Determining access to assisted reproductive technology: reactions of clinic directors to ethically complex case scenarios.

BACKGROUND: Our aim was to increase understanding of how patient selection is handled by assisted reproductive technology (ART) clinicians. METHODS: Ethically complex case scenarios were evaluated by the directors of USA ART clinics. Scenarios included using a son as sperm donor for his father, sex selection without associated disease, treatment of morally irresponsible couples, and a dispute over embryo disposition. Respondents reviewed eight scenarios and gave their opinions on whether to offer treatment. Reasons given for these decisions were placed into one of 13 categories. RESULTS: Survey response rate was 57%. Between 3 and 50% of respondents would treat in each case. Of reasons given, 'conditional' responses (requiring counselling, blood tests or agreement to other 'conditions') were common (31.4%). Non-maleficence (risk) accounted for 29.4% of responses, philosophy of medicine 18.9%, respect for patient autonomy 5.9% and legal concerns 4.6%. Discrimination and threats were each significant in one case. Reasons evoking absolutist beliefs, personal discomfort, commitment to justice, religion and ethical relativism were rare. CONCLUSIONS: Clinicians felt conflict between a desire to respect patient autonomy and their discomfort over the risk associated with the procedure. They raised concerns about misuse of medical technology. Attempts to resolve complex issues through negotiation and compromise were common.

Access to services at assisted reproductive technology clinics: a survey of policies and practices.

OBJECTIVE: Our goal was to investigate policy on patient access to services at assisted reproductive technology clinics in the United States. STUDY DESIGN: Surveys asked about a variety of ethically and socially challenging cases and were mailed to directors of all Society for Assisted Reproductive Technology-associated assisted reproductive technology clinics. RESULTS: Written policies on access to services are present at 40% of assisted reproductive technology clinics. Universal agreement was not found on any issue; 79% of clinics treat single women, 27% treat patients with a history of schizophrenia, 10% treat patients who use alcohol excessively, 7% treat human immunodeficiency virus-positive women, and 2% would treat patients previously convicted of child abuse. A breakdown of the responses indicated that some clinics are more permissive in terms of access to services than others, whereas some are more restrictive. CONCLUSIONS: The data demonstrate considerable variability in policy among clinics on most access-to-services questions. The results highlight the importance of ongoing discussion of the ethical and legal issues related to access and the need to develop consistent methods to deal with complex cases.

The development of morphine-induced antinociception in neonatal rats: a comparison of forepaw, hindpaw, and tail retraction from a thermal stimulus.

Two parallel experiments in rats 2-21 days of age investigated the onset and characteristics of morphine-induced antinociception. One measure of reactivity to pain, limb retraction from a hotplate, was utilized for three different limbs (forepaw, hindpaw, and tail) to chart the development of opioid sensitivity. Morphine-induced antinociception, even in 2-day-old rats, was obtained for all limbs, in a dose-related fashion, and reached peak sensitivity at 6-7 days of age. Naltrexone did not affect limb retraction latencies in nonmorphine treated rats at any age. These studies demonstrate early antinociception to low doses of an opiate and establish that the pain system, like positive reinforcement systems, is opiate sensitive.

Neonatal pain: a comprehensive survey of attitudes and practices.

We surveyed 352 physicians board certified in neonatal-perinatal medicine on their attitudes and practices in the area of pain and pain management in neonates and infants. In contrast to earlier surveys of this type, almost all respondents indicated that even the youngest and most premature infants are able to perceive pain, and most reported that they always advocated anesthesia during the intraoperative period. The use of analgesic agents in the postoperative period, however, was more variable. Respondents who indicated that neonates perceived less pain than adults reported seeing fewer signs of pain and using less analgesia in the postoperative period. They were also more likely to believe that analgesics are too dangerous to use in neonates and that physiologic factors such as incomplete myelination of the pain pathways and neural/physical immaturity (factors now known not to play a role) contribute to diminished pain sensitivity. Conversely, respondents who indicated that neonates do not perceive less pain than adults, the majority of respondents, reported seeing more signs of pain and using more medication in the postoperative period. These physicians also believed that the physiologic stress associated with pain can be more dangerous than the analgesics. We conclude that attitudes and reported practices have changed in the area of neonatal pain and pain management. Furthermore, our data indicate that these attitudes significantly predict reported postoperative medicating practices.

Oxytocin and vasopressin hexapeptide fragments have opposing influences on conditioned freezing behavior.

We investigated the influence of C-terminal fragments of oxytocin (OT) and arginine vasopressin (AVP) on conditioned freezing behavior. Subcutaneous injections of 0.3 microgram AVP(4-9) or OT(4-9) given to rats after shock training or before behavioral observation significantly altered fear-induced freezing behavior. Animals treated with OT hexapeptide froze less than controls, while animals treated with AVP hexapeptide froze more. These results support the concept that the hexapeptide metabolites of oxytocin and vasopressin can selectively modulate certain behavioral processes, and that these peptides have opposite effects on performance in behavioral tests designed to evaluate memory consolidation and retrieval.

Peripheral serotonergic inhibition of suckling.

Systemically administered serotonin, which does not pass the blood-brain barrier, inhibited nipple attachment behavior in 20- and 30-day-old rat pups. Xylamidine, a peripheral serotonin antagonist, attenuated the effects of serotonin, quipazine, and fenfluramine on nipple attachment behavior. Thus, serotonin receptors in the periphery may play an important role in the serotonergic inhibitory mechanism that has been hypothesized as the developing system leading to weaning. However, unlike more general 5-HT antagonists, xylamidine given alone failed to facilitate suckling, suggesting different sites of action for facilitation and inhibition of this infantile behavior.

Weaning in rats: I. Maternal behavior.

Maternal behavior during the weaning period (postpartum Days 14-35) was described from continuous timelapse videorecordings of Norway rat dams and their litters. Time spent nursing declined steadily after Day 20 but persisted until Day 34, about a week longer than suggested by reports of milk transfer. Most of the decline in nursing was due to progressively fewer nursing bouts per day; milk letdowns per day were consequently diminished. Although a private feeding chamber was available to the dams, they did not use this chamber to spend more time away from the pups as weaning progressed. Instead, the dams remained with the pups in the nesting chamber but devoted increasingly less time to nursing. Subtle, progressive changes in maternal behavior are closely orchestrated and coordinated with pup development.

Weaning in rats: II. Pup behavior patterns.

In this study, litters of rat pups and their mothers were continuously video-monitored from Day 14 to Day 35 postpartum in order to describe the behavioral changes that occur during that period. Prior to the onset of solid food intake (Day 18), pups spent most of their active time suckling. During Days 18 to 26, feeding, drinking, grooming, and play-fighting rapidly became frequent daily activities, while suckling gradually began to decline. By Day 28, pups' food and water intake relative to body weight and time allocated to the new behaviors reached asymptote. Pups nevertheless continued to suckle until Day 34. These results suggest that (1) the transition from milk to solid food is embedded in a multitude of behavioral changes; (2) these behavioral changes have distinct temporal characteristics; and (3) the developmental period between Days 14 and 34 can be divided into three phases.

Tonic nociception in neonatal rats.

The issues of whether infants detect noxious stimuli and whether their nociceptive responses are suppressed by analgesics has been the focus of considerable controversy. Therefore, to more completely assess the nociceptive responses of neonatal rat pups to tonic pain, we tested 3-day-old rat pups using the formalin test. The responses of the young pups to formalin-produced injury were similar to those observed in adult rats, both behaviorally and in terms of their responsivity to morphine-induced antinociception. These results provide the first clear-cut evidence of integrated tonic pain responses in the neonate.

The ontogenesis of lithium-induced effects on suckling: inhibition and facilitation.

The ontogenesis of the effect of lithium on suckling behavior was assessed by administering lithium carbonate directly and acutely to 15-, 20-, 30-, and 35-day-old rat pups. Lithium significantly interfered with nipple attachment in 15-day-old rat pups in a dose-dependent pattern, but it facilitated attachment at some doses (40, 60, 80 mg/kg) in weanling-age rat pups. Furthermore, lithium pretreatment reversed quipazine-induced interference of attachment in weanling-age rats. These effects are similar to those previously reported with serotonergic antagonists, suggesting a similar mechanism, perhaps via the inositol phosphate second messenger system.

Relative importance of experience, social facilitation, and availability of milk in weaning of rats.

These studies investigated the role that social facilitation, availability of the dam, and milk play in the maintenance of suckling behavior. Beginning at Day 20, rat pups' suckling experiences were restricted to testing with an anesthetized dam. In the first experiment, nipple attachment was abandoned by about Day 25 in rats that were tested alone with an anesthetized dam for 1 hr per day. When tested in groups of four, nipple attachment was maintained until about Day 27. Increasing exposure to an anesthetized dam to 2 hr per day prolonged nipple attachment about another 4 days. In the second experiment, pups were given either one or two daily 1-hr attachment tests and tested with either an anesthetized dam or an anesthetized dam in which the milk letdown reflex was reinstated. Both increasing the daily exposure to an anesthetized dam and reinstating milk letdown significantly prolonged suckling. Pups given two daily exposures to an anesthetized, milk-laden dam attached until about Day 47, long past the normal age of weaning.

Methysergide-induced nipple attachment depends on suckling experience in juvenile rats.

These studies were designed to investigate the links between pharmacological and behavioral procedures that facilitate suckling in weanling rats by assessing the effects of methysergide on nipple attachment behavior following experiential manipulations known to either promote or attenuate suckling. In the first experiment, methysergide failed to stimulate suckling in 25-day-old rats separated from their dam on Day 20, although it facilitated suckling in rats kept with the dam until either Day 24 or Day 25. In the second experiment, methysergide did not facilitate suckling in 35-day-old rats separated on Day 25, although rats separated on Day 30 or 34 were induced to suckle. In the third experiment, rats were housed with preweanling litters until Day 35 and then separated, housed with 25-day-old litters, or housed with preweanling litters for another 10 days. Rats in a fourth group remained with their dams until Day 35 and were then separated for 10 days. When tested at Day 45, nipple attachment was facilitated by methysergide only in the three groups that had received extended suckling experience. These results demonstrate that serotonergic inhibitory mechanisms modulate nipple attachment only when suckling experience is recent or extensive.

Pro-Leu-Gly-NH2 serves as a conditioned stimulus in the acquisition of conditioned tolerance.

The effect of Pro-Leu-Gly-NH2 (MIF) on the acquisition of tolerance to morphine-induced antinociception and its efficacy as a cue predictive of morphine administration was examined. Daily administration of MIF prior to morphine injection did not attenuate the acquisition of tolerance to the antinociceptive properties of morphine, as measured by the latency to hindpaw lick in a hot-plate test of analgesia. When the animals were tested 72 hr later without MIF pretreatment, they appeared to lose tolerance, as indicated by longer latencies to paw lick. These data suggest that in some situations MIF may interfere with the acquisition of tolerance by acting as a cue that reliably predicts the antinociceptive properties of morphine.

Acute administration of lithium carbonate interferes with suckling in neonatal rats.

These studies provide an animal model for the lithium-induced decrease in suckling reported in the clinical literature that allows for more precise determination of causal mechanisms. Nine-day-old rat pups were administered lithium carbonate via either intraperitoneal (IP) injections or intragastric (IG) gavage in doses approximating that which human infants might receive via breast milk. The pups were tested for their ability to locate and attach to the nipples of an anesthetized dam. Lithium significantly increased the pups' latency to attach to a nipple. Further tests of milk extraction using oxytocin-induced milk-letdowns indicate that lithium also interferes with milk withdrawal. Tests of motor and sensory deficits using an open-field and an olfactory choice test indicated that lithium did not similarly impair these behavioral facets of suckling. Alternative mechanisms for lithium-produced suppression of suckling are discussed.

The ontogeny of opiate tolerance and withdrawal in infant rats.

The acquisition of morphine analgesic tolerance was investigated in neonatal rats. Morphine was found to produce a potent analgesia, as measured by latency to retract a hindpaw from a 52 degree C hotplate, in rat pups as young as 1 day of age. Morphine analgesic tolerance, however, did not develop in rats until the third week of life. Rats given the same daily morphine regimen starting at 15 days of age or older showed rapid tolerance development. The data from four experiments indicate that experience with morphine prior to this age (Day 15) does not impact on the analgesic efficacy of the drug. Similarly, when morphine treatment was discontinued and the rats given a naloxone challenge, withdrawal symptoms were not observed in very young rats. Opiate withdrawal was first detected in rats that started their daily morphine treatment at 30 days of age and were then challenged with naloxone at 52 days of age. Therefore, two correlates of opiate addiction, tolerance and withdrawal, appear to be relatively late-developing phenomena in the rat.

Ethylketocyclazocine and bremazocine analgesia in neonatal rats.

In three experiments we examined the analgesic potency of kappa opioid receptor agonists in 2- and 16-day-old rats. Ethylketocyclazocine (1-50 mg/kg) produced similar dose- and time-dependent increases in the latency to retract a hind paw from a noxious thermal stimulus in rats of both ages. Bremazocine (0.001-10 mg/kg), a kappa agonist with reported antagonist activity at mu receptors, was also effective in producing analgesia in 2-day-old rats. The dose-effect relationship for bremazocine was nonmonotonic. Bremazocine analgesia (0.1 mg/kg) was reversed by both naltrexone and MR2266, a putative kappa opioid antagonist. These results are discussed in terms of the functional integrity of a kappa analgesic system in the developing rat.

Experience during suckling increases weight and volume of rat hippocampus.

Changes in brain anatomy resulting from early suckling experience were explored by measuring wet weight of whole brain, cortex, hippocampus and cerebellum in juvenile rats. Rats provided with ample opportunity to nipple-shift, a behavior associated with enhanced maze learning, had much larger hippocampal mass than rats whose nipple-shifting experience had been restricted. No differences were observed in the other areas measured. This effect of experience was confirmed by histological measurement of hippocampus volume following differential rearing.

Behavioral interactions rather than milk availability determine decline in milk intake of weanling rats.

We examined the relation between milk availability and milk intake during the period in which rat pups gradually abandon milk as a food source. The amount of milk produced by rat dams does not change from postpartum Day 15 to Day 20, but decreases thereafter and completely disappears around Day 30. In contrast, the amount of milk actually obtained by pups does begin to decline between Days 15 and 20. This decline in milk intake can be attenuated by integrating 20-day-old pups into 15-day-old litters. We concluded that pups do not begin to ingest less milk because of diminishing milk supplies. Rather, the decreased tendency of mothers to nurse older pups and the diminished tendency of older pups to extract available milk, together appear to underlie the decline in pups' milk consumption. Milk supplies decline after changes in behavioral interactions and may play an instrumental role in the eventual abandonment of suckling.