Psychological Distress, Stressful Life Events and Social Disadvantage in Pregnant Indigenous Australian Women Residing in Rural and Remote NSW: a Longitudinal Cohort Study.

BACKGROUND: Pregnancy can be a stressful time for many women. Australian Indigenous women of childbearing age (18-44 years) have been found to experience high or very high rates of psychological distress. However, few studies have examined the burden of or any associations between stressful life events, social disadvantage and psychological distress for pregnant Indigenous women in Australia. METHODS: Two hundred sixty-one rural and remote women, pregnant with an Indigenous infant, from New South Wales in Australia were invited to provide data regarding social disadvantage then complete the Kessler-10 and Stressful Life Events surveys via self-report during each trimester of their pregnancy. Descriptive statistics, Pearson's correlations, Mann-Whitney U and Kruskal-Wallis tests were performed to determine the burden of and any associations between the variables of interest. RESULTS: High rates of psychological distress were reported by participants with 16.9% scoring severe distress levels during their pregnancy. Participants also reported high rates of stressful life events with almost 25% experiencing the death of a family member or friend, almost 14% living in overcrowded accommodation, 11% having someone close to them jailed and 8% experience separation from their partner, during their pregnancies. Distress was associated with numerous stressful life events (e.g. witnessing violence, a family member in jail and overcrowding) and one aspect of social disadvantage (smoking status). CONCLUSIONS: Immediate attention needs to focus on the development of interventions to address the high levels of psychological distress and provide appropriate support services during periods of major life events for pregnant Australian Indigenous women.

Pregnancy stress, healthy pregnancy and birth outcomes - the need for early preventative approaches in pregnant Australian Indigenous women: a prospective longitudinal cohort study.

Adverse pregnancy outcomes including prematurity and low birth weight (LBW) have been associated with life-long chronic disease risk for the infant. Stress during pregnancy increases the risk of adverse pregnancy outcomes. Many studies have reported the incidence of adverse pregnancy outcomes in Indigenous populations and a smaller number of studies have measured rates of stress and depression in these populations. This study sought to examine the potential association between stress during pregnancy and the rate of adverse pregnancy outcomes in Australian Indigenous women residing in rural and remote communities in New South Wales. This study found a higher rate of post-traumatic stress disorder, depression and anxiety symptoms during pregnancy than the general population. There was also a higher incidence of prematurity and LBW deliveries. Unfortunately, missing post-traumatic stress disorder and depressive symptomatology data impeded the examination of associations of interest. This was largely due to the highly sensitive nature of the issues under investigation, and the need to ensure adequate levels of trust between Indigenous women and research staff before disclosure and recording of sensitive research data. We were unable to demonstrate a significant association between the level of stress and the incidence of adverse pregnancy outcomes at this stage. We recommend this longitudinal study continue until complete data sets are available. Future research in this area should ensure prioritization of building trust in participants and overestimating sample size to ensure no undue pressure is placed upon an already stressed participant.

Influence of maternal adiposity, preterm birth and birth weight centiles on early childhood obesity in an Indigenous Australian pregnancy-through-to-early-childhood cohort study.

Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother-child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight (P=0.005) and GROW customized birth weight centiles (P=0.008). There was a significant association between maternal percentage body fat (P=0.02) and visceral fat area (P=0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term (P=0.03). GROW customized birth weight centiles was significantly associated with body weight (P=0.01), BMI (P=0.007) and abdominal circumference (P=0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women.

The relationship between maternal obesity and diabetes during pregnancy on offspring kidney structure and function in humans: a systematic review.

Evidence from animal models indicates that exposure to an obesogenic or hyperglycemic intrauterine environment adversely impacts offspring kidney development and renal function. However, evidence from human studies has not been evaluated systematically. Therefore, the aim of this systematic review was to synthesize current research in humans that has examined the relationship between gestational obesity and/or diabetes and offspring kidney structure and function. Systematic electronic database searches were conducted of five relevant databases (CINAHL, Cochrane, EMBASE, MEDLINE and Scopus). Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed, and articles screened by two independent reviewers generated nine eligible papers for inclusion. Six studies were assessed as being of 'neutral' quality, two of 'negative' and one 'positive' quality. Observational studies suggest that offspring exposed to a hyperglycemic intrauterine environment are more likely to display markers of renal dysfunction and are at higher risk of end-stage renal disease. There was limited and inconsistent evidence for a link between exposure to an obesogenic intrauterine environment and offspring renal outcomes. Offspring renal outcome measures across studies were diverse, with a large variation in offspring age at follow-up, limiting comparability across studies. The collective current body of evidence suggests that intrauterine exposure to maternal obesity and/or diabetes adversely impacts renal programming in offspring, with an increased risk of kidney disease in adulthood. Further high-quality, longitudinal, prospective cohort studies that measure indicators of offspring renal development and function, including fetal kidney volume and albuminuria, at standardized follow-up time points, are warranted.

Disparities exist between the dietary intake of Indigenous Australian women during pregnancy and the Australian dietary guidelines: the Gomeroi gaaynggal study.

BACKGROUND: Little is known about the adequacy of nutrient intakes and the overall diet quality of Indigenous Australian pregnant women. The aim of this cross-sectional study was to assess nutrient sufficiency and diet quality, as measured using the Australian Recommended Food Score (ARFS), in pregnant women from the Gomeroi gaaynggal cohort (n = 58). METHODS: Maternal dietary intake during pregnancy was assessed using the Australian Eating Survey Food Frequency Questionnaire, which was self-administered in the third trimester. Diet quality was determined using the ARFS. Food group servings and nutrient intakes were compared to the Australian Guide to Health Eating (AGHE) and Australian Nutrient Reference Values (NRVs). The current analysis examined the adequacy of usual intakes from food sources only, excluding supplements. RESULTS: None of the women met all AGHE daily food group serving recommendations. The highest alignment rates were for dairy (33%), meat/alternatives (31%) and vegetables (29.3%). Almost 93% of participants exceeded the recommended intake of energy-dense, nutrient-poor foods and percentage energy from saturated fat was high (15%). Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving the NRVs were zinc (77.6%) and folate (68.9%), whereas iron was the lowest. Only one person achieved all NRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. The median ARFS was 28 points (maximum of 73). CONCLUSIONS: Although the small cohort limits the generalisability of the findings of the present study, the data obtained indicate that the diets of these Indigenous pregnant women are inadequate. Therefore, strategies aiming to optimise nutrient intakes of Indigenous pregnant women are needed urgently.

A novel embryo culture media supplement that improves pregnancy rates in mice.

The preimplantation embryo in vivo is exposed to numerous growth factors in the female reproductive tract, which are not recapitulated in embryo culture media in vitro The IGF2 and plasminogen activator systems facilitate blastocyst development. We hypothesized that the addition of IGF2 in combination with urokinase plasminogen activator (uPA) and plasminogen could improve rates of blastocyst hatching and implantation in mice. B6BcF1 and CBAB6F2 mouse embryos were divided into one of four supplemented culture media treatment groups: (1) control (media only); (2) 12.5 nM IGF2; (3) 10 µg/mL uPA and 5 µg/mL plasminogen; or (4) a combination of IGF2, uPA and plasminogen treatments. Embryo development to blastocyst stage and hatching were assessed before transfer to pseudopregnant recipient females and implantation, pregnancy rates and postnatal growth were assessed. After 90.5 h of culture, IGF2 + U + P treatment increased the percentage of B6BcF1 embryos that were hatching/hatched and percentage developing to blastocyst stage compared with controls (P < 0.02). Following B6BcF1 embryo transfer, IGF2 + U + P treatment increased implantation sites at day 8 of pregnancy compared with controls (P < 0.05). Replication in the CBAB6F2 mouse strain showed significant improvements in pregnancy rates at days 8 and 18 but not in blastocyst development. No adverse effects were seen on gestational age, litter size or birthweight, or the reproductive capacity of offspring of IGF2 + U + P treated embryos. For embryos susceptible to detrimental effects of in vitro culture, IGF2, uPA and plasminogen supplementation of culture media can improve pregnancy success, but the effect of treatment is dependent on the mouse strain.

A cohort of Indigenous Australian women and their children through pregnancy and beyond: the Gomeroi gaaynggal study.

Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child's first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 2010 the study has recruited over 230 women, and retained 66 postpartum. Recruitment is ongoing, and Gomeroi gaaynggal is currently the largest Indigenous pregnancy-through-early-childhood cohort internationally. Baseline median gestational age was 39.1 weeks (31.5-43.2, n=110), median birth weight was 3180 g (910-5430 g, n=110). Over one third (39.3%) of infants were admitted to special care or neonatal nursery. Nearly half of mothers (47.5%) reported tobacco smoking during pregnancy. Results of the study will contribute to knowledge about origins of chronic disease in Indigenous Australians and nutrition and growth of women and their offspring during pregnancy and postpartum. Study strengths include employment and capacity-building of Indigenous staff and the complementary ArtsHealth programme.

Fetal sex and the circulating renin-angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension.

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.

The effects of cyclic AMP, sex steroids and global hypomethylation on the expression of genes controlling the activity of the renin-angiotensin system in placental cell lines.

The placental renin-angiotensin system (RAS) is involved in placentation. We have shown that prorenin mRNA (REN) is expressed in a first trimester trophoblast cell line (HTR-8/SVneo) but not in a choriocarcinoma cell line (BeWo). We attempted to stimulate RAS expression in these cells by cAMP, 5'-aza-2'-deoxycytidine (AZA; an inhibitor of methylation), cAMP and AZA combined, and the sex steroids medroxyprogesterone acetate (MPA) and estradiol-17ß (E(2)) with and without cAMP. RAS mRNAs were measured by qPCR and prorenin concentration in supernatants measured by an ELISA. In HTR-8/SVneo cells, all treatments increased REN expression compared to controls and cAMP + AZA combined was more effective than either treatment alone. Prorenin levels in supernatants were similarly upregulated. In HTR-8/SVneo cells, angiotensinogen (AGT) mRNA expression was increased by MPA + E(2) either with or without cAMP. AGT expression was also significantly increased by AZA. BeWo cells did not express REN or prorenin and it was not inducible with any treatment. AGT expression was significantly increased with AZA, the combination of cAMP + AZA, and MPA + E(2) + cAMP treatments. Since cAMP, AZA, cAMP and AZA combined, or MPA and E(2) with and without cAMP in HTR-8/SVneo cells, a cell line most similar in its RAS expression to the in vivo placenta, these factors may affect placental RAS activity. Surprisingly, these treatments also induced AGT expression in BeWo cells. Whether they are involved in regulating AGT in choriocarcinomas in vivo remains to be determined.

Regulation of the renin-angiotensin system (RAS) in BeWo and HTR-8/SVneo trophoblast cell lines.

OBJECTIVES: The renin-angiotensin system (RAS) is implicated in placentation. We determined which RAS pathways are present in two trophoblast cell lines (HTR-8/SVneo and BeWo cells) and the effects of cAMP, which stimulates renal renin. STUDY DESIGN: The effect of cAMP on RAS gene expression and on prorenin and angiotensin peptides in HTR-8/SVneo and BeWo cells were investigated. RESULTS: In HTR-8/SVneo cells, prorenin mRNA (REN) and protein, (pro)renin receptor (ATP6AP2) and angiotensin II type 1 receptor (AGTR1) were stimulated by cAMP (P < 0.05, P < 0.05, P < 0.001 and P < 0.05, respectively). HTR-8/SVneo cells also expressed angiotensinogen (AGT) and angiotensin converting enzyme 1 (ACE1), but did not express AGTR2 or ACE2 nor the Ang 1-7 receptor (MAS1). BeWo cells did not express REN, and REN was not inducible by cAMP, but cAMP increased ACE2 and MAS1 (both P < 0.05) and decreased AGT (P < 0.05). BeWo cells expressed AGT, ACE1, ACE2 and MAS1 but not ATP6AP2, AGTR1 nor AGTR2. There was net destruction of Ang II in media from HTR-8/SVneo and BeWo incubations and net production of Ang 1-7 by BeWo and untreated HTR-8/SVneo cells. CONCLUSION: HTR-8/SVneo cells express REN and produce prorenin as well as expressing other RAS genes likely to regulate Ang II/AT(1)R interactions and respond to cAMP, like renal renin-secreting cells. They are more similar to early gestation placentae and are therefore useful for studying effects of renin/ACE/Ang II/AT1R on cell function. BeWo cells express the ACE2/Ang 1-7/Mas pathway, which is sensitive to cAMP and therefore are useful for studying the effects of ACE2/Ang 1-7/Mas on trophoblast function.

The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: roles in trophoblast invasion and angiogenesis?

The renin-angiotensin system (RAS) is thought to regulate placentation, however, the expression and localization of RAS pathways in early gestation human placenta is not known. Here we describe the expression of prorenin (REN), (pro)renin receptor (ATP6AP2), angiotensinogen (AGT), angiotensin-converting enzyme 1 and 2 (ACE; ACE2), angiotensin II type 1 and 2 receptors (AGTR1; AGTR2) and angiotensin 1-7 receptor (MAS1), as well as the angiogenic factor, vascular endothelial growth factor (VEGF), and transforming growth factor-ß1 (TGF-ß1), in early gestation (6-16 weeks) and term (>37 weeks) human placentae. We also describe the location of all of the key RAS proteins in the early gestation placentae. The highest levels of REN, ATP6AP2, AGT, AGTR1 and ACE2 mRNAs were found in early gestation, whereas ACE1 mRNA was highest at term. AGTR2 and MAS1 mRNA expression were low to undetectable in all samples. REN, ATP6AP2 and AGTR1 mRNA levels were correlated with VEGF expression, but not with TGF-ß1 mRNA. In early gestation placentae, prorenin, (pro)renin receptor and the angiotensin II type 1 receptor (AT(1)R) were localized to extravillous trophoblast cells, suggesting they play a key role in trophoblast migration. ACE2 in syncytiotrophoblasts could regulate release of Ang 1-7 into the maternal circulation contributing to the vasodilation of the maternal vasculature. ACE was only found in fetal vascular endothelium and may specifically target the growing fetal placental vessels. Because REN, ATP6AP2 and AGTR1 show strong correlations with expression of VEGF this pathway is likely to be important in placental angiogenesis.

Molecular characterization of renin-angiotensin system components in human intrauterine tissues and fetal membranes from vaginal delivery and cesarean section.

A prorenin-angiotensin system (RAS) could, via the (pro)renin receptor (ATP6AP2), have various effects in human intrauterine tissues, either directly by prorenin/ATP6AP2 cell signaling, or indirectly via angiotensin II and/or angiotensin 1-7. Here we describe RAS components in fetal membranes, decidua and placenta collected at elective cesarean section (non-laboring), after spontaneous delivery (after labor, n = 38), and in myometria (n = 16) from elective (non-laboring) or emergency cesarean (laboring) deliveries. Angiotensinogen (AGT), angiotensin-converting enzyme 1 and 2 (ACE; ACE2), angiotensin receptor 1 and 2 (AGTR1; AGTR2) and angiotensin 1-7 receptor (MAS1) mRNAs were measured by qRT-PCR and proteins were localized by immunohistochemistry. In myometrium, prorenin (REN), ATP6AP2, and downstream signaling proteins zinc finger and BTB domain-containing protein 16 (ZBTB16), transforming growth factor-ß1 (TGFß1) and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNAs were also measured. RAS mRNAs, except AGTR1 and AGTR2, were abundant in decidua and lowest in amnion compared to the other tissues. ACE, AGT and PTGS2 mRNAs were higher in laboring than non-laboring myometrium, suggesting that the myometrial RAS is involved in labor. Angiotensinogen and prorenin staining in amnion, chorion and decidua was pervasive despite their mRNAs being low in amnion and chorion. In placenta, prorenin, angiotensinogen and AGTR2 were present in syncytiotrophoblasts, ACE was in fetal endothelium, while ACE2 distribution was diffuse. AGTR1 and AGTR2 mRNAs and proteins were abundant. No differences were evident in the staining patterns with labor. These results are consistent with the hypothesis that fetal vascular ACE might contribute angiotensin II to the fetus, whilst syncytial ACE2 might hypothetically have a role in converting angiotensin II to angiotensin 1-7 in maternal blood.

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth.

Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming.

Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy.

In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.

Complex interactions between hypoxia inducible factors, insulin-like growth factor-II and oxygen in early murine trophoblasts.

The human first trimester placenta experiences a low oxygen environment. The hypoxia inducible factors (HIFs) mediate the response to low oxygen, inducing genes such as insulin-like growth factor (IGF)-II. Interestingly, IGF-II has been shown to promote placental growth and function. Currently, the interaction between oxygen, IGF-II and HIFs in the regulation of trophoblast behaviour are unclear. Murine implantation sites from days 5.5-10.5 were collected for immunohistochemical analyses. Use of the hypoxia marker pimonidazole indicated that the early mouse implantation site is exposed to low oxygen levels similar to those seen in the early human placenta. HIF-1alpha protein immunostaining was also observed in the implantation site. Culturing murine ectoplacental cones in decreasing oxygen concentrations (20%, 5% and 1% O(2)), either with or without the addition of IGF-II, induced complex responses by trophoblasts in terms of their migration and differentiation. Following 3 days exposure to low oxygen there was reduced EPC outgrowth, reduced Igf2 and increased Tpbp mRNA levels, suggesting commitment to the spongiotrophoblast lineage. In addition, Hif-1alpha mRNA levels were decreased, whilst Hif-2alpha mRNA was unchanged. This decrease in Hif-1alpha may be due to the observed increase in antisense (as) Hif-1alpha mRNA levels in 1% cultures. Furthermore, expression of Hif-2alpha and the HIF target genes: asHif-1alpha, Vegf and Slc2a1 were reduced under low oxygen with the addition of IGF-II. In conclusion, Hif-1alpha and Hif-2alpha are differentially regulated by oxygen and IGF-II in cultured trophoblast cells and asHif-1alpha may mediate the response to prolonged hypoxia in murine trophoblasts.

New light on early post-implantation pregnancy in the mouse: roles for insulin-like growth factor-II (IGF-II)?

Successful placental development and the associated changes to the decidual vasculature during early pregnancy are critical to pregnancy outcome. This study utilised immunohistochemistry to provide a photomicrographic account of trophoblast invasion, as well as the changes in the uterine vasculature in the decidua from days 5.5 to 10.5 of murine pregnancy. The pattern of trophoblast invasion during this time is particularly interesting because, unlike in humans, murine trophoblast giant cells (TGCs) do not invade the endometrium individually but remain in close contact with the expanding giant cell layer. Therefore, trophoblast cells are unlikely to play a direct role in remodelling the maternal vessels in early to mid pregnancy. Nevertheless, the decidual vessels appear to undergo extensive angiogenesis and remodelling to form a network of dilated vessels that presumably maximize placental blood supply. Importantly, the vessels closest to the conceptus lacked a smooth muscle layer throughout early pregnancy and therefore cannot strictly be described as spiral arterioles. TGCs may secrete molecules that can act to induce these vascular changes. Here we show that insulin-like growth factor-II (IGF-II) is expressed throughout early pregnancy in the entire conceptus including trophoblast cells, supporting its role in promoting early placental growth. In addition, the co-localisation of IGF-II and both IGF receptors in the developing blood vessels and/or adjacent stromal cells in the mesometrial, but not in the anti-mesometrial, decidua suggest that IGF-II, upon binding to one of these receptors, may play a role in both decidual angiogenesis and placental differentiation.