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Nutritional approaches to optimize cattle health and performance during the receiving period are warranted. This experiment evaluated the impacts of supplementing organic complexed Cu, Co, Mn, and Zn on productive and health responses of high-risk beef cattle during a 60-day backgrounding phase. Crossbred steers (120) were purchased at auction and transported to the experimental facility, where BW was recorded (day-1; initial shrunk BW = 227.7 ± 1.3 kg). On day 0, steers were ranked by BW and allocated to one of eight groups and housed in drylot pens equipped with GrowSafe automated feeding systems (Model 8000; two bunks/pen). Groups were randomly assigned to receive a total mixed ration containing: (1) sulfate sources of Cu, Co, Mn, and Zn (INR; n = 40); (2) organic complexed sources of the same minerals (AAC; Zinpro Availa 4 based on a metal:amino acid complex ratio of 1:1 for Zn, Cu, and Mn in addition to cobalt glucoheptonate; Zinpro Corp., Eden Prairie, MN; n = 40); or (3) AAC and an organic complexed trace mineral drench (APF; 30 mL/hd; Zinpro ProFusion, Zinpro Corp.) on day 0 and with morbidity treatment (n = 40). Diets provided the same daily amount of all nutrients and minerals based on 7 g/steer daily of Zinpro Availa 4. Steers were assessed for bovine respiratory disease (BRD) signs daily. Liver biopsies were performed on days 0, 28 and 60. Blood samples were collected on days 0, 2, 6, 10, 13, 21, 28 and 45. No treatment differences were detected (P ≥ 0.23) for feed intake, final BW, average daily gain, or BRD incidence. Mean liver Co concentrations were greater (P = 0.02) in AAC and APF compared to INR steers. Mean liver Cu was greater (P = 0.02) in APF compared to AAC steers. Liver Zn tended to be greater (P = 0.10) on day 28 but less (P = 0.05) on day 60 for INR compared to AAC and APF steers. Plasma cortisol was lowest (P = 0.05) for AAC steers on day 6, whereas AAC steers tended to have greater (P = 0.09) plasma cortisol on day 13 compared with APF. Plasma haptoglobin tended to be greater (P ≤ 0.10) for INR steers on days 28 and 45 compared to AAC and APF. While supplementing cattle with AAC or INR results in similar animal performance and clinical disease, AAC and APF reduce stress and acute phase protein responses., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

One of the ten greatest public health achievements is childhood vaccination because of its impact on controlling and eliminating vaccine-preventable diseases (VPDs). Evidence-based immunization policies and practices are responsible for this success and are supported by epidemiology that has generated scientific evidence for informing policy and practice. The purpose of this report is to highlight the role of epidemiology in the development of immunization policy and successful intervention in public health practice that has resulted in a measurable public health impact: the control and elimination of VPDs in the United States. Examples in which epidemiology informed immunization policy were collected from a literature review and consultation with experts who have been working in this field for the past 30 years. Epidemiologic examples (e.g., thimerosal-containing vaccines and the alleged association between the measles, mumps, and rubella (MMR) vaccine and autism) are presented to describe challenges that epidemiologists have addressed. Finally, we describe ongoing challenges to the nation's ability to sustain high vaccination coverage, particularly with concerns about vaccine safety and effectiveness, increasing use of religious and philosophical belief exemptions to vaccination, and vaccine hesitancy. Learning from past and current experiences may help epidemiologists anticipate and address current and future challenges to respond to emerging infectious diseases, such as COVID-19, with new vaccines and enhance the public health impact of immunization programs for years to come., (Copyright © 2020. Published by Elsevier Inc.)

In the early stage of the intestinal phase of Trichinella spiralis infection, the host triggers a Th1-type immune response with the aim of eliminating the parasite. However, this response damages the host which favours the survival of the parasite. In the search for novel pharmacological strategies that inhibit the Th1 immune response and assist the host against T. spiralis infection, a recent study showed that resiniferatoxin had anti-inflammatory activity contributed to the host in T. spiralis infection. In this study, we evaluated whether RTX modulates the host immune response through the inhibition of Th1 cytokines in the intestinal phase. In addition, it was determined whether the treatment with RTX affects the infectivity of T. spiralis-L1 and the development of the T. spiralis life cycle. Our results show that RTX decreased serum levels of IL-12, INF-γ, IL-1β, TNF-α and parasite burden on muscle tissue. It was observed that T. spiralis-L1 treated with RTX decreased their infectivity affecting the development of the T. spiralis life cycle in mouse. These results demonstrate that RTX is able to inhibit the production of Th1 cytokines, contributing to the defence against T. spiralis, which places it as a potential drug modulator of the immune response., (© 2017 John Wiley & Sons Ltd.)

Caffeine is known to activate influx of both mono- and divalent cations in various cell types, suggesting that this xanthine opens non-selective cation channels at the plasma membrane. This possibility was investigated in human erythrocytes, studying the caffeine action on net Ca(2+), Na(+) and K(+) movements in ATP-depleted cells. Whole populations and subpopulations of young and old erythrocytes were employed. Caffeine was tested in the presence of known mechanosensitive channel blockers (Gd(3+), neomycin and amiloride) and ruthenium red as a possible inhibitor. Caffeine enhanced net cation fluxes in a concentration-dependent way. In whole populations, the Ca(2+) entry elicited by 20 mM caffeine was fully suppressed by Gd(3+) (5 microM), amiloride (250 microM) and ruthenium red (100 microM) and partially blocked by neomycin (100 microM). The above blockers also inhibited caffeine-dependent Na(+) entry whilst showing antagonistic effects on the corresponding K(+) efflux. These compounds fully suppressed hypotonically-induced (-35 mOsm/kg) Ca(2+) influx at nearly the same concentrations completely blocking caffeine-stimulated Ca(2+) entry. The effect of inhibitors on Ca(2+) influx in young cells exceeded that in old cells at similar concentrations. The results clearly show that caffeine stimulates a stretch-activated Ca(2+) channel in human red cells and that aged cells are less susceptible to mechanosensitive channel blockers., ((c) 2002 Elsevier Science Ltd. All right reserved.)

Objective: To assess the risks of congenital varicella syndrome and other birth defects in offspring of women who inadvertently received varicella vaccine during pregnancy or within 3 months of conception., Methods: Pregnant women inadvertently exposed to varicella vaccine, reported voluntarily, were enrolled in the Pregnancy Registry for VARIVAX (Merck & Co., Inc., West Point, PA). The pregnancies were monitored and the outcomes ascertained from questionnaires completed voluntarily by the health care providers. The rates of congenital varicella syndrome and congenital anomalies were calculated for seronegative women prospectively reported to the registry., Results: From March 17, 1995 through March 16, 2000, 362 pregnancy outcomes were identified from prospective reports. Ninety-two women were known to be seronegative to varicella, of whom 58 received their first dose of vaccine during the first or second trimester. No cases of congenital varicella syndrome were identified among 56 live births (rate 0%, 95% confidence interval [CI] 0, 15.6). Among all the prospective reports of live births, five congenital anomalies were reported. No specific pattern was identified in either the susceptible cohort or the sample population as a whole., Conclusion: No abnormal features have been reported that suggested the occurrence of congenital varicella syndrome or other birth defects related to vaccine exposure during pregnancy. Because of the small numbers, this study has limited precision, so continued surveillance is warranted. However, these results should provide some assurance to health care providers and women with inadvertent exposure before or during pregnancy.

Problem/condition: High vaccination levels in the population are necessary to decrease disease transmission and prevent disease; therefore, an important component of the U.S. vaccination program is the assessment of vaccination coverage. Current goals are for > or = 90% coverage with recommended vaccines during the first 2 years of life., Reporting Period: January-December 1998., Description of Systems: The National Immunization Survey (NIS) is an ongoing, random-digit-dialed telephone survey that gathers vaccination coverage data for children aged 19-35 months in all 50 states and 28 urban areas. Vaccination coverage rates derived from NIS data are adjusted statistically for households with multiple telephone lines, household nonresponse, the proportion of households without telephones, and vaccination provider nonresponse. The results were also adjusted to match the known total population of children in each survey area., Results: On the basis of NIS data, national coverage was > or = 90% for three doses of poliovirus vaccine (Polio), three doses of Haemophilus influenzae type b vaccine (Hib), and one dose of measles-containing vaccine (MCV). Coverage was the highest ever reported for four doses of any diphtheria and tetanus toxoids and pertussis vaccine (DTP) (i.e., diphtheria and tetanus toxoids and pertussis vaccine, diphtheria and tetanus toxoids [DT], or diphtheria and tetanus toxoids and acellular pertussis vaccine [DTaP]) (83.9%), three doses of hepatitis B vaccine (Hep B, 87.0%), and one dose of varicella vaccine (43.2%). The number of states achieving the > or = 90% goal was 47 for three doses of Hib, 40 for three doses of Polio, 40 for one dose of MCV, nine for three doses of Hep B, and seven for four doses of DTP. Proportionally fewer urban areas achieved the > or = 90% goal: 23 of 28 for three doses of Hib, 13 for three doses of Polio, 16 for one dose of MCV, five for three doses of Hep B, and one for four doses of DTP. No state or urban area has yet achieved the > or = 90% goal for varicella., Interpretation: Findings from the 1998 NIS indicate that national vaccination coverage levels for routinely recommended childhood vaccines are at the highest levels ever reported. However, substantial variation in coverage remains at the state and urban area levels., Public Health Actions: The public health community and vaccination providers in areas with low coverage should intensify their efforts to implement recommended strategies for increasing vaccination coverage to ensure that children are equally well protected throughout the United States.

The goal of eliminating indigenous rubella and congenital rubella syndrome (CRS) in the United States in the near future is now within reach, because rubella incidence has been sustained at record-low levels since the mid-1990s. Effective prevention strategies to eliminate CRS and rubella require improvement in the surveillance of CRS and congenital rubella infection (CRI). The purpose of the workshop was to review rubella and CRS epidemiology, as well as current clinical, diagnostic, and laboratory practices, to determine whether new strategies are needed to achieve and document CRS elimination. Workshop participants agreed that surveillance for CRS must be strengthened, particularly through augmented laboratory capabilities, and the case definition for CRS must be revised to reflect the current scientific information available. Further studies of methods are needed to identify high-risk populations and geographic areas for rubella and CRS and to enhance identification of infants with CRS.

This report describes biomedical causes of mental retardation (MR) among school-age children and associated medical conditions in children for whom no cause was reported. This study involved 715, 10-year-old children with MR (intelligence quotient [IQ] 70 or less) born between 1975 and 1977. We determined biomedical causes of MR using a hierarchical approach based on the timing of the event (i.e. prenatal, perinatal, or postneonatal). Among children with no identified biomedical cause the occurrence of associated medical conditions was examined. No reported biomedical cause could be found in 78% of children with MR (87% mild, IQ 50 to 70; 57% severe, IQ < 50). Prenatal causes were present in 12%, perinatal causes in 6%, and postneonatal causes in 4%. On the basis of these findings it was concluded that intensive use of public health prevention strategies can reduce the number of children who receive a diagnosis of MR.

We report the descriptive epidemiology of holoprosencephaly and arhinencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system with multiple sources of ascertainment. From 1968-1992, we ascertained 63 cases of holoprosencephaly and arhinencephaly from approximately 734,000 births, for a birth prevalence of 0.86 per 10,000. Thirteen case infants with holoprosencephaly and four case infants with arhinencephaly were categorized as having syndromes. Of the case infants with non-syndromic holoprosencephaly, 55% had malformations not attributable to the underlying brain defect. The rate of holoprosencephaly and arhinencephaly increased from 0.58 per 10,000 during 1968-1972 to 1.2 per 10,000 during 1988-1992 (P for trend = 0.016). Rates were higher for females than for males (risk ratio = 1.45, 95% C.I. 0.88-2.41) and higher for nonwhites than for whites (risk ratio = 1.74, 95% C.I. 1.06-2.86). There was a U-shaped distribution of risk associated with maternal age with a slightly increased risk for younger women (risk ratio for maternal age < 20 years, compared with age 25-29 years = 1.68, 95% C.I. 0.77-3.62) and older women (risk ratio for maternal age > 34 years, compared with age 25-29 years = 2.30, 95% C.I. 0.93-5.7), but this was not statistically significant. The increased risk in the older age group could be largely explained by the presence of cases with autosomal trisomies. Neonatal mortality was higher for infants with malformations that were not attributable to the underlying brain defect and for infants with syndromes than for infants with isolated holoprosencephaly. This analysis is the first population-based study with long-term data on this rare defect. Further epidemiologic studies will be necessary to assess the risk factors for holo-prosencephaly and arhinencephaly.

The results of the British Medical Research Council's randomized controlled trial proved that folic acid can prevent spina bifida and anencephaly. The trial provided critical scientific data upon which to base public health policy for preventing folic acid-preventable spina bifida and anencephaly. Within weeks of publication of the results, the Centers for Disease Control and Prevention in the US developed and issued guidelines for women who had had a pregnancy affected by spina bifida or anencephaly. A year later, the US Public Health Service issued the recommendation that all women of child-bearing age who are capable of becoming pregnant should consume 0.4 mg of folic acid per day. The Public Health Service needed a year to make inferential judgements about dose, target groups, safety, timing of ingestion, and existing and proposed vitamin and drug policies and regulations. Current policy discussions concern whether to permit manufacturers of vitamins or food products to claim that folic acid will prevent folic acid-preventable spina bifida and anencephaly and whether to allow a food staple to be fortified with folic acid.

A disaster has been defined as a disruption of human ecology that exceeds the capacity of the community to function normally. Little is known about the adverse effects of natural disasters on reproductive outcomes. Important lessons can be derived from several disasters caused by human factors, such as the Minamata Bay disaster. Adverse reproductive outcomes include infertility, early pregnancy loss, stillbirths, congenital malformations, and serious developmental disabilities such as cerebral palsy and mental retardation. Recent disasters like the Chernobyl and Bhopal explosions have provided important lessons on the need for accurate and sound information about the risk of prenatal exposures for adverse reproductive outcomes. To study questions of adverse reproductive outcomes and disasters requires a well-planned approach. It should include early development of surveillance for adverse reproductive outcomes, analytic studies on the risk of disasters from direct and indirect effects, sensitive methods to measure early pregnancy loss, and long-term follow-up programs to assess outcomes such as developmental disabilities.

We studied the risk for specific birth defects among infants of mothers with gestational and chronic diabetes using data collected by the Spanish Collaborative Study of Congenital Malformations (ECEMC). For the years 1976 to 1985, we identified 10,087 infants with malformations and 9,994 control infants; 155 of the case infants and 89 of the controls were born to diabetic mothers. The crude odds ratio for any minor or major defect and insulin-treated diabetes was 5.5 (95% CI = 1.2, 24.8), and for major malformations it was 8.7 (95% CI = 1.8, 34.7). The risk for defects involving the central nervous system (CNS), skeletal system and cardiovascular system were significantly increased. Infants of non-insulin-treated diabetic mothers were 2.9 times more likely to have a major congenital birth defect (95% CI = 1.2, 7.2). The crude odds ratio for any major or minor defect and mothers with gestational diabetes requiring insulin was 1.9 (95% CI = 1.1, 3.4). Similar risk was observed for major defects (OR = 1.9, 95% CI = 1.0, 3.7). These results suggest that infants of insulin-treated diabetic mothers have an increased risk of developing malformations of the CNS, cardiovascular system and skeletal system. We also found an increased risk for specific defect categories among infants of mothers with gestational diabetes treated with insulin.

Research suggests that, perhaps through mechanisms initiated by vasoconstriction and leading to vessel thrombosis or embolism, cocaine causes vascular disruption defects, and that frequent cocaine use during early pregnancy could disrupt multiple organ systems in the fetus. We hypothesized that if cocaine is an important cause of multiple vascular disruption defects, a rising prevalence of cocaine use by mothers during pregnancy should be accompanied by rising rates of these defects in their offspring. Using data from the Metropolitan Atlanta Congenital Defects Program, we identified all infants born in Atlanta from 1968 through 1989 who had nonsyndromic, provisional vascular disruption defects affecting more than one organ system: 61 infants (78%) had gastrointestinal and genitourinary defects, 7 (9%) had gastrointestinal and abdominal wall defects, 2 (3%) had gastrointestinal and limb reduction defects, 2 (3%) had limb reduction and abdominal wall defects, 2 (3%) had central nervous system and gastrointestinal defects, 2 (3%) had genitourinary and limb reduction defects, 1 (1%) had genitourinary and abdominal wall defects, and 1 (1%) had central nervous system and genitourinary defects. The prevalence of Atlanta infants with more than one vascular disruption defect is 0.13 per 1,000 live births. Chi-square analysis for trends showed no increase in prevalence during the study period. Our data are from one of the first population-based studies in which trends for defects potentially caused by maternal cocaine use are examined; the results of our study show no significant change in the prevalence of multiple vascular disruption defects over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimates of the Apert syndrome birth prevalence and the mutation rate are reported for Washington State, Nebraska, Denmark, Italy, Spain, Atlanta, and Northern California. Data were pooled to increase the number of Apert births (n = 57) and produce a more stable birth prevalence estimate. Birth prevalence of the Apert syndrome was calculated to be approximately 15.5/1,000,000 births, which is twice the rate determined in earlier studies. The major reason appears to be incomplete ascertainment in the earlier studies. The similarity of the point estimates and the narrow bounds of the confidence limits in the present study suggest that the birth prevalence of the Apert syndrome over different populations is fairly uniform. The mutation rate was calculated to be 7.8 x 10(-6) per gene per generation. Apert syndrome accounts for about 4.5% of all cases of craniosynostosis. The mortality rate appears to be increased compared to that experienced in the general population; however, further study of the problem is necessary.

Registries can be very useful scorecards for tracking the occurrence of birth defects and genetic diseases and for monitoring the effectiveness of prevention programs. They can also help us to identify causes and risk factors and develop new prevention approaches. For registries to be useful, however, their data must be precise and focus on time, place, person, and diagnosis.

The Acyclovir in Pregnancy Registry was established to gather data on prenatal exposure to acyclovir. Exposed pregnancies are tracked prospectively to ascertain exposure, risk factors, and pregnancy outcome. Through June 30, 1990, 312 acyclovir-exposed pregnancies had been reported and followed. Of these, 239 were exposed during the first trimester; outcomes included 24 spontaneous fetal losses, 47 induced abortions, 159 live births of infants without congenital abnormalities, and nine outcomes with congenital abnormalities. Among the 73 second- and third-trimester exposures, one infant was born with an abnormality. Exposures are also reported to the registry retrospectively, ie, after the outcome of pregnancy is known. Registry findings to date do not show an increase in the number of birth defects among the prospective reports when compared with that expected in the general population, and there is no consistent pattern of abnormalities among retrospective or prospective reports. These findings should provide some reassurance in counseling women following inadvertent prenatal exposure. The cases accumulated to date represent a sample of insufficient size for reaching reliable and definitive conclusions about the safety of acyclovir for pregnant women and their developing fetuses. Therefore, until further information is available, the Acyclovir in Pregnancy Registry Advisory Committee recommends following the 1989 Centers for Disease Control Sexually Transmitted Diseases Treatment Guidelines for the use of acyclovir in pregnancy, and encourages reporting of all prenatal exposures to the registry (1-800-722-9292, ext. 8465).

Isotretinoin causes serious birth defects in about 25% of babies exposed in the first trimester of pregnancy. Despite warnings about the drug's teratogenicity, cases of isotretinoin embryopathy continue to occur; more than 80 such cases have been reported since 1982. The true magnitude of the problem is unknown, however, and case estimates range to more than 1,000. The need for isotretinoin embryopathy (IE) surveillance is therefore great. Sixty-one known cases were evaluated to determine the sensitivity (proportion of cases with a given defect pattern) of various defect combinations. Using data from the Metropolitan Atlanta Congenital Defects Program for the period before isotretinoin was available, we evaluated the specificity (proportion of malformed infants without exposure who do not have the pattern of defects) for the various defect combinations. Ear malformations (microtia, anotia, absence or stricture of auditory canal, missing pinnae) have an associated sensitivity of 70.5% and a specificity of 99.5%. Ear defects combined with central nervous system (CNS) defects (microcephalus, hydrocephalus, reduction deformities of the brain) and cardiovascular (CVS) defects (conotruncal defects, aortic arch abnormalities) have an associated sensitivity of 19.7% and a specificity of 100.0%. The case definition of ear defects combined with either CNS or CVS defects maximizes both specificity (99.9%) and sensitivity (45.9%). The investigators are now evaluating the feasibility of using this pattern of defects to monitor for IE within a national monitoring program.

Published data regarding the human teratogenic potential of 157 drug components that are frequently prescribed to outpatients in the United States were evaluated according to a protocol developed for TERIS, an automated clinical teratology resource. This protocol stipulates that a bibliographic search be performed on each agent, a brief narrative summary of the available teratologic information prepared, and a risk rating assigned. The ratings are determined by consensus of five clinical teratologists, who independently assess the magnitude of teratogenic risk associated with each agent under usual therapeutic conditions as "none," "minimal," "small," "moderate," "high," and "undetermined." Forty-nine percent of the components of these frequently prescribed drugs had insufficient published information available to assess the risk of human teratogenicity. Of the agents that could be rated, the teratogenic risk in usual therapeutic doses was considered to be minimal or less in 92.5%. Many of these agents have also been assigned Pregnancy Categories by the United States Food and Drug Administration (FDA) according to a system designed to provide therapeutic guidance. There was no more agreement than that expected by chance between TERIS ratings and the FDA Pregnancy Categories for 83 agents that were classified according to both systems. We believe that the FDA Pregnancy Categories should not be used to provide counseling regarding the risk of teratogenic effects to women who have taken medication during pregnancy. Such counseling should be based on a more comprehensive evaluation of the teratologic literature and clinical situation, but need not involve consideration of the therapeutic benefit of the agent.

Environmental factors may have significant adverse effects on the developing fetus. Prescribed and illicit drugs, environmental chemicals, physical factors, and maternal diseases may affect the developing fetus directly or may interact with genetic factors to cause birth defects.

Although the excess risk for birth defects among children of mothers with diabetes mellitus is well documented, there are few data concerning the risk for specific malformations. In the Atlanta Birth Defects Case-Control Study, those risks for malformations were evaluated. The population-based study included 4929 live and stillborn babies with major malformations ascertained by the Metropolitan Atlanta Congenital Defects Program in the first year of life born to residents of Metropolitan Atlanta between 1968 and 1980. The study also included 3029 nonmalformed live babies who were frequency-matched to case babies by race, period of birth, and hospital of birth. The relative risk for major malformations among infants of mothers with insulin-dependent diabetes mellitus (n = 28) was 7.9 (95% confidence interval [CI]1.9, 33.5) compared with infants of nondiabetic mothers. The relative risks for major central nervous system and cardiovascular system defects were 15.5 (95% CI = 3.3, 73.8) and 18.0 (95% CI = 3.9, 82.5), respectively. The absolute risks for major, central nervous system, and cardiovascular system malformations among infants of diabetic mothers were 18.4, 5.3, and 8.5 per 100 live births, respectively. Infants of mothers with gestational diabetes mellitus who required insulin during the third trimester of pregnancy were 20.6 (95% CI = 2.5, 168.5) times more likely to have major cardiovascular system defects than infants of nondiabetic mothers. The absolute risk for infants of this group of diabetic mothers was 9.7%. No statistically significant differences were found among infants of mothers with gestational diabetes mellitus who did not require insulin during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Three males with similar malformations including hypertelorism, telecanthus, cleft lip and palate, and hypospadias, have been evaluated. One also had a laryngotracheoesophageal cleft and therefore was considered to have the G syndrome. The other two had no stridor, aspiration, or difficulty swallowing, and were considered to have the BBB syndrome. Both disorders are associated with multiple malformations and can be most readily distinguished by the presence of laryngoesophageal abnormalities in the G syndrome and differences in facial features evident later in childhood. The BBB syndrome appears to be inherited as an X-linked disorder with the affected female showing only telecanthus and hypertelorism. The G syndrome exhibits autosomal dominant inheritance with males more severely affected, although a few few females have had serious malformations in addition to telecanthus and hypertelorism. In the family with the G syndrome evaluated for this report, the mother of the affected infant had telecanthus, hypertelorism, and anosmia, the latter a feature not previously noted in this disorder.

Wilms tumor developed in five cousins in a family. Two with bilateral tumors have died, but three with unilateral lesions have survived. None of the patients had associated chromosome defects, aniridia, hemihypertrophy, or other anomalies. The pattern of Wilms tumor in the family is consistent with several postulated mechanisms of inheritance of the neoplasm, and shows that relatives within affected families may be at risk.

Several studies have suggested that maternal use of exogenous sex hormones during early pregnancy may be associated with various congenital malformations. We conducted a case-control study of first-trimester sex hormone exposure among mothers of 1,091 infants with Down syndrome or at least one of 11 major malformations. For each malformation category, the infants with other malformations served as the control group. Associations were found between esophageal atresia and any sex hormone exposure (odds ratio, 2.84); progestins (odds ratio, 2.87); nonspecified sex hormones (odds ratio, 2.99); and hormonal pregnancy tests (odds ratio, 2.81). We found no potentially confounding variables for these associations. We found no statistically significant association between any malformation category and oral contraceptive exposure. Even if the relationship between esophageal atresia and noncontraceptive sex hormone exposure is causal, the absolute risk would be low, on the order of six per 10,000 exposed live births.

Using data from the population-based Metropolitan Atlanta Congenital Defects Program, the association of seven relatively common and easily ascertainable groups of midline defects was studied. These defects were neural tube defects (575 patients), oral clefts (633 patients), omphalocele (141 patients), esophageal atresia/tracheoesophageal fistula (88 patients), imperforate anus (151 patients), conotruncal heart defects (289 patients), and diaphragmatic hernia (75 patients). Known syndromes were excluded from the analysis. Of 1743 infants with at least one midline defect, 86 (4.9%) had at least a second midline defect, and 9 (0.5%) had two additional midline defects. Pairwise analysis of the seven defects shows that, although most midline defects tend to be statistically associated with other midline defects, specific combinations of midline defects are seen. For example, neural tube defects are more strongly associated with cleft lip with or without cleft palate than with cleft palate alone; imperforate anus is more strongly associated with spina bifida than with anencephaly or encephalocele. Moreover, some combinations of defects are not observed (eg, neural tube defect and conotruncal heart defect, clefts and diaphragmatic hernia, omphalocele and esophageal atresia/tracheoesophageal fistula). These data point to the need for further refinement in the study of the association of midline defects in terms of embryologic and pathogenetic mechanisms because most midline defects tend to occur as an isolated defect, some midline defects occur with nonmidline defects (such as limb defects), and specific associations among midline defects are observed.

We studied the birth prevalence of autosomal dominant mutations in Spain and estimated how a decrease in maternal age distribution may lead to reduction in dominant mutations. The data were collected by the Estudio Colaborativo Español de Malformaciones Congénitas from April, 1976, to December, 1985. Among 553,270 liveborn infants monitored during the period, 66 infants with autosomal dominant conditions were identified. These included Apert, Crouzon, Hay-Wells, Treacher-Collins, Robinow, Stickler, Adams-Oliver, and the blepharophimosis syndromes, achondroplasia, cleidocranial dysostosis, and thanatophoric dysplasia. The overall rate of autosomal dominant conditions was 1.2 per 10,000 liveborn infants. Thirteen (20%) had an affected relative, and 52 (79%) had a negative family history. One case was excluded because of insufficient family data. The rate of autosomal dominant mutations was 0.9 per 10,000 liveborn infants, or 47 per 1 million gametes. A reduction in the maternal age distribution of mothers age 35 years and older from the current 10.8% to 4.9%, as in Atlanta, Georgia, would reduce the rate of Down syndrome in Spain by 33% and through a change in parternal age distribution may lead to a reduction in dominant mutations of about 9.6%. This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.

We studied the first-trimester exposure to Bendectin for several major categories of birth defects among infants ascertained through the Metropolitan Atlanta Congenital Defects Program from 1968 to 1978. No associations were found between any of these defect categories and Bendectin exposure. An association, however, was found for the amniotic bands cases--a subgroup of limb reductions. We stratified our data to reflect the 1976 change in formulation when one of the three ingredients was removed. An association was found between esophageal atresia and the three-ingredient product and another between encephalocele and the two ingredient product. These statistical associations do not establish a causal relationship between Bendectin and the birth defects we studied. Furthermore, even if the associations are causal, the implied risk is extremely low, approximately one in 1,000 births.

Using the population-based data from the Metropolitan Atlanta Congenital Defects Program, the interrelation of the six defects that are components of the VACTERL association were investigated. There were 400 cases with two or more of these defects, whereas only 29 cases would be expected if the defects had occurred together randomly. There were 76 cases with three or more defects, whereas less than one case was expected. Of these 76 cases, seven had recognized causes (five chromosomal anomalies, two single-gene disorders); another 19 had recognized clinical phenotypes or syndromes of unknown etiology. In the remaining 50 cases, ventricular septal defect was the most common cardiovascular defect (30.0%), and renal agenesis was the most common renal anomaly (30%). Their most common limb defects were reduction deformities (34%) and polydactyly (20%). This study confirms the clinically recognized nonrandom occurrence of the VACTERL association. It also shows that the association is a spectrum of various combinations of its components, which can be a manifestation of several recognized disorders, rather than a distinct anatomic or etiologic entity. A common denominator of the VACTERL association is suggested to be a defective mesodermal development during embryogenesis, due to a variety of causes and leading to overlapping manifestations.

In several studies investigators have suggested that maternal use of exogenous sex hormones during early pregnancy may be associated with various congenital malformations. A group of malformations, the VACTERL (vertebral, anal, cardiac, trachea, esophageal, renal, limb-acronym) association, has been statistically associated with maternal exposure to exogenous sex hormones during the first trimester of pregnancy. The VACTERL association is a nonrandom group of major malformations that occur together more often than would be expected on the basis of chance. To assess this association, we conducted a case-control study of first-trimester exposure to sex hormones among mothers of 34 infants with the VACTERL association and of 1,024 comparison infants with one or more of ten major malformations or Down syndrome. The study subjects were malformed infants born between July 1970 and June 1979 and registered in a population-based birth defects registry. Information concerning the use of exogenous sex hormones during pregnancy was obtained by systematically interviewing the mothers of the malformed infants. Most of the mothers were interviewed within 6 months of their children's births. Each mother was interviewed within a year of her child's birth. We found an odds ratio of 0.98 (90% confidence limits 0.40, 2.38) for the relationship between VACTERL association and use of any sex hormone in the first trimester of pregnancy. Our study had adequate statistical power to detect a true relative risk of 2.8 or greater.

A cohort of 169 births to women who were exposed throughout pregnancy to chloroquine 300 mg base once a week for chemosuppression of malaria was studied. The birth defects in this cohort were compared with those in a control group of 454 births to women who were not exposed to chloroquine, most of whom lived in non-malarious areas. The proportion of birth defects in the exposed group was not significantly different from that in the control group. This observation must be considered within the limitations of the study, which could detect only a strong teratogenic effect. It could not exclude risks lower than a 5.7-fold increase in the incidence of birth defects when chloroquine was used. Women using chloroquine during pregnancy for chemosuppression of malaria can be reassured that it is not a strong teratogen, but if it is to be used the risk of developing malaria should be balanced against the lack of data to determine whether it carries a low teratogenic risk.

We used data from the population-based Metropolitan Atlanta Congenital Defects Program to study the epidemiology of the early amnion rupture spectrum of defects. For the period 1968 through 1982, we identified 45 patients among 388,325 live births, for a birth prevalence rate of 1.16 per 10,000. The prevalence for male infants was 0.91 and for female infants, 1.44. The defects occurred 1.76 times more often in blacks than in whites (95% confidence interval 0.98, 3.13). Infants of young, black multigravidas (less than 20 years, more than one pregnancy) showed the highest rate (6.2), and infants of older, black multigravidas showed the lowest rate (0.5) (rate ratio = 12.4, 95% confidence interval 4.2, 36.4). These findings suggest that young, black multigravidas are at much higher risk than are older, black multigravidas of having infants with this spectrum of defects. Ascertainment (diagnostic) differences between hospitals probably account for some of the racial discrepancy in birth prevalence, but they do not explain the maternal age effects in black multigravidas. Because the higher rates for blacks probably reflect more accurate diagnoses, the findings also suggest that a closer estimate of the true birth prevalence may be about 3 per 10,000 live births.

Observational epidemiologic methods are being used to evaluate the safety of acyclovir in pregnancy. An essential component of this research is the establishment of a baseline expectation of pregnancy outcomes among women with herpes not receiving acyclovir. Continuing studies will be described in this report. To supplement these structured studies, an international case registration study was established. Through the Acyclovir in Pregnancy Registry, all cases of reported prenatal exposures to acyclovir are tracked to ascertain maternal exposure, risk factor, and pregnancy outcome information. The reports originate in all countries where oral acyclovir is marketed; data consolidation and analysis are coordinated at Burroughs Wellcome Co. with the assistance of a government/industry advisory panel. This presentation summarizes provisional data from the prospective reports, including trimester of exposure and reported outcomes of pregnancy. The total number of monitored pregnancies remains too small to support conclusions about the safety of acyclovir during pregnancy at this point. The potential for the registry and other epidemiologic studies to address the safety-in-pregnancy question will be discussed.

We conducted a structured telephone survey of state public health laboratory directors of neonatal screening programs to determine the extent of the problem of missed cases of phenylketonuria (PKU) and congenital hypothyroidism. A total of 76 missed cases were reported--43 PKU and 33 congenital hypothyroidism. We looked at the following characteristics of the missed cases: the stage at which the miss occurred, which included specimen collection, laboratory procedures, or follow-up; the size of the program; the type of screening program; the age of the infant at the time of screening; and any legal action that resulted from the miss. The 76 missed cases probably represent an underascertainment of the true number, yet we believe that our data provide an overview of some of the problems associated with mass neonatal screening. There was one missed case of PKU for every 70 cases detected, and one missed case of congenital hypothyroidism for every 120 cases detected; in other words, two congenital hypothyroidism cases were missed for every 1 million infants screened. Regarding the stage of screening in which the miss occurred, 14% occurred during specimen collection, 45% during the laboratory procedures stage, 16% during follow-up, 11% were the result of biologic variation, and in 14% the stage could not be identified. We conclude that neonatal screening programs have been highly successful but that there may be additional safeguards to be developed, tested, and implemented when practical.

This population-based case-control study was designed to investigate risk indicators for the occurrence of the birth defect craniosynostosis in Colorado. A total of 173 children who underwent craniectomy for craniosynostosis and 759 children without craniosynostosis were included in the study. Multivariable logistic regression analysis of birth certificate data showed that male sex (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.1-2.2), maternal five-year age "increase" (OR = 1.3, 95% CI = 1.1-1.5), plural birth (OR = 3.0, 95% CI = 1.2-7.1) and black maternal race (OR = 0.0, 95 per cent CI = 0.0-0.6) were independently associated with craniosynostosis. There was a weak positive association between craniosynostosis and the altitude of the town closest to the maternal residence, but no association was found with maternal education, marital status, number of previous births, or previous pregnancy termination. The association of craniosynostosis with plural birth is consistent with the hypothesis of fetal head constraint.

Pediatric endocrinologists in Puerto Rico reported a threefold increase in the number of patients with premature thelarche seen between 1978 and 1981. A matched-pairs case-control study was conducted to evaluate associations with potential environmental exposures to substances with estrogenic activity, as well as with familial factors. Analysis was performed on 120 pairs, the case subjects of which were selected from those diagnosed between 1978 and 1982. In subjects 2 years of age or older at the onset of thelarche, no significant associations were found. In subjects with onset before 2 years of age, significant positive associations were found with a maternal history of ovarian cysts, consumption of soy-based formula, and consumption of various meat products. A statistically significant negative association was found with consumption of corn products. These statistical associations are probably not sufficient to explain the reported increase because in over 50% of the case subjects there was no exposure to any of the risk factors for which statistical associations were found. Exposure to other substances with possible estrogenic effect, such as waste products from pharmaceutical factories and pesticides, was also excluded as a possible cause. These findings suggest that better diagnosis and reporting, or conceivably the presence of entirely new, unsuspected factors, could account for the reported increase.

To study the association of maternal cocaine use during early pregnancy with the occurrence of congenital urogenital anomalies, we analyzed data from the population-based Atlanta Birth Defects Case-Control Study. We identified 276 and 791 case-babies with urinary and genital anomalies, respectively, who were live born and stillborn to residents of metropolitan Atlanta from 1968 through 1980. There were 2835 and 2973 respective control-babies born without birth defects randomly selected through birth certificates. Maternal cocaine use during early pregnancy was defined as reported use at any time from 1 month before the pregnancy began through the first 3 months of pregnancy. We found a statistically significant association of reported cocaine use with an increased risk for urinary tract defects (crude odds ratio, 4.39; 95% confidence interval, 1.12 to 17.24) and no statistically significant association with genital organ defects (odds ratio, 2.26; confidence interval, 0.67 to 7.62). The findings from this study were consistent with a previously reported association of maternal cocaine use and urinary tract anomalies in animal and clinical studies.