Embryo-fetal toxicity signals for 17alpha-hydroxyprogesterone caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with progestins.

OBJECTIVE: A large National Institutes of Health (NIH) study showed that pharmacy-compounded 17alpha-hydroxyprogesterone caproate (17-OHP-C) reduced the incidence of preterm birth. The study results included a signal that 17-OHP-C may be associated with an increase in the rate of miscarriages and stillbirths. The most probable cause of an increased incidence of miscarriage/stillbirths may be the use of 17-OHP-C in high-risk patients. The current search of the non-clinical literature was performed to identify whether there were any signals from studies in animals that might suggest concerns for the safe use of progestins generally, and 17-OHP-C specifically, in the prevention of preterm birth in humans. METHODS: An extensive literature search was performed for progesterone, 17-hydroxyprogesterone, and 17-OHP-C, using Medline and Toxline databases, textbooks, and then the obtained publications. Because 17-OHP-C does not have a standardized clinical formulation or optimal route of administration identified, all formulations, vehicles, routes and doses were included in the search, as well as treatment during any stage of pregnancy. All publications obtained were reviewed for relevancy; those in German, French, Italian or Russian were translated. RESULTS: None of the relevant non-clinical studies conducted in mice, rats, rabbits, guinea pigs, horses or non-human primates met current standards for determining reproductive and developmental effects as part of the process of drug development. Most studies focused on the potential of 17-OHP-C for teratogenicity. Many studies used supra-pharmacologic and/or high multiples of human exposure in their study design. Overall, 17-OHP-C was consistently shown to be less potent than progesterone, and neither progesterone nor 17-OHP-C consistently adversely affected maternal weight, embryo-fetal viability or caused malformations. One study in rhesus monkeys raises concerns because resorption/abortion occurred at the human equivalent dose of 17-OHP-C, 10 mg/kg; this finding did not occur in cynomolgus monkeys. The absence of information regarding the serum levels of both progesterone and 17-OHP-C in the animal studies and in humans, as well as presumed inter-species metabolic differences, make it difficult to conclude that the findings with 17-OHP-C in rhesus monkeys and the signal in the NIH trial are related. A few studies in rats raised questions regarding potential effects on postnatal development, but in the absence of better study designs, the relevancy of these findings to human risk are also questionable at best. CONCLUSION: There is a signal for embryo-fetal toxicity associated with 17-OHP-C in the two largest clinical trials conducted to date; there is also a signal for embryo-fetal toxicity with 17-OHP-C in rhesus monkeys and possibly one in rodent species. The relationship between these signals is unclear given the absence of state-of-the-art reproductive toxicology studies and human pharmacokinetic studies.

Update on new developments in the study of human teratogens.

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.

Teratogen update: evaluation of the reproductive and developmental risks of caffeine.

Caffeine is a methylated xanthine that acts as a mild central nervous system stimulant. It is present in many beverages, including coffee, tea, and colas, as well as chocolate. Caffeine constitutes 1-2% of roasted coffee beans, 3.5% of fresh tea leaves, and approximately 2% of mate leaves (Spiller, '84; Graham, '84a,b). Many over-the-counter medications, such as cold and allergy tablets, headache medicines, diuretics, and stimulants also contain caffeine, although they lead to relatively minimal intake (FDA, '86). In epidemiological studies, it is assumed that one cup of coffee contains < or =100 mg of caffeine, and soft drinks, such as colas, contain 10-50 mg of caffeine per 12-ounce serving. The per-capita consumption of caffeine from all sources is estimated to be about 3-7 mg/kg per day, or approximately 200 mg/day (Barone and Roberts, '96). Consumption of caffeinated beverages during pregnancy is quite common (Hill et al., '77) and is estimated to be approximately 144 mg/day, or 2.4 mg/kg for a 60-kg human (Morris and Weinstein, '81). However, pregnant women appear to consume slightly less than do other adults, approximately 1 mg/kg per day (Barone and Roberts, '96). This decrease may be interrelated with taste aversion (Hook, '76; Little, '82). The medical literature contains many varied references that appear to indicate that human adverse reproductive/developmental effects are produced by caffeine. If caffeine indeed causes such effects, the reproductive consequences could be very serious because caffeine-containing foods and beverages are consumed by most of the human populations of the world, and consumption in the United States is estimated to be 4.5-kg/person/year (Narod et al., '91). Therefore, the medical literature dealing with developmental and reproductive risks of caffeine was reviewed, and the biological plausibility of the epidemiological and animal findings, as well as the methods and conclusions of previous investigators, were evaluated. The epidemiological studies describe exposures of women to caffeine during pregnancy, as well as the occurrence of congenital malformations, fetal growth retardation, small-for-date babies, miscarriages (spontaneous abortions), behavioral effects, and maternal fertility problems that presumably resulted from the caffeine consumption. A few epidemiological studies were concerned with the genetic effects of preconception exposures to caffeine. Animal studies, conducted mostly in pregnant rats and mice, were designed to produce malformations. The objectives of the present review are to summarize the findings from the various clinical and animals studies, objectively discuss the merits and/or faults inherent in the studies and establish a global reproductive risk assessment for caffeine consumption in humans during pregnancy. It should be noted that evaluation of the developmental risks of caffeine based solely on epidemiological studies is difficult because the findings are inconsistent. Even more important, is the fact that caffeine users are subject to multiple confounding factors that make analyses difficult and prevent investigators from reaching definitive conclusions. For example, the caffeine content of foods and beverages can vary considerably, which can interfere with obtaining valid interpretations from many human studies. Isolated epidemiological studies dealing with the risk of abortion, without evaluating other developmental and reproductive effects, are the most difficult to interpret, because they present special problems that are sometimes ignored in epidemiological studies. The results of animal studies are probably most helpful in solving some of the dilemmas created by the epidemiological studies. An animal study reported in 1960 first focused our attention on the potential developmental effects of caffeine. However, the exposure reported by Nishimura and Nakai ('60) was an intraperitoneal dosage of 250 mg/kg in the mouse, an extremely high dosage that would result in a blood plasma level that could never be obtained from consuming caffeine containing products. More recent animal studies have demonstrated, that depending on the method of administration and species, the developmental NOEL in rodents is approximately 30 mg/kg per day, the teratogenic NOEL is 8,100 mg/kg per day, and the reproductive NOEL approximately 80-120 mg/kg per day. Lack of biological plausibility to support the concept that caffeine has been responsible for human malformations is another important part of this analysis. For example, no one has described the Caffeine "teratogenic syndrome," a cluster of malformations associated with caffeine ingestion. Proven human teratogens have an identifiable syndrome. The malformations described in the animal studies at very high doses fit the description of vascular disruptive types of malformations. (ABSTRACT TRUNCATED)

A history of the Teratology Society.

BACKGROUND: The 39-year history of the Teratology Society is reviewed. An abbreviated history is outlined in table form, along with listings of the Warkany Lectures, the postgraduate courses, and officers of the Society. METHODS: A year-by-year description of the events, including the scientific and social content of the annual meetings and changes in the business of the Society, is given, in many cases using comments from the past presidents. The valuable and unique diversity of the members is discussed and illustrated, presenting the disciplines and main research area of the presidents. The number of submitted abstracts and the various categories are tabulated, averaging the number and type over four periods. Within the past 10 years, a significant increase in the number of abstracts dealing with epidemiology and developmental biology is evident. The Society's development is compared with that of a human, and the question is asked: Have we reached the maturational stage of old age or senescence, or is the Society still maturing gracefully? This question needs further discussion by all the members. RESULTS: During the past 40 years, we have developed the scientific basis to prevent birth defects caused by rubella, alcoholism, and folate deficiency, as well as many other prenatal exposures. CONCLUSIONS: We must now engage in the political battles to obtain the resources needed to conduct further research and to implement the prevention programs, as well as to provide care and rehabilitation for persons with birth defects.

Effects of supplemental methionine on antiserum-induced dysmorphology in rat embryos cultured in vitro.

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 D-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.

Effects of methionine supplement on methionine incorporation in rat embryos cultured in vitro.

The effect of supplementary L-methionine (Met) on the incorporation of methionine was evaluated in 9.5-day rat conceptuses cultured in vitro. Parallel experiments with L-leucine (Leu) were performed for comparison. Conceptuses were cultured for 24 hr in the presence of 3H-labeled Met or Leu, and the incorporation of radiolabel into the embryo and visceral yolk sac was measured. Supplementary Met proportionately increased the incorporation of Met, but supplementary Leu did not have as great an effect on the incorporation of Leu. A hypothesis is presented to explain these findings. It is proposed that Met, but not Leu, is a rate-limiting nutrient for organogenesis-stage rat embryos cultured in rat serum. The results are also discussed with reference to the established efficacy of supplementary folic acid in decreasing the incidence of neural tube defects in human populations and to claims that Met reverses certain teratogenic phenomena, both in vitro and in vivo.

Utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures.

The subject of the reproductive toxicity of various forms of radiation can be anxiety provoking to the public on two accounts, since reproductive failure engenders an unusual level of guilt and anger in the affected families, and radiation effects are misunderstood and feared by the public. Reproductive problems include an array of genetic and acquired diseases affecting parents and their offspring. Many of these problems are associated with the risk of being induced by preconception and/or postconception exposures to environmental agents. For the various forms of radiation, namely, ionizing radiation, ultrasound, low-frequency electromagnetic fields (EMF), and microwaves, the potential for producing reproductive effects varies considerably with the form of "radiation" and, of course, the dose. Whether the exposure occurs preconceptionally or postconceptionally is another major consideration. In evaluating the actual reproductive risks, we rely on accurate dosimetry and information obtained in epidemiological studies and animal studies. Epidemiological studies must demonstrate consistency of the reproductive finding, and animal studies should be designed to add to the findings of the epidemiological studies. Most importantly, the conclusions must not contradict the basic principles of teratology, genetics, and reproductive biology, and they should be biologically plausible. But frequently important basic science principles are ignored in the evaluation process. Yet developmental basic science principles can be instrumental in refuting or supporting the concern about possible risks. Although there is some overlap with regard to the preconception and intrauterine effects of ionizing radiation, there are significant differences. Preconception effects are mainly stochastic effects, while intrauterine effects are mainly deterministic effects. The stochastic genetic risks are lower than the deterministic risks at equivalent exposures. Thus, it is frequently difficult to demonstrate the occurrence of stochastic effects in populations that have received low preconception exposures to ionizing radiation. The reproductive effects from preconception and intrauterine exposures to electromagnetic fields (low-frequency EMF, video display terminals, microwaves) and ultrasound represent much different problems, since the main effects of microwaves and ultrasound occur because of their hyperthermic effects at high exposures. Low-frequency EMF does not have the capacity to produce hyperthermia, and none of these forms of nonionizing radiation has the specificity to damage the DNA comparable to the specificity of ionizing radiation. Not only do they not have targeted mutagenic effects at the usual exposures that populations receive, they are not cytotoxic at these exposure levels as well. From the viewpoint of biological plausibility, these other forms of radiation are much less likely to have the potential for producing reproductive toxicity at the usual population exposures.

Intrauterine effects of ultrasound: animal studies.

During the past several decades, the use of ultrasound technology in the clinical setting has greatly increased. Because nearly every pregnant woman receives at least one sonographic procedure today, there has been developing concern about the safety of such procedures. Since ultrasound exposure can result in hyperthermia and other physiological effects, the determination of a threshold or no-effect exposure has become a high-priority goal. Animal research has been important to the study of the effects of various exposures at all stages of pregnancy, since the clinical use of ultrasonography can occur during the preimplantation, organogenic, and fetal stages. Animal experiments using various mammalian species have been able to determine no-effect exposure levels for embryonic loss, congenital malformations and neurobehavioral effects. The preponderance of evidence from these studies indicates that, in the absence of a thermal effect, ultrasonography represents no measurable risk when used at recommended intensity levels.