Search

Aims/hypothesis: Offspring of obese women are at increased risk of features of the metabolic syndrome, including obesity and diabetes. Lifestyle intervention in pregnancy might reduce adverse effects of maternal obesity on neonatal adiposity., Methods: In the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention (DALI) lifestyle trial, 436 women with a BMI ≥29 kg/m 2 were randomly assigned to counselling on healthy eating (HE), physical activity (PA) or HE&PA, or to usual care (UC). In secondary analyses of the lifestyle trial, intervention effects on neonatal outcomes (head, abdominal, arm and leg circumferences and skinfold thicknesses, estimated fat mass, fat percentage, fat-free mass and cord blood leptin) were assessed using multilevel regression analyses. Mediation of intervention effects by lifestyle and gestational weight gain was assessed., Results: Outcomes were available from 334 neonates. A reduction in sum of skinfolds (-1.8 mm; 95% CI -3.5, -0.2; p = 0.03), fat mass (-63 g; 95% CI -124, -2; p = 0.04), fat percentage (-1.2%; 95% CI -2.4%, -0.04%; p = 0.04) and leptin (-3.80 μg/l; 95% CI -7.15, -0.45; p = 0.03) was found in the HE&PA group, and reduced leptin in female neonates in the PA group (-5.79 μg/l; 95% CI -11.43, -0.14; p = 0.05) compared with UC. Reduced sedentary time, but not gestational weight gain, mediated intervention effects on leptin in both the HE&PA and PA groups., Conclusions/interpretation: The HE&PA intervention resulted in reduced adiposity in neonates. Reduced sedentary time seemed to drive the intervention effect on cord blood leptin. Implications for future adiposity and diabetes risk of the offspring need to be elucidated., Trial Registration: ISRCTN70595832.

Background: Depression during pregnancy is associated with higher maternal morbidity and mortality, and subsequent possible adverse effects on the cognitive, emotional and behavioral development of the child. The aim of the study was to identify maternal characteristics associated with poor mental health, in a group of overweight/obese pregnant women in nine European countries, and thus, to contribute to better recognition and intervention for maternal depression., Methods: In this cross-sectional observational study, baseline data from early pregnancy (< 20 weeks) of the DALI (Vitamin D and Lifestyle Intervention for gestational diabetes mellitus prevention) study were analyzed. Maternal mental health was assessed with the World Health Organization Well-Being Index (WHO-5). Women were classified as having a low (WHO-5 ≤ 50) or high wellbeing., Results: A total of 735 pregnant women were included. The prevalence of having a low wellbeing was 27.2%, 95% CI [24.0, 30.4]. Multivariate analysis showed independent associations between low wellbeing and European ethnicity, OR = .44, 95% CI [.25, .77], shift work, OR = 1.81, 95% CI [1.11, 2.93], insufficient sleep, OR = 3.30, 95% CI [1.96, 5.55], self-efficacy, OR = .95, 95% CI [.92, .98], social support, OR = .94, 95% CI [.90, .99], and pregnancy-related worries (socioeconomic: OR = 1.08, 95% CI [1.02, 1.15]; health: OR = 1.06, 95% CI [1.01, 1.11]; relationship: OR = 1.17, 95% CI [1.05, 1.31])., Conclusions: Mental health problems are common in European overweight/obese pregnant women. The identified correlates might help in early recognition and subsequent treatment of poor mental health problems during pregnancy. This is important to reduce the unfavorable effects of poor mental health on pregnancy outcomes., Trial Registration: ISRCTN70595832 , 02.12.2011.

Introduction: We explored beliefs, perceived barriers, and preferences regarding lifestyle changes among overweight European pregnant women to help inform the development of future lifestyle interventions in the prevention of gestational diabetes mellitus., Methods: An explorative mixed methods, two-staged study was conducted to gather information from pregnant European women (BMI ≥ 25 kg/m2). In three European countries 21 interviews were conducted, followed by 71 questionnaires in six other European countries. Content analysis and descriptive and chi-square statistics were applied (p < 0.05)., Results: Women preferred to obtain detailed information about their personal risk. The health of their baby was a major motivating factor. Perceived barriers for physical activity included pregnancy-specific issues such as tiredness and experiencing physical complaints. Insufficient time was a barrier more frequently reported by women with children. Abstaining from snacking was identified as a challenge for the majority of women, especially for those without children. Women preferred to obtain support from their partner, as well as health professionals and valued flexible lifestyle programs., Conclusions: Healthcare professionals need to inform overweight pregnant women about their personal risk, discuss lifestyle modification, and assist in weight management. Lifestyle programs should be tailored to the individual, taking into account barriers experienced by overweight first-time mothers and multipara women.

The environment in utero and in early neonatal life may induce a permanent response in the fetus and the newborn, leading to enhanced susceptibility to later diseases. This review concentrates on the role and mechanisms of events during the antenatal and immediate postnatal period resulting in later life diseases, concentrating on abnormal growth patterns of the fetus. Fetal overgrowth is related to exposure to a diabetic intra uterine environment, increasing the vulnerability to transgenerational obesity and hence an increased sensitivity to more diabetic mothers. This effect has been supported by animal data. Fetal growth restriction is complex due to malnutrition in utero, catch up growth due to a high caloric intake and low physical activity in later life. Metabolic changes and a transgenerational effect of intra uterine malnutrition has been supported by animal data. In recent years the discovery of alterations of the genome due to different influences during embryonic life, called epigenetics, has led to the phenomenon of fetal programming resulting in changing transgenerational metabolic effects.

Aims/hypothesis: Accumulating evidence suggests that maternal obesity may increase the risk of metabolic disease in the offspring. We investigated the effects of established maternal diet-induced obesity on male and female offspring appetite, glucose homeostasis and body composition in rats., Methods: Female Wistar rats were fed either a standard chow (3% fat, 7% sugar [wt/wt]) or a palatable obesogenic diet (11% fat, 43% sugar [wt/wt]) for 8 weeks before mating and throughout pregnancy and lactation. Male and female offspring of control and obese dams were weaned on to standard chow and assessed until 12 months of age., Results: At mating, obese dams were heavier than control with associated hyperglycaemia and hyperinsulinaemia. Male and female offspring of obese dams were hyperphagic (p < 0.0001) and heavier than control (p < 0.0001) until 12 months of age. NEFA were raised at 2 months but not at 12 months. At 3 months, OGTT showed more pronounced alteration of glucose homeostasis in male than in female offspring of obese animals. Euglycaemic-hyperinsulinaemic clamps performed at 8 to 9 months in female and 10 to 11 months in male offspring revealed insulin resistance in male offspring of obese dams (p < 0.05 compared with control). Body compositional analysis at 12 months also showed increased fat pad weights in male and female offspring of obese animals., Conclusions/interpretation: Diet-induced obesity in female rats leads to a state of insulin resistance in male offspring, associated with development of obesity and increased adiposity. An increase in food intake may play a role.

This commentary summarizes current knowledge on the pathophysiology of gestational diabetes, focusing on the role of the endocrine pancreas and the beta-cells, their adaptation in normal pregnancy, and recent insights in the molecular basis for deficient adaptation in diabetes occurring during pregnancy. Additionally, the effects of disturbed maternal glucose metabolism during pregnancy on the glucose metabolism of the offspring are discussed.

Older age is an assumed risk factor for the development of gestational diabetes mellitus (GDM) in women. Here, we studied the effect of age and pregnancy on fat mass and glucose tolerance in rats. We performed intravenous glucose tolerance tests (IVGTTs) in 3- and 9-month-old rats, either nonpregnant or pregnant (day 20). In addition, we measured maternal fat mass, by dual-energy x-ray absorptiometry, and plasma leptin and lipid levels, as well as fetal parameters, on day 22. Nine-month-old rats had higher fat mass and plasma leptin, cholesterol, and triglyceride concentrations than 3-month-old rats. Glucose levels during the IVGTTs were elevated at several time points in 9-month-old rats, and the area under the curve (AUC) was increased. Pregnancy did not affect fat mass or the AUC for glucose during the IVGTT. The AUC for insulin during the IVGTTs was increased by age as well as pregnancy, but there was no interaction between the two by 2-factor analysis of variance. Reproductive performance was less optimal in 9-month-old rats, with a reduction of individual fetal and placental weight. In conclusion, 9-month-old rats exhibit a deterioration in glucose tolerance, possibly linked to the age-dependent increase in fat mass and leptin concentrations. Pregnancy also comprises certain adaptations in lipid and glucose metabolism, but because no interaction was found between both factors, the effect of pregnancy is not aggravated by aging. This may suggest than an increased gestational diabetes mellitus prevalence in older women can similarly be explained by age as such.

The mammalian fetus develops inside the uterus of its mother and is completely dependent on the nutrients supplied by its mother. Disturbances in the maternal metabolism that alter this nutrient supply from mother to fetus can induce structural and functional adaptations during fetal development, with lasting consequences for growth and metabolism of the offspring throughout life. This effect has been investigated, by several research groups, in different experimental models where the maternal metabolism during pregnancy was experimentally manipulated (maternal diabetes and maternal malnutrition) and the effect on the offspring was investigated. The altered maternal/fetal metabolism appears to be associated with a diabetogenic effect in the adult offspring, including gestational diabetes. This diabetic pregnancy in the offspring again induces a diabetogenic effect into the next generation, via adaptations during fetal development. These experimental data in laboratory animals are confirmed by epidemiological studies on infants of mothers suffering from diabetes or malnutrition during pregnancy. It can be concluded that fetal development in an abnormal intra-uterine milieu can induce alterations in the fetal metabolism, with lasting consequences for the glucose tolerance of the offspring in adult life. The most marked effect is the development of gestational diabetes, thereby transmitting the diabetogenic tendency to the next generation again. The concept of fetal origin of adult diabetes therefore is of major significance for public health in the immediate and the far future.

Exposure to maternal diabetes in utero (GD) may 'program' for obesity. Orexigenic neuropeptides, like neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic neuropeptides, like proopiomelanocortin (POMC) and alpha-melanocyte-stimulating hormone (MSH), are decisively involved in body weight regulation. We investigated consequences of GD and its treatment by pancreatic islet transplantation in rats for development of neuropeptidergic neurons in the arcuate hypothalamic nucleus (ARC) in weanling offspring. In GD, islet transplantation on d15 of pregnancy led to normalized blood glucose. Sham-transplanted GD mothers (TSGD) remained hyperglycemic. Twenty-one-day-old TSGD offspring developed hypothalamic 'malorganization'. Despite of normal leptin and insulin levels in TSGD offspring, increased immunopositivity of NPY and AGRP appeared. TSGD offspring showed unchanged POMC, but decreased MSH-immunopositivity. In conclusion, untreated diabetes in pregnant rats leads to 'malprogramming' of hypothalamic neuropeptidergic neurons in offspring, probably contributing to later development of overweight. These acquired alterations are preventable by treatment of maternal GD.

An overview is given on the scientific education of the Trainees (Specialists in Training in Europe). European legislation is clear and insists on the scientific formation in the undergraduate as well as in the Postgraduate education. It is the task of the national (or regional) authorities to create possibilities for research during clinical training. In most of the national training programmes Research activities are included. Moreover in the European visiting system Research facilities are an important item. Examples are shown how the Royal College of Obstetricians and Gynaecologists (U.K.) and the European Board and College of Obstetrics and Gynaecology have implemented these Research activities in the training programme.

Objectives: Obesity is one of the most important risk factors for the development of gestational diabetes mellitus (GDM). However, in obese women, it is difficult to disentangle the genetic and environmental contributions. The aim of this study was to investigate whether diet-induced obesity results in GDM in rats with the same genetic background., Study Design: Female Wistar rats were fed a cafeteria-style diet (CAF) or the standard control (C) diet from 70 days of age onward. After 4 weeks on the diets, subgroups of CAF and C rats were mated. In virgin and late-pregnant CAF and C rats, we determined body weight, body composition by dual-energy x-ray absorptiometry (DEXA), glucose tolerance by intravenous glucose tolerance test (IVGTT), and insulin sensitivity by hyperinsulinemic euglycemic clamp in nonanesthesized rats. Plasma leptin concentrations were also measured., Results: Body weight increased after 4 weeks in virgin CAF rats (P<.0001) and exceeded that of C rats throughout pregnancy. This resulted exclusively from increased fat mass, as determined by DEXA, and was associated with a rise in plasma leptin concentrations in nonpregnant and pregnant (both P<.0001) CAF rats. During the IVGTT, nonpregnant CAF rats showed normal glucose levels but increased insulin levels compared with C rats (P<.05 for the area under the curve for insulin: AUC(insulin)). In pregnant CAF animals, glucose tolerance was clearly impaired (AUC(glucose): P<.001) with insulin also raised (AUC(insulin): P<.05). On day 22, fetal weight was comparable between C and CAF rats, but litter weight was higher in CAF rats (P<.05) owing to an increase in litter size. Hyperinsulinemic clamp studies revealed unequivocal insulin resistance in nonpregnant CAF rats, which was aggravated by pregnancy, the proportional effect of obesity being higher than that of pregnancy., Conclusion: Diet-induced obesity in rats is associated with glucose intolerance during pregnancy but not in the nonpregnant state. This is likely to result from the additive effects of obesity and pregnancy on insulin sensitivity. This obese rat model is an attractive model to study further the physiologic and molecular abnormalities in GDM.

Exposure to gestational diabetes (GD) in rats leads to dysplasia of the ventromedial hypothalamic nucleus (VMN), decisively involved into the regulation of body weight and metabolism. Recently, we have shown here that VMN malformation is absent in adult offspring of GD mothers treated by pancreatic islet transplantation during gestation. We therefore now investigated whether VMN malformation and its prevention are already present at the early postnatal end of the critical hypothalamic differentiation period. Already at weaning, the total number of VMN neurons, the volume of the VMN relative to total brain volume, and the numerical density of neurons in the anterior subnucleus of the VMN were reduced in offspring of sham-transplanted mothers (all P<0.05), but did not differ between offspring of islet-transplanted mothers and controls. No morphometric alterations occurred in the paraventricular hypothalamic nucleus. In conclusion, prevention of VMN malformation in offspring of islet-transplanted diabetic mothers is a direct consequence of normalized maternal metabolism during critical perinatal development.

Fetal development is dependent on maternal supply of fuels and building blocks. Disturbed maternal metabolism or inappropriate maternal nutrition confronts the fetus with an unfavourable intra-uterine milieu. Structural and functional adaptations occur during development and maturation of organs. Consequences of these fetal alterations persist postnatally and may result in metabolic alterations throughout life. Gestational diabetes can occur in these offspring and transmit the effect to the next generation. These alterations in fetal development can be associated with fetal macrosomia (maternal diabetes) or fetal growth-restriction (maternal/fetal malnutrition). The relation between birth weight and later metabolic disease therefore is U-shaped. Adult metabolic condition is thus to a considerable extent programmed in utero, fetal and neonatal weight being symptoms of disturbed fetal development. This concept of intra-uterine programming of disease is illustrated with a review of epidemiological human studies and experimental animal studies.

Objective: In the present review we discuss rat models in which intra-uterine growth restriction is obtained through pharmacological (streptozotocin), dietary (global food restriction, low protein diet), or surgical (uterine artery ligation) manipulation of the maternal animal., Methods: A MEDLINE search was performed on rat models of intrauterine growth restriction (IUGR), ie, streptozotocin, food restriction, low protein diet, or uterine artery ligation and pregnancy and fetal programming, long-term effects or adult offspring., Results: We address the impact of the different maternal conditions for the fetal and neonatal development. The rat models we concentrate on were all associated with fetal hypoinsulinemia and intrauterine growth restriction. Both fetus and neonate adapt to the altered perinatal environment. Some of these adaptations may predispose the offspring to the development of insulin resistance, cardiovascular disease, obesity, and even overt diabetes in later life., Conclusion: The adaptations of the fetal metabolism to the altered intrauterine environment have consequences for the offspring, persisting into adulthood and into the next generation.

Objective: To examine the use of streptozotocin (SZ) in rats as a model for gestational diabetes mellitus (GDM)., Methods: We studied various doses of SZ, either as a single administration (30, 35, 40, or 50 mg/kg, intraperitoneally) on day 1 of pregnancy or as 2 low doses (30 and 20 or 30 and 30 mg/kg) administered 2 days before mating and on day 1 of pregnancy. We examined the effect on maternal and fetal glucose and insulin concentrations and on fetal weight on day 20 of pregnancy. In a second series of experiments, we studied two groups (SZ 30/20 and SZ 35) with fetal hyperinsulinemia on day 20 of pregnancy. We performed an intravenous glucose tolerance test (IVGTT) on day 20, and in separate groups we reassessed fetal weight and insulin concentrations at term (day 22)., Results: There was considerable variability in glucose concentrations with most SZ doses. Lower doses of SZ (30, 30/20, and 35 mg/kg) did not significantly increase maternal and fetal glucose levels, in contrast to higher doses of SZ (30/30 and 50 mg/kg). Fetuses were smaller on day 20 with all doses except SZ 30 and SZ 30/20; fetal insulin concentrations were elevated with SZ 30, 30/20, and 35. The IVGTT showed glucose intolerance in SZ 35 and SZ 30/20, but the insulin response was unaffected in either group. Fetuses were smaller on day 22 in both these SZ groups, whereas fetal insulin levels at term were not different compared with controls., Conclusions: Low-dose SZ is not a good model for GDM because of the high variability in glucose levels, the normal insulin response to a glucose load, the absence of fetal macrosomia, and the inconsistent effect on fetal insulin concentrations.

There is ample evidence that an adverse intrauterine environment has harmful consequences for health in later life. Maternal diabetes and experimentally induced hyperglycaemia result in asymmetric overgrowth, which is associated with an increased insulin secretion and hyperplasia of the insulin-producing B-cells in the fetuses. In adult life, a reduced insulin secretion is found. In contrast, intrauterine growth restriction is associated with low insulin secretion and a delayed development of the insulin-producing B-cells. These perinatal alterations may induce a deficient adaptation of the endocrine pancreas and insulin resistance in later life. Intrauterine growth restriction in human pregnancy is mainly due to a reduced uteroplacental blood flow or to maternal undernutrition or malnutrition. However, intrauterine growth restriction can be present in severe diabetes complicated by vasculopathy and nephropathy. In animal models, intrauterine growth retardation can be obtained through pharmacological (streptozotocin), dietary (semi-starvation, low protein diet) or surgical (intrauterine artery ligation) manipulation of the maternal animal. The endocrine pancreas and more specifically the insulin-producing B-cells play an important role in the adaptation to an adverse intrauterine milieu and the consequences in later life. The long-term consequences of an unfavourable intrauterine environment are of major importance worldwide. Concerted efforts are needed to explore how these long-term effects can be prevented. This review will consist of two parts. In the first part, we discuss the long-term consequences in relation to the development of the fetal endocrine pancreas and fetal growth in the human; in the second part, we focus on animal models with disturbed fetal and pancreatic development and the consequences for later life.

Objective: Our purpose was to evaluate which factors regulate insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in preterm fetuses., Study Design: We studied 76 singleton births between 25 and 36 weeks of gestation. Forty-nine pregnancies were complicated by hypertensive disease; 24 pregnancies were complicated by preterm labor or preterm rupture of membranes; and antenatal glucocorticoids were given in 49 pregnancies. Pathology reports showed infarct(s) or hematoma(s) in 31 of 69 placentas. We recorded blood gas values in umbilical artery and vein and measured glucose, C-peptide, and insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in umbilical vein., Results: Birth weight correlated with umbilical vein insulin-like growth factor-I (r = 0.68, P <.0001) and inversely with insulin-like growth factor binding protein-1 (r = -0.26, P =.02). Babies with birth weight of 25th percentile. Two-factor analysis of variance showed that umbilical vein insulin-like growth factor-I was determined by gestational age (P =.0004) and birth weight percentile (P <.0001), whereas insulin-like growth factor binding protein-1 was not affected by gestational age. Umbilical vein C-peptide was highly correlated with insulin-like growth factor binding protein-1 (r = -0.55, P <.0001), but not insulin-like growth factor-I, levels. Blood gas values in umbilical artery and vein, particularly umbilical artery PO (2), were correlated with umbilical vein insulin-like growth factor-I and insulin-like growth factor binding protein-1 (r = 0.51 and -0.48, respectively; P <.0001); changes in insulin-like growth factor-I and insulin-like growth factor binding protein-1 occurred at umbilical artery PO (2) <14.8 mm Hg. Multiple regression analysis showed that umbilical vein insulin-like growth factor-I was predicted by umbilical artery PO (2), gestational age, and the presence of placental infarcts/hematomas (R (2) of model = 0.58, P <.0001), and umbilical vein insulin-like growth factor binding protein-1 by umbilical vein C-peptide, umbilical artery PO (2), and placental infarcts/hematomas (R (2) = 0.49, P <.0001)., Conclusion: In the preterm fetus, circulating insulin-like growth factor-I is related to gestational age and the in utero growth potential, whereas insulin-like growth factor binding protein-1 is related only to the in utero growth potential. The PO (2) is a robust determinant of both insulin-like growth factor-I and insulin-like growth factor binding protein-1 levels; hypoxia may restrain fetal growth through its effects on the insulin-like growth factor/insulin-like growth factor binding protein axis. Insulin is a powerful determinant of insulin-like growth factor binding protein-1, but not insulin-like growth factor-I, concentrations in the preterm fetus.

A male newborn with multiple cutaneous hemangiomatosis is described. Pregnancy was complicated by polyhydramnios and a large placental chorioangioma. After an initial outburst of the hemangiomas in the first two weeks of life, spontaneous and almost complete regression occurred before the age of 3 months. The relationship between hemangiomas and placental chorioangioma is briefly discussed.

Vitamin D (D) deficiency during human pregnancy appears to disturb fetal growth and mineralization, but fetal development is normal in D-deficient rats and vitamin D receptor gene-ablated mice. We used the guinea pig model to investigate maternal and fetal effects of D deficiency. Pregnant (Pr) and nonpregnant (NPr) animals were fed a D-replete (+D) or D-deficient diet (-D) for 8 weeks. We further studied whether the effects of a -D diet are reversed by continuous 1,25(OH)2D3 infusion (-D+1,25) and/or by a lactose-, Ca- and P-enriched D-deficient diet (-D+Ca/P). Bone analyses included histomorphometry of the proximal tibiae, dual-energy X-ray absorptiometry (DXA), and quantitative computed tomography (QCT) of the femora. Depletion of 25(OH)D3 and 1,25(OH)2D3 levels and the D-deficiency syndrome were more severe in pregnant animals. Indeed, Pr/-D but not NPr/-D guinea pigs were hypophosphatemic, and showed robust increases in growth plate width and osteoid surface and thickness; in addition, bone mineral density on DXA was lower in Pr/-D animals only, which was exclusively in cortical bone on QCT. Bone phenotype was partly normalized in Pr/-D+1,25 and Pr/-D+Ca/P animals. Compared with +D fetuses, -D fetuses had very low or undetectable 25(OH)D3 and 1,25(OH)2D3, were hypercalcemic and hypophosphatemic, and had lower osteocalcin levels. In addition, body weight and total body bone mineral content were 10-15% lower; histomorphometry showed hypertrophic chondrocyte zone expansion and hyperosteoidosis. 1,25(OH)2D3 levels were restored in -D+1,25 fetuses, and the phenotype was partially corrected. Similarly, the fetal +D phenotype was rescued in large part in -D+Ca/P fetuses, despite undetectable circulating 25(OH)D3 and 1,25(OH)2D3. We conclude that pregnancy markedly exacerbates D deficiency, and that augmenting Ca and P intake overrides the deleterious effects of D deficiency on fetal development.

Problem: To study effects of interleukin-11 (IL-11) on blastocyst development and decidualization., Method of Study: Rats, injected with buffer (C) or IL-11 [1 mg/kg/day = high dose (HD), 60 microg/kg/week = low dose (LD)-1, 30 microg/kg twice a week = low dose (LD)-2] were made pregnant or pseudopregnant to obtain blastocysts or deciduomata., Results: As compared with C, more LD-2 blastocysts hatched in culture, while hatching and attachment of HD blastocysts was decreased. Blastocysts from untreated rats in IL-11 supplemented medium (4 ng/mL) demonstrated increased hatching and attachment. The weight of the decidualized uterus in HD and LD-2 pseudopregnant rats was reduced as compared with C and LD- 1. On deciduomata sections from IL-11 treated rats, the area inside the uterine muscle layer was reduced, and mitotic over pycnotic indices were increased in the anti-mesometrial area and decreased in the mesometrial area., Conclusions: Low doses of IL-11 improve hatching and attachment of blastocysts, but both high and low doses impair decidualization.