Role of interferons in maternal recognition of pregnancy in ruminants.

It has recently become evident that a type I interferon (IFN) subtype signals the presence of a viable conceptus to the mother during early pregnancy in cattle, sheep, and related mammalian species. This IFN, which is a product of the epithelium (trophectoderm) of the expanding trophoblast, is expressed in extremely large quantities for a few days just prior to implantation. It appears to be involved in modulating the release of the luteolytic hormone, prostaglandin F2 alpha, from the uterine endometrium and, hence, preventing the destruction of the corpus luteum that normally occurs at the end of an estrous cycle if an egg has not been fertilized. These trophoblast IFN have antiviral, antiproliferative, and immunomodulatory properties quite similar to other type I IFN, such as IFN-alpha, -beta, and -omega. However, they constitute a structurally and serologically distinct subtype. In addition, they are poorly inducible by virus, and the promoter regions of their genes are organized differently than other type I IFN. The genes for these trophoblast IFN are confined to ruminant species in the Artiodactyla order and probably evolved from IFN-omega less than 55 million years ago. There is no evidence for comparable production of type I IFN by trophoblast and placental tissues of mammals outside this ruminant group. Recent experiments have indicated that IFN treatment may have value in improving reproductive performance of sheep when provided during the period of maternal recognition of pregnancy, when much embryonic loss is believed to occur.     

Ovarian oxytocin and the maternal recognition of pregnancy

The secretion of oxytocin by the corpus luteum is thought to stimulate the episodic release of PGF-2 alpha from the uterus, thereby contributing to luteolysis. In pregnancy corpus luteum function is maintained, and secretion of oxytocin, or its actions on the uterus, appear to be inconsistent with the successful establishment of gestation. Protection against the effects of oxytocin is ensured by a number of mechanisms, including the cessation of luteal oxytocin secretion, which is evident by Day 20 after mating in sheep, and the maintenance of low levels of the oxytocin receptor in the uterus.     

The maternal recognition of pregnancy in mammals

Progesterone secreted by the corpora lutea stimulates uterine secretion of nutrients required for embryonic growth. But progesterone also blocks maturation of ovarian follicles and oestrous behaviour. When conception fails, therefore, the corpora lutea must lyse, in order to allow a second ovulation and oestrus, while in pregnancy the corpora lutea must be maintained. A number of different endocrine mechanisms exist to ensure the corpora lutea are controlled appropriately depending on pregnancy status; among the best studied of these are the secretion by the developing conceptus of interferons (in ungulates) or chorionic gonadotropins (in primates). These and other mechanisms are reviewed.     

Trophoblastic factors and the maternal recognition of pregnancy in sheep and cattle

The establishment of pregnancy in domestic ruminants depends upon the continued secretion of progesterone by the corpora lutea. In non-pregnant cycles the corpora lutea regress between days 12-15 after oestrus in the sheep; this process must be blocked to ensure continued exposure of the uterus to progesterone. This review discusses the evidence that embryonic products are involved in the maintenance of corpus luteum function, the identification of factors which may be responsible for this maintenance and the probable mechanism of action. The discussion centres on the recent identification of a trophoblast interferon which is thought to be the major trophoblastic factor preventing luteolysis in sheep and cattle.     

Conceptus influences the distribution of uterine leukocytes during early porcine pregnancy

Pregnancy in humans and rodents is associated with dramatic changes in leukocyte populations within the uterus. In these species, recruitment of leukocytes, mostly natural killer (NK) lymphocytes, accompanies decidualization of endometrial stroma even in the absence of pregnancy. In the pig, a nondecidualizing species, the predominant lymphocytes in the pregnant uterus are T and/or NK cells, but their distribution relative to embryonic attachment sites has not been reported. The objective of this study was to compare the abundance of leukocytes in porcine endometrium in contact with trophoblast with that between attachment sites during the early postattachment period. Uteri were recovered on Days 15-17 (n = 4), 18 and 19 (n = 4), 21 and 22 (n = 5), and 25-27 (n = 2) of gestation and from cycling pigs during the luteal phase (Day 15; n = 3). Leukocytes were identified in uterus obtained at versus between attachment sites using an antibody reactive with all leukocytes (CD44). In all pregnant animals, leukocytes were diffusely scattered throughout the endometrial stroma but were rare or absent in the luminal epithelium. Leukocyte density was approximately 3-fold greater in endometrium in contact with conceptuses than in endometrium between attachment sites throughout the early postattachment period. Leukocyte density during the luteal phase was similar to that between attachment sites, suggesting that leukocyte recruitment was a localized response to the embryo. The ability of an individual porcine conceptus to recruit maternal leukocytes to the adjacent stroma may be a vital step in early placental development and embryo survival.     

Puromycin-sensitive aminopeptidase is essential for the maternal recognition of pregnancy in mice

Maternal recognition of pregnancy in rodents requires semicircadian surges of hypophyseal PRL secretion during early gestation, which are required for the formation of the corpus luteum of pregnancy (CLP). Here we show that puromycin-sensitive aminopeptidase (Psa)-deficient mice display female infertility that results from impaired formation of CLP. Transplantation of mutant ovaries into normal females restored fertility but not vice versa. Psa-deficient females revealed no semicircadian surges of PRL induced after mating stimuli. Pregnancy in the mutant females was restored by grafting intact pituitaries to elevate circulating levels of PRL. Psa is thus required for the appearance of the semicircadian surges of PRL secretion that are crucial for maintaining pregnancy in rodents.     

Enhancement of maternal recognition of pregnancy with parthenogenetic embryos in bovine embryo transfer

This study was performed to elucidate the changes in IFNT messenger RNA (mRNA) levels in in vivo–fertilized and parthenogenetic bovine embryos and their interferon-τ (IFNT) secretion amounts during the elongation phase. We assessed the induction capability of maternal recognition of pregnancy by parthenogenetic embryos and attempted cotransfer of in vivo–fertilized and parthenogenetic embryos. The expression level of IFNT mRNA in in vivo–fertilized embryos peaked on Day 18 after estrus, and the highest amount of uterine IFNT was observed on Day 20. Transfer of 10 parthenogenetic embryos produced a detectable amount of uterine IFNT. Transfer of one or three parthenogenetic embryos inhibited luteolysis. An increase in ISG15 mRNA levels in peripheral granulocytes was induced by the transfer of three parthenogenetic embryos. Cotransfer of three parthenogenetic embryos significantly improved the pregnancy rate on Day 40 in code 3 in vivo–fertilized embryos compared with single transfer without parthenogenetic embryos (65% vs. 35%). However, the pregnancy rate on Day 90 (35%) in cotransfer of code 3 in vivo–fertilized embryos did not differ from that upon single transfer (29%), because the cotransfer group had a higher incidence of pregnancy loss than with single transfer (47% vs. 17%) after Day 40. Cotransfer did not affect the pregnancy rate of code 2 in vivo–fertilized embryos. The incidence of pregnancy loss was higher in cotransfer of code 2 in vivo–fertilized embryos than in single transfer (30% vs. 7%). In conclusion, parthenogenetic embryos in the elongation phase secreted IFNT, enabling induction of maternal recognition of pregnancy. The present study revealed that enhancement of the maternal recognition of pregnancy using parthenogenetic embryos promoted the viability of poor-quality embryos until Day 40 of gestation. However, the incidence of pregnancy loss increased after Day 40 in the cotransfer of parthenogenetic embryos. A technique for promoting the full-term survival of poor-quality embryos is needed.     

Protein production by sheep embryos during the period of maternal recognition of pregnancy

An embryo must be present in the uterus 12-13 days after estrus to prevent regression of the ovine corpus luteum. The present experiments were designed to determine if embryo-specific secretory proteins could be detected in the maternal blood at the time of maternal recognition of pregnancy. In two experiments, 92 embryos were flushed from 47 ewes at 14-15 days after estrus. Embryos were incubated in vitro for 24 h and the proteins in the media were harvested. Antisera to proteins in both flushing and incubation medium were produced in rabbits. In experiment 1, crude fractions were used for antibody production and radioimmunoassays were established for protein peaks separated on a 1.1 X 75 cm G-100 Sephadex column. Two low molecular weight fractions (EPiv and EPv) appeared to be embryo specific but were not detectable in jugular vein sera of 14- to 15-day pregnant animals. In experiment 2, proteins derived from uterine flushes and from embryo incubations were chromatographed on a 2.5 X 85 cm column of G-100 Sephadex. The protein peaks were measured, pooled, lyophilized, and used for immunization of rabbits. As in experiment 1, antisera were generated, some of which seemed to be directed against embryo-specific proteins. However, we could not detect these fractions in the uterine vein blood of pregnant animals. Thus, embryo-specific proteins are either confined to the uterus or they appear in the blood in quantities that are undetectable with our assay system.     

A role for interferons in early pregnancy

In order to survive, the developing conceptus must interrupt the normal ovarian cycle of the mother and extend the production of progesterone by the corpus luteum. An unusual Type 1 interferon (IFN), related structurally to the IFN-alpha molecule and produced in massive amounts for only a few days by the first epithelium (trophectoderm) of the preimplantation conceptus, has been implicated as the antiluteolytic agent in sheep and cattle. IFN-alpha therapy during this critical period can also improve pregnancy success in sheep. It remains unclear, however, whether the trophoblast IFN have specialized biological properties or whether they are unique merely in the timing, magnitude and site of their expression.     

The critical period for the maternal recognition of pregnancy in pony mares.

Two experiments were performed to deterine the critical time at which the equine blastocyst must be present within the uterus of the mare to prevent regression of the corpus luteum, and thus establish the critical time for the maternal recognition of pregnancy. A non-surgical blastocyst collection technique was developed to study this relationship between the blastocyst and the maternal ovary. Results from these experiments demonstrated that the cyclic life-span of the corpus luteum is not affected by the presence of the blastocyst within the mare's uterus until after Day 14 after ovulation. Luteal function was prolonged when blastocysts were removed on Day 15 or later. The critical period for the maternal recognition of pregnancy in the Pony mare appears to be confined to the period between Days 14 and 16 after ovulation.     

Thrombosis in pregnancy and maternal outcomes

Pregnancy increases the risk of thrombosis four‐ to five‐fold. Seventy‐five to eighty percent of pregnancy‐related thrombotic events are venous and twenty to –twenty‐five percent are arterial. The main reason for the increased risk is hypercoagulability. Women are hypercoagulable because they have evolved so that they are protected against the bleeding challenges of pregnancy, miscarriage, or childbirth. Both genetic and acquired risk factors can further increase the risk of thrombosis. The maternal consequences of thrombosis of pregnancy include permanent vascular damage, disability, and death. While the maternal outcomes of thrombosis can be modified by anticoagulation therapy, management of thrombosis during pregnancy is the subject of another paper in this issue (see paper by B. Konkle). This review will focus on the epidemiology, pathophysiology, risk factors, and maternal consequences of thrombosis in pregnancy. Birth Defects Research (Part C) 105:159–166, 2015. © 2015 Wiley Periodicals, Inc.     

Receptors for prostaglandins F2 alpha and E2 in ovine corpora lutea during maternal recognition of pregnancy.

Plasma membrane receptors for prostaglandins (PG) F2 alpha and E2 were quantified in ovine corpora lutea obtained from nonpregnant and pregnant ewes on Days 10, 13, and 15 post-estrus, and from additional ewes on Days 25 and 40 of pregnancy. Regardless of reproductive status or day post-estrus, concentrations of luteal receptors for PGF2 alpha were 7- to 10-fold greater than those for PGE2. In pregnant ewes the concentration of receptors for PGF2 alpha was highest on Day 10 (35.4 +/- 2.8 fmol/mg) and lowest on Day 25 (22.3 +/- 2.5 fmol/mg). A difference in the concentration of luteal receptors for PGF2 alpha between pregnant and nonpregnant ewes was apparent only on Day 15 post-estrus, at which time the concentration of receptors for PGF2 alpha was higher in pregnant ewes than in nonpregnant ewes (27.1 +/- 2.7 vs. 17.7 +/- 2.7 fmol/mg). Concentrations of receptors for PGE2 in pregnant ewes were similar (p > 0.05; 2.8 +/- 0.3 to 3.7 +/- 0.2 fmol/mg) between Days 13 and 40 but were higher (p < 0.05) than in corpora lutea obtained from nonpregnant ewes on Days 10 (5.0 +/- 0.4 vs. 4.1 +/- 0.2 fmol/mg) and 15 (3.7 +/- 0.2 vs. 2.0 +/- 0.4 fmol/mg) post-estrus. Although concentrations of receptors for both PGF2 alpha and PGE2 were lowest in corpora lutea obtained from nonpregnant ewes on Day 15, this was not due to luteal regression since the weights and concentrations of progesterone in corpora lutea on Day 15 were not lower than those for corpora lutea obtained on Days 10 and 13.(ABSTRACT TRUNCATED AT 250 WORDS)     

Roles of maternal HDL during pregnancy

BackgroundHigh density lipoproteins (HDL) were first linked to cardiovascular disease (CVD) over 30 years ago when an inverse relationship was shown between CVD and HDL-cholesterol levels. It is now apparent that HDL composition and function, not cholesterol levels, are the pertinent measurements describing HDL's role in various disease processes, especially those with subclinical or overt inflammation.Scope of reviewPregnancy is also an inflammatory state. When inflammation becomes excessive during pregnancy, there is an increased risk for adverse outcomes that affect the health of the mother and fetus, including preterm birth and preeclampsia. Though studies on HDL during pregnancy are limited, recent evidence demonstrates that HDL composition and function change during pregnancy and in women with adverse outcomes.General significanceIn this review, we will discuss how HDL may play a role in maintaining a healthy pregnancy and how impairments in function could lead to pregnancies with adverse outcomes.     

Congenital malformations and maternal smoking during pregnancy

The relationship between smoking during pregnancy and congenital malformations was studied in prospective studies of 33,434 live births in the Kaiser-Permanente Birth Defects Study and 53,512 live births in the Collaborative Perinatal Project (CPP). In the Kaiser study, statistically significant positive associations (P less than .05) were observed for ventral hernias, omphaloceles, and "other major gut abnormalities," but, for each comparison the estimates were based on one or two unexposed cases. Statistically significant negative associations were found for ventricular septal defects (odds ratio, 0.5 [95% confidence interval, 0.2-0.96]), hydroceles (0.7 [0.6-0.9]), clubfoot (0.7 [0.6-0.9]), pigmented nevi (0.7 [0.6-0.9]), hemangiomas (0.8[0.7-0.98]) and Down syndrome (0.2 [0.1-0.9]). To determine if the findings noted above were an artifact of multiple comparisons, seven of these nine malformations were analyzed by smoking status for women in the CPP. All but one of the associations were not confirmed in the CPP. Previously described associations between smoking and specific congenital malformations were also tested using data from the CPP. We conclude that smoking is unlikely to be responsible for a large increase in malformations at birth.