Overview of Current Research in Parturition

The mechanism of human parturition is not understood and further research into this important physiological process is needed. Preterm labour remains a major cause of perinatal mortality and morbidity and there is controversy about the effectiveness of current tocolytic agents. In some species, notably the sheep, parturition is preceded by an activation of the fetal hypothalamic-pituitary-adrenal axis. However, in primates this axis has a supportive, rather than essential, role. A fall in maternal progesterone levels is a prerequisite for parturition in most mammals and this takes place either through increased conversion of progesterone to oestrogens in the placenta, or through the demise of the corpus luteum of pregnancy, depending on the species. In primates and guinea-pigs parturition occurs without an apparent fall in maternal progesterone levels. Gene targeting experiments in mice have demonstrated the critical role of prostaglandin FP receptors, necessary to mediate the luteolytic effect of PGF(2alpha) before parturition. Prostaglandin synthesis is required for the onset and progress of labour as demonstrated by experiments with cPLA(2)- and PGHS-1-deficient mice. The importance of local tissue conversion of progesterone to reduced androgens in the regulation of cervical ripening has been demonstrated in 5alpha-reductase-deficient mice. The chronic and ubiquitous gene inactivation obtained with conventional methods has disadvantages, in that it may allow the activation of compensating pathways, making the interpretation of results difficult. This problem may be overcome by using pulsed and tissue-selective gene knockout strategies. The study of human parturition is complicated by the lack of access to direct experimentation, whereas the endocrine differences between species make it difficult to extrapolate animal data to humans. However, the development of genomic/proteomic technologies that allow the simultaneous screening of thousands of genes and gene products in small samples of tissue, and new methods to study the biochemistry of receptors and proteins involved in smooth muscle physiology promise new insights into the control of human labour. Nevertheless, the integration of rapidly expanding knowledge into a complete understanding of the roles of the mother and the fetus in the initiation of parturition, and the development of selective medication for the effective management of preterm labour remain an arduous challenge for the next decade. Experimental Physiology (2001) 86.2, 213-222.     

Fetal magnesium homeostasis in the sheep.

The fetal plasma magnesium concentration exceeds that of the mother but the difference is small compared to that of ionized calcium concentration. Although not fully independent of changes in maternal magnesaemia, fetal magnesaemia showed a high degree of autonomy during both hypermagnesaemic and hypomagnesaemic changes induced in the ewe. As with calcium, the placental gradient is reversed after fetal thyroparathyroidectomy (TXPTX) with thyroxine replacement. During perfusion in situ of the placenta from such TXPTX fetuses isolated from the fetus itself, a stable positive placental gradient of magnesium concentration could be re-established between the perfusing blood and the maternal circulation. As with calcium, this gradient could be increased by fetal calf parathyroid extract, parathyroid hormone-related protein (PTHrP 1-141), PTHrP (1-84) but not by PTHrP (1-34). It was concluded that a mid-molecule portion of PTHrP can stimulate a putative placental pump which is responsible for the gradients of both calcium ions and magnesium across the ovine placenta.     

An excitatory body-antral reflex in the sheep abomasum.

This paper describes an abomasal body-antral excitatory reflex in acute experiments in sheep anaesthetized with chloralose. The abomasum was either surgically intact or acutely transected to form separate compartments of the abomasal body and antrum. Inflation of a balloon situated in the abomasal body and active contraction of the abomasal body increased the amplitude of antral contraction. In the intact preparation, inflation of the abomasal body increased the amplitude of antral contraction before and after extrinsic denervation. The antral response was reduced by 75% after extrinsic denervation. In the acutely transected preparation, inflation of the abomasal body and electrically induced contraction of the abomasal body also increased antral contraction amplitude. The antral response was abolished by bilateral section of the cervical vagus nerves in five of six experiments. Selective extrinsic neurotomy of either compartment abolished all responses. It was concluded that the neural mechanisms controlling abomasal motility in the sheep resemble those found in species with simple stomachs: excitation of in-series tension receptors of the abomasal body causes an increase in antral contraction amplitude by vago-vagal reflex pathways. Antral motility is also modulated by changes of tension in the abomasal body by intrinsic reflex pathways and reflexes involving abdominal preganglia may also be present. In a restricted number of experiments the splanchnic nerve was shown to play an important role.     

Numerical density of nuclei in the sheep placenta.

A method is described for estimating the number of nuclei of different cell types in the sheep placenta. The method was applied to the study of six placentas of different ages and the results have been correlated with data on the chemical composition and the physiology of the ovine placenta. In agreement with studies of placental DNA content, there is no demonstrable increase in the total number of placental nuclei in the last two months of gestation. However, the number of fetal mesenchymal nuclei decreases and there is a concomitant increase of fetal endothelial nuclei from 80 days to term. These changes correlate with a decrease in volume of the core of the placental villi and increase in umbilical blood flow.     

Uteroplacental blood flow during alkalosis in the sheep.

Uteroplacental blood flow was measured by the radioactive-microsphere technique in eight near-term pregnant ewes during a normal control period and during maternal metabolic alkalosis. All measurements were made on awake, unanesthetized animals. Alkalosis, defined for this study as an arterial pH of 7.60 or greater, was produced by the oral administration of sodium bicarbonate, 3 g/kg body wt. The rise in pH thus produced was unaccompanied by significant changes in systemic arterial blood pressure and cardiac output, while maternal arterial Pco2 rose slightly from control levels. Cotyledonary blood flow declined from a control value of 1,177 ml/min to 1,025 ml/min during alkalosis. This decline of 13 percent in cotyledonary blood flow is significant (P smaller than 0.002). Blood flow to the remaining uterine tissue, or noncotyledonary uterus, did not change with alkalosis, being maintained at approximately 195 ml/min. It is concluded that maternal alkalosis, unaccompained by major changes in Pco2 and systemic arterial pressure, causes a small increase in the resistance of the uteroplacental circulation.     

Parturition: Its role in the long term retention of maternal behavior in the rat

The role of parturition in the establishment of the long-term retention of maternal behavior in the rat was investigated. Primigravid rats caesarean sectioned on Day 22 of gestation that responded maternally immediately (<22 hr) following surgery were permitted to be maternal towards test pups for 48–70 hr at which time test pups were separated from the experimental animals. When reexposed to rat pups some 25 days later 50% of the caesarean sectioned animals responded maternally within 1 hr while the remaining 50% responded maternally within 5 test days. The level of maternal responsiveness of caesarean sectioned animals did not differ from that of primiparous animals given only 2 days of pup exposure postpartum and then tested for the retention of maternal behavior 25 days later. Forty-two percent of the primiparous animals responded maternally during the first test period 25 days following litter removal. Although a slight reduction in latency to respond maternally was evident in nulliparous animals upon reexposure to rat pups 25 days after an initial sensitization period, both caesarean sectioned and primiparous animals responded maternally significantly faster than did previously sensitized nulliparous females. The data demonstrate that the act of parturition is not essential for the establishment of the long-term retention of maternal behavior in the rat, and suggest that exposure to pups following termination of pregnancy may serve to intensify the process whereby the retention of maternal behavior is established.     

Humoral immune responses in foetal sheep.

A total of fifty-two foetal sheep between 49 and 126 days gestation were injected with polymeric and monomeric flagellin, dinitrophenylated monomeric flagellin, chicken red blood cells, ovalbumin, ferritin, chicken gamma-globulin and the somatic antigens of Salmonella typhimurium in a variety of combinations. Immune responses were followed in these animals by taking serial blood samples from them through indwelling vascular cannulae and measuring the circulating titres of antibody. Of the antigens tested, ferritin induced immune responses in the youngest foetuses. A short time later in gestation, the majority of foetuses responded to chicken red blood cells, polymeric flagellin, monomeric flagellin and dinitrophenylated monomeric flagellin. Only older foetuses responded regularly to chicken gamma-globulin and ovalbumin. However, antibodies to all these antigens were first detected over the relatively short period of development between 64 and 82 days gestation and this made it difficult to define any precise order in the development of immune responsiveness. Of the antigens tested only the somatic antigens of S. typhimurium failed to induce a primary antibody response during foetal life. The character and magnitude of the antibody responses in foetuses changed throughout in utero development. Both the total amount of antibody produced and the duration of the response increased with foetal age. Foetuses younger than 87 days gestation did not synthesize 2-mercaptoethanol resistant antibodies or IgG1 immunoglobulin to any of the antigens tested, whereas most foetuses older than this regularly did so.     

Experimental visna in foetal Icelandic sheep.

Visna is a chronic neurological disease of sheep caused by a slow infection with a naturally occurring ovine retrovirus. The present study was focused on the influence of age on the pathogenesis of this infection and involved intrauterine inoculation of 7 sheep foetuses at about 90 days of gestation with slaughter at birth, 6 to 7 weeks later. The results were compared with prior observations in newborn lambs and adult sheep infected with the same visna virus strain.Pathological lesions of the CNS in foetal sheep were of similar character, localization and severity as those in both newborn and adult sheep. The distribution of virus, the generally low titres of free infectious virus, and the requirement for explantation to isolate virus in some instances, were similar in foetal and in older sheep. However, the more frequent virus isolations from foetal and newborn sheep indicate a slightly greater permissiveness for virus replication. In general, age apparently has little effect on the course of this slow infection.