effects) are congenital malformations, mental retardation, decreased intelligence quotient, microcephaly, neurobehavioral effects, convulsive disorders, growth retardation (height and weight), and embryonic and fetal death (miscarriage, stillbirth). All these effects are consistent with having a threshold dose below which there is no increased risk. The risk of cancer in offspring that have been exposed to diagnostic x-ray procedures while in utero has been debated for 55 y. High doses to the embryo or fetus (e.g., >0.5 Gy) increase the risk of cancer. Most pregnant women exposed to x-ray procedures and other forms of ionizing radiation today received doses to the embryo or fetus

I am pleased to respond to the request of the editors of Pediatrics to comment on the special article entitled the “ Daubert Opinion Requires Judges to Screen Scientific Evidence.”1 My understanding of the purpose of publishing a discussion of the implications of the Daubert decision by knowledgeable attorneys is the hope that their article would be helpful to pediatricians and their attorneys if they were personally involved in a lawsuit. The most important aspect of the special article by Sartore and van Doren1 pertains to the implications of the Daubert decision. They stated the following: “Under Daubert , a court must first make a ‘preliminary assessment of whether the reasoning or methodology underlying the testimony is scientifically valid and of whether that reasoning or methodology properly can be applied to the facts in issue.’ The Daubert court identified the following factors that, although not mandated or exclusive, might be helpful to a court's inquiry: 1. whether the scientific knowledge either can be or has been tested; 2. whether the ‘theory or technique has been subjected to peer review and publication’; 3. whether the technique has a ‘known or potential rate of error’; and 4. whether there is ‘general acceptance’ of the scientific technique.” The court's focus of the inquiry must be solely on principles and methodology, not on the conclusions that they generate. My simplistic interpretation of the Daubert decision is as follows: the court (judge) can reject the testimony of an expert if the scientific methodology used by the expert witness as the basis of the expert opinion is not accepted by the scientific community. However, the court must accept the opinion of an expert if the methodology of the expert is acceptable even if the court may not consider the expert's opinion to be scientifically correct. If the litigants … Address correspondence to Robert Brent, MD, PhD, DSc, duPont Hospital for Children, Room 306, A/R Building, PO Box 269, Wilmington, DE 19899. E-mail: rbrent{at}nemours.org

Health physicists and knowledgeable clinicians have the responsibility to counsel women of reproductive age about the reproductive risks of ionizing radiation exposure before conception or during pregnancy. It is important to realize that lay individuals have many misconceptions about the reproductive risks of ionizing radiation. Many patients who have already had or will undergo some type of radiological test are apprehensive about the reproductive and developmental risks of diagnostic radiological procedures. Epidemiological studies and animal studies indicate that high exposures of ionizing radiation can cause miscarriage, congenital malformations, growth retardation, stillbirth, and cancer. With the exception of cancer, there are threshold exposures for those outcomes, with exposures below certain radiation doses not increasing the reproductive or developmental risks. The threshold exposure for birth defects at the most sensitive stage of development is 0.2 Gy, and the threshold for growth retardation and miscarriage is even higher. However, embryonic loss can occur from low exposures during the preimplantation and presomite stages of development ("the all or none period"). This is a stage when the embryo is more likely to die than survive malformed. The most sensitive period for the induction of mental retardation is from the 8th week to the 15th week of gestation. The threshold for deterministic effects increases after early organogenesis and also as the exposure is protracted, e.g., with radionuclides or multiple radiological procedures. Awareness that the threshold dose for developmental effects increases as the fetus develops complicates counseling because we do not have definitive data on threshold exposures at all stages of gestation. Ionizing radiation exposures prior to pregnancy represent a very low risk for the increased incidence of genetic disease in the offspring of the parents who have had radiation exposures to the ovary or testes. Counseling patients requires knowledge of embryology, genetics, radiation teratology, and the principles of teratology in order for the counselor to provide sympathetic, accurate, scholarly advice.

The medical, social and legal risks of immunizing pregnant women are obstacles preventing the initiation of programs to immunize women for their protection and for their infant's protection. Recent projects devoted to vaccine development have focused on protecting newborns and infants. But there are many other reasons for developing or utilizing vaccines before or during pregnancy, beyond the protection of the newborn. Besides the usual reasons for utilizing immunizations to protect the mother and the neonate, the threat of bio-terrorism adds a new dimension to the necessity for addressing this issue. The potential advantages for thinking about vaccinating pregnant women include an array of possible programs associated with risks and benefits. The immunization of pregnant women or women of reproductive age has multiple purposes: to protect the mother, to protect the newborn and infant and to prevent diseases and complications of pregnancy. (1) Preparation of vaccines against infectious agents that are known to result in reproductive pathology and congenital malformation if the infection of the mother occurs during pregnancy. (2) To utilize vaccines used routinely to protect the non-pregnant population, for administration during pregnancy, i.e., influenza, tetanus and other vaccines. Should these vaccines and other routinely used vaccines for children and non-pregnant adults be administered to women during pregnancy if they are medically indicated? (3) Utilization of vaccines to protect women from diseases to which they are susceptible because of pregnancy (poliomyelitis, hepatitis). (4) Utilization of vaccines for use before or during pregnancy, primarily to protect the newborn and infant via maternal transplacental antibodies, i.e., GBD (group B streptococcus). (5) The prevention of intrauterine infection that has been alleged to initiate premature labor. (6) The preparation of a vaccine for use before or during pregnancy to protect both the mother and the neonate, i.e., botulism toxin vaccine. The regulatory agencies and the vaccine producers will need a great deal of objective scientific advice and support and it is the scientific community's responsibility to provide that support. If the scientific and medical community ignores the opportunity to develop vaccines that could reduce the occurrence of reproductive and developmental problems, then we can be accused of acquiescing to the "risk of doing nothing."

Significant numbers of therapeutic abortions are performed for radiation-exposed pregnant women because of concerns about the teratogenic risk. However, available data suggest that current diagnostic radiation procedures are not teratogenic.

In the late 1960s and 1970s, a number of epidemiological studies were published indicating that pregnant women who were exposed to an array of sex steroids delivered infants with an increased incidence of nongenital congenital malformations. Because of these publications, the Food and Drug Administration (FDA), in conjunction with various pharmaceutical companies, labeled the therapeutic exposure of progestational drugs and contraceptives in pregnant women as a risk factor for limb-reduction defects (LRDs) and congenital heart defects (CHDs). Subsequently there was a rapid decrease in the exposure of pregnant women to these drugs and the initiation of numerous lawsuits alleging that a particular progestational drug was responsible for a child's nongenital congenital malformation. Wilson and Brent (1981) published an article indicating that epidemiological and animal studies of these drugs, and basic science did not support the package insert's warnings. Many new and previous animal and epidemiological studies did not support the FDA box warning. In 1987 the FDA held a hearing in which the FDA, the Teratology Society, the Centers for Disease Control and Prevention, the American College of Obstetrics and Gynecology, and other organizations supported the position that progestational agents did not result in nongenital malformations. An editorial appeared in Teratology congratulating the FDA for removing the warning label on oral contraceptives regarding nongenital malformations. In 1999 the FDA published new wording for package inserts that removed warnings for nongenital malformations for all progestational agents. In spite of the recent changes in the package inserts, lawsuits have alleged that progestational drugs cause nongenital malformations. It took 22 years from the time a box warning was required by the FDA until the warnings were removed in 1999. The 1999 FDA publication, which is a scholarly and objective document, should put an end to 2 decades of concern and anxiety for pregnant women or women of reproductive age. Could scientists, the pharmaceutical companies, or the FDA have prevented the mislabeling of progestational drugs with regard to their teratogenic risks? Was the epidemiological or teratology community at fault because they did not critique and respond to the early publications? Did the FDA act too slowly? The epidemiologic analyses, animal studies, and basic science principles have been reviewed, and it is obvious that clinically utilized progestational drugs do not cause nongenital malformations (i.e., LRDs and CHDs).

In the preface1 to this supplement, we pointed out that pediatricians and other clinicians have made major contributions to the discovery of environmental toxicants. Many acute illnesses that are caused by high exposures to some toxicants are clinically diagnosable or at least are commonly in the differential diagnosis, eg, organophosphate poisoning, infant botulism, acute lead encephalopathy, carbon monoxide poisoning, acrodynia, hypervitaminosis A and some cases of aplastic anemia, convulsions, asthma, respiratory distress, methemoglobinemia, Reyes syndrome, kernicterus, and many of the recognizable syndromes that result from exposures to teratogenic drugs and chemicals. In contrast to the obvious effects of high exposures to environmental toxicants, there is less information and less certainty concerning the magnitude of the contribution of many low exposures of environmental toxicants to morbidity, mortality, and subtle alterations in children as well as adults or how the effects of these exposures vary with age or chronicity of exposure. We also informed the readership that we were going to address the issue of environmental toxicology from both a clinical and a toxicologic viewpoint. Very low exposures to environmental toxicants may lead to diseases that resemble many common illnesses that have other causes, or they may lead to decrements in functioning that are subtle or nonspecific. It is an almost insurmountable task for individual practitioners to conclude a cause-and-effect relationship from low exposures to environmental toxicants among patients in the physician’s patient population. Only well-planned, sophisticated epidemiologic and animal studies can answer the questions that pertain to the toxicity of low-level exposures to environmental toxicants, given that not all individuals will be affected equally, if at all, at any particular level of exposure. Many of the previous multi-authored compendia that have been published by groups of scientists have been unified in their conclusions that environmental toxicants are a very serious … Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail rbrent{at}nemours.org

There have been amazing advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years that have provided scientists and clinicians with a better perspective on the causes of congenital malformations. We still cannot provide the families of children with malformations a definitive diagnosis and cause in every instance. The purpose of this article is to inform pediatricians about environmental drugs, chemicals, and physical agents that have been documented to produce congenital malformations and reproductive effects and to indicate that the multitude of teratogenic agents account for only a small proportion of malformations. The most common known cause is genetic, but the largest group, unfortunately, There have been amazing advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years that have provided scientists and clinicians with a better perspective on the causes of congenital malformations. We still cannot provide the families of children with malformations a definitive diagnosis and cause in every instance. The purpose of this article is to inform pediatricians about environmental drugs, chemicals, and physical agents that have been documented to produce congenital malformations and reproductive effects and to indicate that the multitude of teratogenic agents account for only a small proportion of malformations. The most common known cause is genetic, but the largest group, unfortunately, is unknown. There are a number of important clinical rules that are important for clinicians to use when determining the cause of their patient's congenital malformations: 1. No teratogenic agent should be described qualitatively as a teratogen, because a teratogenic exposure includes not only the agent but also the dose and the time in pregnancy when the exposure has to occur. 2. Even agents that have been demonstrated to result in malformations cannot produce every type of malformation. Known teratogens may be presumptively implicated by the spectrum of malformations that they produce. It is easier to exclude an agent as a cause of birth defects than to conclude definitively that it was responsible for birth defects, because of the existence of genocopies of some teratogenic syndromes. 3. When evaluating the risk of exposures, the dose is a crucial component in determining the risk. Teratogenic agents follow a toxicologic dose-response curve. This means that each teratogen has a threshold dose below which there is no risk of teratogenesis, no matter when in pregnancy the exposure occurred. 4. The evaluation of a child with congenital malformations cannot be performed adequately unless it is approached with the same scholarship and intensity as the evaluation of any other complicated medical problem. 5. Each physician must recognize the consequences of providing erroneous reproductive risks to pregnant women who are exposed to drugs and chemicals during pregnancy or alleging that a child's malformations are attributable to an environmental agent without performing a complete and scholarly evaluation. 6. Unfortunately, clinical teratology and clinical genetics is not emphasized in medical school and residency education programs, but pediatricians have a multitude of educational aids to assist them in their evaluations, which includes consultations with clinical teratologists and geneticists, the medical literature, and the OMIM web site.

Toxicology studies using animals and in vitro cellular or tissue preparations have been used to study the toxic effects and mechanism of action of drugs and chemicals and to determine the effective and safe dose of drugs in humans and the risk of toxicity from chemical exposures. Studies in pregnant animals are used to determine the risk of birth defects and other reproductive effects. There is no question that whole animal teratology studies are helpful in raising concerns about the reproductive effects of drugs and chemicals, but negative animal studies do not guarantee that these agents are free from reproductive effects. There are examples in which drug testing was negative in animals (rat and mouse) but was teratogenic in the human (thalidomide), and there are examples in which a drug was teratogenic in an animal model but not in the human (diflunisal). Testing in animals could be improved if animal dosing using the mg/kg basis were abandoned and drugs and chemicals were administered to achieve pharmacokinetically equivalent serum levels in the animal and the human. Because most human teratogens have been discovered by alert physicians or epidemiology studies, not animal studies, animal studies play a minor role in discovering teratogens. In vitro studies play an even less important role, although they are helpful in describing the cellular or tissue effects of the drugs or chemicals. One cannot determine the magnitude of human risks from these in vitro studies. Performing toxicology studies on adult animals is performed by pharmaceutical companies, chemical companies, the Food and Drug Administration, many laboratories at the National Institutes of Health, and scientific investigators in laboratories throughout the world. Although a vast amount of animal toxicology studies are performed on pregnant animals and numerous toxicology studies are performed on adult animals, there is a paucity of animal studies using newborn, infant, and juvenile animals. This deficiency is compounded by the fact that there are very few toxicology studies performed in children. That is why pregnant women and children are referred to as “therapeutic orphans.” When animal studies are performed with newborn and developing animals, the results demonstrate that generalizations are less applicable and less predictable than the toxicology studies in pregnant animals. Although many studies reveal that the infant and the developing animal have difficulty in metabolizing drugs and are more vulnerable to the toxic effects of environmental chemicals, there are exceptions that indicate that infant and developing animals may be less vulnerable and more resilient to some drugs and chemicals. In other words, the generalization indicating that developing animals are always more sensitive to environmental toxicants is not valid. For animal toxicology studies to be useful, animal studies have to use modern concepts of pharmacokinetics and toxicokinetics, as well as method-of-action studies to determine whether animal data can be used for determining human risk. One example is the inability to determine carcinogenic risks in humans for some drugs and chemicals that produce tumors in rodents, because the oncogenesis is the result of peroxisome proliferation, a reaction that is of diminished importance in humans. Scientists can use animal studies to study the toxicokinetic and toxicodynamic aspects of environmental toxicants, but they have to be performed with the most modern techniques and interpreted with the highest level of scholarship and objectivity. Threshold exposures, maximum permissible exposures, and toxic effects can be estimated but have to be interpreted with caution when applying them to the human. Well-performed epidemiology studies are still the best method for determining the human risk and the effects of environmental toxicants.

There is realistic concern about the impact of environmental influences on the health of human populations. First, exposure to environmental agents continues despite successes in reducing exposures to known toxicants such as lead, polychlorinated biphenyls (PCBs) and tobacco smoke. Second, there has been increasing concern about the cause of autism and other neurodevelopmental problems and hypotheses that environmental influences may play a role in the prevalence of these and other such childhood and adult conditions as asthma and obesity. Third, many other conditions are directly or indirectly related to environmental influences and are preventable, such as injuries, untoward consequences of alcohol, suicide, drug addiction, and gun-related deaths. There have been numerous publications since the 1970s of symposia, proceedings, monographs, and articles dealing with the increased susceptibility of the embryo, infant, and child to environmental toxicants,1–17 reflecting a greater level of concern about embryonic and childhood exposures. Indeed, great deal of attention has been paid to the vulnerability of the embryo and the fetus to environmental chemicals, drugs, and physical agents. In fact, the publication edited by Miller1 was primarily devoted to exposures to the embryo and the fetus. Because the embryo and the child are growing and their tissues and organs are differentiating, deleterious effects may occur at lower exposures to some chemicals, drugs, and physical agents and produce more severe effects than those seen in adults. In fact, some effects may not occur in adults. Thus, maximal permissible exposures (MPEs) for some environmental chemicals should be lower for the embryo and the child. It is important to note that children and adolescents have better recuperative capacities than adults for many toxic agents, and, similarly, appropriate drug dosages may be lower or higher on a mg/kg or surface area basis in children than in adults to … Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail: rbrent{at}nemours.org

Pediatricians are fully aware of the major environmental causes of observable childhood morbidity and mortality (Table 1). It is also important for pediatricians to be aware of the variety of parental concerns regarding exposures to environmental chemicals. During their training and practice, one of their tasks is to counsel and educate parents on how to reduce or prevent the more common environmental risks (Table 1), but they have to be knowledgeable about the presence of environmental chemical and physical toxicants and the emerging literature on potential effects of low-level exposures of these agents to answer patients’ questions and provide reassurance or warnings about the valid risks of some of these toxicants. This article focuses on areas of counseling for which the pediatrician can feel assured that we have sufficient information so that attention to these issues and concerns will improve child health. Some of the material in this article can be found in more detail in the excellent Handbook of Pediatric Environmental Health .1 We have also used a format for categorizing children’s environmental risks in various age categories that was used by Napier2 in Chapter 13 of Juberg’s text on environmental chemicals.2 View this table: TABLE 1. Leading Causes of Death for Different Age Groups There has been some very good news concerning population exposures to environmental toxicants published by the Centers for Disease Control and Prevention (CDC) in 2003.3 The report indicated that there has been “encouraging signs that levels of lead, pesticides, and other chemicals in the body generally have declined over the past decade or so.”3 The report included 27 substances that included lead, mercury, cadmium, other metals, metabolites of organophosphorous pesticides, cotinine, phthalates, polycyclic aromatic hydrocarbons, dioxins, furans, coplanar polychlorinated biphenyls, noncoplanar polychlorinated biphenyls, phytoestrogens, selected organophosphate pesticides, carbamate pesticides, herbicides, pest repellants, and disinfectants. … Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail rbrent{at}nemours.org

Severe ovarian hyperstimulation syndrome (OHSS) affects 2–4% of in vitro fertilization (IVF) patients, which may rarely result in an ischemic stroke secondary to a hypercoagulable state. We describe a case of a 38-year-old IVF patient who developed early-onset OHSS with a viable pregnancy who presented at 18 days post embryo transfer with an ischemic stroke resulting from a thrombus in the right middle cerebral artery. As the use of recombinant tissue plasminogen activator was relatively contraindicated owing to a recent intra-abdominal drain placement, a radiologically guided thrombectomy was performed. This resulted in neurological improvement in the mother and the birth of a normal term infant, without significant ionizing effects to the developing embryo.

Establishing successful vaccine programs for pregnant women would be the quintessence of preventive medicine when you realize the preventive potential for reproductive problems of many of the new and old vaccines. The development of vaccines to prevent maternal, fetal and newborn disease is actually in its infancy. The risks and benefits are discussed in detail as well as the most appropriate and inappropriate time to immunize women of reproductive age and pregnant women. The great majority of risks are theoretical, but the problem is that birth defects and other developmental and reproductive problems are in the group of "diseases of affliction" which means that there are tremendous emotional upheavals in families affected with serious reproductive problems. The failures in reproduction are so common that immunization of a pregnant women has potential deleterious consequences. A consortium of government, academia and industry must work together and an appeal to the more responsible members of the law profession to solve the problem of non-meritorious litigation has be in place before manufacturers of vaccines will be willing to initiate the development of new vaccines. The potential for reducing the incidence of birth defects, prematurity and neonatal infectious disease exists, but it will be difficult to initiate these programs because vaccine makers may be unwilling to assume an additional burden of negligence litigation. Certainly, it is clear that we could provide a safe vaccine for Group B streptococcus and infant botulism that would be of immediate benefit and the potential for reducing other diseases is realistic. This is not going to be an easy task.

The study published in this issue of Birth Defects Research Part A, “Bendectin and Birth Defects: Ecological Analysis,” by Kutcher et al. (2002) deals with two aspects pertaining to the effects of Bendectin. It is an excellent research article. The first area investigated was related to the question as to whether Bendectin was a human teratogen based on ecological analysis. The second area investigated was whether admissions to the hospital for intractable nausea and vomiting of pregnancy increased after the withdrawal of Bendectin from the market. The evaluation of the merits of the allegation as to whether Bendectin represents any reproductive risks has been reported in review articles in the teratology and legal literature (Brent, 1995a, 1997) utilizing a methodology that has been described previously (Brent, 1978, 1985c, 1986). This evaluative process has been utilized on several occasions for other drugs, chemicals and physical agents (Brent et al., 1991, 1992, 1993, 1995a, 1997, 1999a; Brent et al., 1991, 1993; Christian and Brent, 2001). The method of evaluation is listed in Table 1 and consists of five components of the evaluation process, which include 1) consistency of epidemiological studies, 2) secular trend analysis, 3) animal studies, 4) toxicokinetics and pharmacokinetics, and 5) basic science principles. Kutcher et al. (2002) focused on two aspects of the Bendectin saga in their article: 1) ecological analysis, and 2) the impact of the withdrawal of Bendectin from the market on the treatment of nausea and vomiting and the clinical effects of the withdrawal of Bendectin from the market place.

Background and Methods The purpose of this annual article is to highlight and briefly review new and significant information on agents that may be teratogenic in pregnant women. Various sources of on-line and printed information are given. Results The following topics have been discussed: 1) lithium medication: decreased estimate of risk; 2) cigarette smoking and genotype as contributors to oral-facial clefts and clubfoot; 3) trimethoprim; 4) methimazole syndrome?; 5) glucocorticoids and oral-facial clefts; 6) binge drinking; 7) fetal valproate syndrome; and 8) carbamazepine. Conclusions We have highlighted several maternal exposures during pregnancy that are associated with small but increased rates of birth defects, generally only a few cases per 1,000 infants. These exposures include cigarette smoking, and treatment with lithium, trimethoprim, methimazole, or corticosteroids. This weak teratogenic effect was usually identified by the linkage of an uncommon treatment with an unusual birth defect outcome. The use of modern epidemiologic techniques, especially prospective multicenter studies that provide increased numbers, has helped to strengthen the evidence for these associations. We discuss how teratogenic risks that are small in comparison to the background risk can be presented to at-risk women and their doctors. We have briefly listed some elements that might be used in prioritizing further studies of suspected teratogenic exposures. Various existing methods for expressing the strength of evidence for human teratogenicity are also given. Teratology 65:153–161, 2002. © 2002 Wiley-Liss, Inc.

Objective We analyzed the perinatal risks of midwife-attended planned home births in the United States from 2010 through 2012 and compared them with recommendations from the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) for planned home births. Study Design Data from the US Centers for Disease Control and Prevention's National Center for Health Statistics birth certificate data files from 2010 through 2012 were utilized to analyze the frequency of certain perinatal risk factors that were associated with planned midwife-attended home births in the United States and compare them with deliveries performed in the hospital by certified nurse midwives. Home birth deliveries attended by others were excluded; only planned home births attended by midwives were included. Hospital deliveries attended by certified nurse midwives served as the reference. Perinatal risk factors were those established by ACOG and AAP. Results Midwife-attended planned home births in the United States had the following risk factors: breech presentation, 0.74% (odds ratio [OR], 3.19; 95% confidence interval [CI], 2.87–3.56); prior cesarean delivery, 4.4% (OR, 2.08; 95% CI, 2.0–2.17); twins, 0.64% (OR, 2.06; 95% CI, 1.84–2.31); and gestational age 41 weeks or longer, 28.19% (OR, 1.71; 95% CI, 1.68–1.74). All 4 perinatal risk factors were significantly higher among midwife-attended planned home births when compared with certified nurse midwives–attended hospital births, and 3 of 4 perinatal risk factors were significantly higher in planned home births attended by non–American Midwifery Certification Board (AMCB)–certified midwives (other midwives) when compared with home births attended by certified nurse midwives. Among midwife-attended planned home births, 65.7% of midwives did not meet the ACOG and AAP recommendations for certification by the American Midwifery Certification Board. Conclusion At least 30% of midwife-attended planned home births are not low risk and not within clinical criteria set by ACOG and AAP, and 65.7% of planned home births in the United States are attended by non-AMCB certified midwives, even though both AAP and ACOG state that only AMCB-certified midwives should attend home births.

The risk of cancer in offspring who have been exposed to diagnostic X-ray procedures while in utero has been debated for 55 years. High doses at high dose rates to the embryo or fetus (e.g. >0.5 Gy) increase the risk of cancer. This has been demonstrated in human epidemiology studies as well as in mammalian animal studies. Most pregnant women exposed to diagnostic X-ray procedures or the diagnostic use of radionuclides receive doses to the embryo or fetus

1. Robert L. Brent, MD, PhD, DSc* 1. 2. *Distinguished Professor of Pediatrics, Radiology, and Pathology, Anatomy, and Cell Biology; Louis and Bess Stein Professor of Pediatrics; Emeritus Chairman, Department of Pediatrics, Jefferson Medical College, Philadelphia, PA; Head, Laboratory of Clinical and Environmental Teratology, Research Department, Alfred I. DuPont Hospital for Children, Wilmington, DE. Objectives After completing this article, readers should be able to: 1. List the environmental drugs, chemicals, and physical agents that have been documented to result in congenital malformations and have reproductive effects. 2. List the requirements for a teratogenic exposure. 3. Describe the importance of dose when evaluating the risk of exposures. 4. Describe the most important advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years. When I was a medical student at the University of Rochester, I was fortunate to have James G. Wilson, an embryologist, as one of my teachers in the anatomy course. He was working on the effects of radiation on the embryo, which is how I became interested in congenital malformations. Many of the faculty members discouraged me from pursuing the study of the causes of birth defects as an academic goal, “Because we are never going to solve that problem.” In 1955, when I had completed medical school and graduate school, the scientific world did not even have the correct figure for the number of human chromosomes. Gregg had recently described the teratogenicity of rubella virus infection during pregnancy. The teratogenic risk of the folic acid antagonists was established, and there were experimental studies indicating that nutritional deficiencies could produce birth defects in animals. What have we learned and accomplished in the past 50 years? Thousands of previously unknown genetic diseases have been described, and many of their genes have been identified. The fields of prenatal intrauterine diagnoses, intervention, and treatment have been created. Metabolic and biochemical screening have become standard care for pregnant women and newborns. More than 50 teratogenic environmental drugs, chemicals, and physical agents have been described by using modern epidemiologic tools and the superb talents of clinical dysmorphologists. The basic science and clinical rules for evaluating teratogenic risks have …

This review article dealig with the subject of “The Cause and Prevention of Human Birth Defects” was prepared in celebration of the 40th anniversary of the Japanese Teratology Society. It begins with recollections of some of the important contributions of Japanese scientists in the fields of teratology and embryology and a summary of the many scientific and medical accomplishments of the past 50 years in the fields of teratology, genetics, developmental biology, epidemiology and genetics. The review includes a summary of the drugs, chemicals and physical agents that have been documented to result in congenital malformations and reproductive effects when pregnant women are exposed during pregnancy. The principles of teratology were also summarized and emphasize that 1) no teratogenic agent can be described qualitatively as a teratogen, since a teratogenic exposure must include not only the agent, but also the dose and the time in pregnancy when the exposure occurs. 2) Even agents that have been demonstrated to result in malformatins cannot produce every type of malformation. 3) Known teratogens can be presumptively identified by the spectrum of malformations they produce. 4) It is easier to exclude an agent as a cause of birth defects than to definitively conclude that it was responsible for birth defects. 5) When evaluating the risk of exposures, the dose is a crucial component in determining the risk. 6) Teratogenic agents follow a toxicological dose response curve. This means that each teratogen has a threshold dose, below which, there is no risk of teratogenensis, no matter when in pregnancy the exposure occurred. 7) The evaluation of a child with congenital malformations connot be adequately performed unless it is approached with the same scholarship and detail, as is any other complicated medical problem. 8) Each physician must recognize the consequences of providing erroneous reproductive risks to pregnant women exposed to drugs and chemicals during pregnancy or alleging that a child's malformations are due to an environmental agent without performing a complete and scholarly evaluation.

Arava™ (leflunomide) is a pyrimidine synthesis inhibitor used in the treatment of active rheumatoid arthritis (RA). The chemical name for leflunomide is N-(49-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. Because the drug has been successful in the treatment of rheumatoid arthritis, it is being widely prescribed. In spite of the clear warning that the drug should not be prescribed for pregnant women, approximately 30 women have become pregnant while taking leflunomide as of December 1999. This commentary was prepared to aid teratology counselors and genetic counselors who might be contacted by physicians or patients about the risk of leflunomide exposure during pregnancy. Before the subject of risk is discussed, it is important to understand the results of preclinical testing, phamacokinetic studies, and clinical studies that are available.

In our target article we showed that the Letter of Concern (LoC) fails to meet accepted standards for presenting empirical data for the purpose of supplementing a normative claim and for argument-b...

Birth defects are an urgent global health priority. They affect millions of births worldwide. But their prevalence and impact are largely under-ascertained, particularly in middle- and low-income countries. Fortunately, a large proportion of birth defects can be prevented. This review examines the global prevalence and primary prevention methods for major preventable birth defects: congenital rubella syndrome, folic acid-preventable spina bifida and anencephaly, fetal alcohol syndrome, Down syndrome, rhesus hemolytic disease of the fetus and the newborn; and those associated with maternal diabetes, and maternal exposure to valproic acid or iodine deficiency during pregnancy. Challenges to prevention efforts are reviewed. The aim of this review is to bring to the forefront the urgency of birth defects prevention, surveillance, and prenatal screening and counseling; and to help public health practitioners develop population-based birth defects surveillance and prevention programs, and policy-makers to develop and implement science-based public health policies.

Background: Heterologous antiserum to the visceral yolk sac (AVYS) is teratogenic, inducing a spectrum of malformations in vivo and producing similar effects in vitro. Numerous studies support the concept that AVYS-induced malformations result from embryonic nutritional deficiency, without affecting the maternal nutritional status. This has provided a useful model with which to investigate the nutritional requirements of the early embryo, as well as the role of various nutrients in the etiology of congenital defects. Methods: In the current investigation, we examined the effects of methionine and other nutrients on AVYS-induced embryotoxicity in vitro. For these experiments, we cultured rat embryos (9.5 p.c) for 48 hr with AVYS and/or methionine at several concentration levels. Results: The addition of L-methionine to AVYS-exposed cultures reduced dysmorphology and open neural tube; this effect was concentration dependent. AVYS-induced dysmorphology was completely prevented at a concentration of L-methionine corresponding to 50-fold the basal serum concentration. Utilization of methionine, L-leucine, or folic acid (5-methyltetrahydrofolate, MTHF) instead of L-methionine had no protective effects. Conclusions: These results suggest that, although AVYS limits the supply of all amino acids to the embryo, embryopathy largely results from a deficiency of methionine. Furthermore, although endocytosis and degradation of proteins by the VYS supplies most amino acids to the embryo, free amino acids may be compensatory when this source is reduced. These results support those of previous investigations that suggest methionine is required for normal NT closure and that methionine is a limiting nutrient for embryonic development.