Growth Restriction in Balb/c Mice Irradiated With X-Rays During Late Gestation: Role of Irradiation Timing, Dose Fractionation and Adaptive Response

In recent years, considerable epid-emiological and experimental data have accrued which indicates that alterations in the trajectory of fetal growth and development due to suboptimal intrauterine conditions has profound, persistent effects on metabolic function in later life (Hales & Ozanne, 2003; De Blasio et al. 2007; Owens et al. 2007b). Specifically, the relationship between weight at birth and the incidence of diseases such as type 2 diabetes mellitus, hypertension, cardiovascular disease, and obesity in adulthood has received increased attention as the occurrence of this constellation of disorders has reached epidemic proportion in many parts of the world. Collectively, these disorders have come to be recognized as the metabolic syndrome X (Hales & Ozanne, 2003). Whilst remarkable progress has been made characterizing a variety of models for the developmental origins of health and disease (DOHaD), there have been relatively few studies of the fetal physiological adaptations that are likely to underlie this phenomenon. Recently, Owens et al. (2007a) reported in the The Journal of Physiology the first evidence that impaired placental growth and function is associated with reduced glucose stimulated insulin secretion in the late gestation sheep fetus. These important findings indicate that impaired placental function (i.e. placental restriction), which is regarded as being a significant cause of intrauterine growth restriction in humans, has deleterious effects on glucose stimulated insulin secretion that begin during fetal life. Moreover, these data in concert with previous work from the same laboratory show that these effects on glucose stimulated insulin secretion and/or glucose metabolism form a continuum throughout the lifespan of the organism (i.e. fetal life, early postnatal, and adulthood). The present study complements earlier work by making several methodological advances that permit a more thorough evaluation of fetal physiology at different gestational ages. One such advance was the administration of glucose directly to the fetus in this model of placental restriction as opposed to glucose administration to the mother (Harding et al. 1985), in which fetal glucose delivery is limited by glucose transporters 1 and 3. Thus, the authors were able to measure glucose stimulated insulin secretion in both growth-restricted and control fetuses. Furthermore, the authors show for the first time that dysregulated glucose stimulated insulin secretion presages impaired postpartum glucose stimulated insulin secretion in this model of fetal growth restriction. Another methodological advance was employing predictive fetal weight curves that were developed in the authors' laboratory for both control and placental restricted fetuses. The growth curves allowed the authors to adjust the glucose and l-arginine doses to accommodate the increased size of the fetus in later gestation (day of gestation (DG) 120 versus DG 140). Despite the observed discrepancies between predicted and observed fetal weights in the present work, this effort demonstrated excellent forethought. Further, this additional manoeuvre allowed the authors to show that there is an increase in the magnitude of the acute insulin release in response to glucose infusion from DG 120 to DG 140, which suggests an improved capacity for rapid insulin release in late gestation, an observation that is consistent with insulin being an important anabolic factor in the late gestation fetus. Predictors of insulin secretion and glucose tolerance were also identified by Owens et al. (2007a). The authors observed that fetal plasma glucose concentration was positively correlated with placental weight rather than fetal weight, and that fetal plasma insulin concentrations correlated positively with fetal plasma glucose concentration, and fetal and placental weight. The authors suggest that these findings indicate that fetal glucose supply is the primary stimulus for basal insulin secretion and reduced anabolic stimulus from insulin may contribute to growth restriction in the placental restricted fetuses. As expected, the authors observed evidence of accelerated maturational increase in fetal plasma cortisol concentration in the placental restricted fetuses. Interestingly, in contrast to previous studies in the rat that have implicated plasma cortisol concentrations as a programming mechanism for postnatal glucose metabolism (Nyirenda et al. 1998) the authors reported that fetal plasma cortisol concentrations were not related to outcomes in this cohort (Owens et al. 2007a). This observation may indicate that insulin has important maturational effects in late gestation that remain unrecognized, and may reveal a new direction for additional studies in the future. The examination of the developmental origins of disease raise a variety of intriguing questions, not the least of which is that of the optimum time to intervene in an attempt to ameliorate the health concerns of both the mother and the fetus/offspring. Analysing the disruptions in fetal physiology and following the animals through to later life in a model such as the one at present employed by Owens et al. (2007a) has allowed the authors to clearly identify fetal life as an important period for prophylactic treatment of intrauterine growth restriction. Moreover, studies such as these in long gestation species allow investigators the ability to clearly identify differential effects across the discrete windows of programming. As these studies continue, it will be exciting to find out if intervention during late gestation can prevent sequelae such as metabolic syndrome X. Another important question with regard to intervention in fetal life that is raised by the present study is whether or not the sex-dependent differences in metabolic function reported in the offspring originate during early life. Since it has been observed that the growth curves of male and female fetuses (at least in humans) diverge near mid-gestation, with male fetuses growing to be larger for any given age in the last half of gestation (Parker et al. 1984), it follows that the critical windows of sensitivity to programming insults may be shifted depending upon the sex of the fetus. The authors pursued the idea of sex differences in the response to placental restriction in a paper published earlier this year (Owens et al. 2007b). In that work they demonstrated that placental restriction was predictive of impaired glucose homeostasis and insulin secretion in males at 1 year of age, but not in age-matched placental restricted females. Nevertheless, placental restricted females that were thinner at birth became heavier at 1 year of age without a concomitant increase in frame size, suggesting an increased deposition of adipose tissue, which is predictive of impaired insulin sensitivity later in life. This previous study by Owens et al. viewed in concert with the current study suggest that these altered windows of sensitivity may exist not only in the fetus but also in the offspring. Thus, many important questions remain unanswered regarding the contributions of fetal sex to the mechanisms of programming in this and other DOHaD models. In summary, these important observations shed further light on the mechanisms of fetal growth restriction and suggest that decreased energy substrate rather than dysregulated fetal endocrine responses may be a primary defect. Furthermore, the studies of Owens et al. (2007a,b) provide new insight into the matter of how early interventions might be required to remedy the effects of intrauterine growth restriction. The present results, viewed in concert with previous observations from clinical studies in IUGR children and adolescents (Jaquet et al. 2000) and experimental data from IUGR lambs (De Blasio et al. 2007; Owens et al. 2007b) clearly demonstrate that with respect to glucose stimulated insulin secretion, fetal size, at least during late gestation, really does matter.

Stresses during pregnancy that increase maternal glucocorticoids reduce birth weight in several species. However, the role of natural glucocorticoids in the mother in fetal acquisition of nutrients for growth remains unknown. This study aimed to determine whether fetal growth was reduced as a consequence of altered amino acid supply when mice were given corticosterone in their drinking water for 5 day periods in mid to late pregnancy (day, D, 11-16 or D14-19). Compared to controls drinking tap water, fetal weight was always reduced by corticosterone. At D16, corticosterone had no effect on materno-fetal transfer of [(14)C]methylaminoisobutyric acid (MeAIB), although placental MeAIB accumulation and expression of the Slc38a1 and Slc38a2 transporters were increased. However, at D19, 3 days after treatment ended, materno-fetal transfer of MeAIB was increased by 37% (P < 0.04). During treatment at D19, placental accumulation and materno-fetal transfer of MeAIB were reduced by 40% (P < 0.01), although expression of Slc38a1 was again elevated. Permanent reductions in placental vascularity occurred during the earlier but not the later period of treatment. Placental Hsd11b2 expression, which regulates feto-placental glucocorticoid bioavailability, was also affected by treatment at D19 only. Maternal corticosterone concentrations inversely correlated with materno-fetal MeAIB clearance and fetal weight at D19 but not D16. On D19, weight gain of the maternal carcass was normal during corticosterone treatment but reduced in those mice treated from D11 to D16, in which corticosterone levels were lowest. Maternal corticosterone is, therefore, a physiological regulator of the amino acid supply for fetal growth via actions on placental phenotype.

To determine the relationship between placental delivery of oxygen and glucose, circulating insulin-like growth factors (IGFs) and fetal growth, the effect of variable restriction of placental growth was determined in sheep in late gestation. Arterial blood was obtained via indwelling catheters at 120 and 127 days of gestation, prior to necropsy at 130 days to measure fetal and placental weights. Plasma was acidified and subjected to size-exclusion high-performance liquid chromatography at pH 2.8 to dissociate and separate IGFs from their binding proteins. The acid-dissociated IGF fraction was analysed by sensitive and highly specific radioligand assays for IGF-I and IGF-II, previously defined using ovine IGFs. Fetal weight and blood pO2 and glucose at 120 and 127 days of gestation correlated positively with placental weight. Plasma IGF-I was positively associated with fetal weight and fetal liver weight, and with blood pO2 and glucose at both ages. Plasma IGF-II levels also correlated positively with fetal weight, fetal liver weight and with blood glucose and pO2, but only at 127 days of gestation. In the most severely growth-retarded fetal sheep, blood glucose and pO2 and plasma IGF-I were significantly reduced when compared with normal fetuses at 120 days. All decreased further by 127 days of gestation as did plasma IGF-II in severely growth-retarded fetal sheep compared with normal fetuses. These observations are consistent with the hypothesis that both IGF-I and IGF-II are chronically regulated by oxygen and nutrition in utero and mediate part of the influence of placental supply of substrate over fetal growth.

A role of fetal exposure to maternal steroids is suggested as a potential mechanism that contributes to the developmental programming of adult CV risk. We hypothesize that the placenta of the IUGR fetus has a higher levels of corticosterone leading to a reduction in placental size and that transmission of maternal steroids to the fetus may serve as a potential mediator of later programmed CV risk. At day 14 gestation RUPP was performed on pregnant rat dams with sham surgeries performed on Control pregnant rat dams. Fetuses were sacrificed at E19 and E20 and P14. Sampling indicated a significant decrease in fetal weight and PW at E19 in the IUGR compared to the Control fetus; PW was significantly decreased at E20 in IUGR compared to Control. However, placental efficiency was significantly higher in IUGR relative to Control at E19 and E20. BW was significantly decreased in IUGR pups compared to Control. A significant increase in plasma levels of corticosterone were observed at E19 in RUPP compared to E19 Control dams; circulating corticosterone levels were also significantly increased in P14 RUPP dams. However, fetal plasma corticosterone levels were not altered in IUGR at E19 compared to Control. In conclusion, early measurements indicated that IUGR fetal weight and weight at birth were significantly reduced by placental insufficiency; however, placental efficiency was increased perhaps indicative of a compensatory mechanism.

Background Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age thus pregnancy in lupus patients is a common clinical scenario. SLE adversely affects pregnancy outcomes and pregnancy leads to SLE flares Aim of the work Determining the frequencies and predictors of maternal and fetal pregnancy outcomes in women with SLE by a prospective cohort study Patients and methods seventy-one pregnant lupus patients were followed prospectively, and their data compared to age-matched pregnant healthy controls attending Ain Shams University Hospital clinics Results Thirteen Patients had activity at conception. Sixty-six(93%) Where on treatment. Flares occurred in 51 patients (72%) during pregnancy with nephritis being the most common occurring in 78%. The prevalence of anemia, AKI and hypertension (HTN) during pregnancy were higher in SLE group than control group (P &amp;lt; 0.01). The rate of delivery by Cesarean section (CS), PTL, postpartum hemorrhage, preeclampsia (PE), severe PE and HELLP were higher in SLE group then control group (P &amp;lt; 0.01) as well as an increase in rate of postpartum infection (P &amp;lt; 0.05). There was an increase in rate of fetal loss, prematurity, intrauterine growth restriction (IUGR), NICU admission, still birth/intrauterine fetal death and highly significant decrease in fetal weight in SLE group than control group (P &amp;lt; 0.01). Pregestational HTN was independently associated with PE (OR 91.228; CI 6.791-1225.538). Proteinuria and HTN during pregnancy were independently associated with prematurity (OR 14.162 CI 1.029-194.958 &amp; OR 10.596, CI 1.460-76.894). Conclusion Pregnancy in lupus patients carries a higher risk of pregnancy morbidity and worse fetal outcomes than the controls.

Umbilical cord length has long been investigated as a potential marker of intrauterine events that may place the neonate at risk for future adverse developmental sequelae. Experimentally, significantly shortened cords have been reported in association with prenatal exposure to common drugs of abuse. This study in rats reports the time course of effects on umbilical cord length of a daily maternal ethanol gavage (3,200 mg/kg) from gestational day 6 through termination of pregnancy at either day 17, 18, 19, or 20. A total of 786 fetuses derived from 60 litters were examined. Control fetuses demonstrated a linear increase in umbilical cord length and body weight gain during late gestation, findings that support previous studies. The body weights of the ethanol-exposed fetuses were reduced significantly on all gestational days examined, indicating intrauterine growth retardation, a characteristic of fetal alcohol syndrome. Similarly, acute fetal akinesia as well as long-term sequelae stemming from impaired neurological development would result from the elevated blood ethanol levels achieved in this study. The umbilical cords of ethanol-exposed fetuses were significantly shorter on gestational days 19 and 20 in comparison to their controls, while cord lengths on days 17 and 18 were not shortened significantly. A stretch hypothesis has been proposed suggesting that the degree of fetal activity is the main determinant of umbilical cord length. In rats, there is a physiologic diminution of the volume of amniotic fluid (oligohydramnios) in late gestation (day 19 to term), which restricts fetal movements but does not appear to alter the linear relationships between gestational age and cord length in controls, thus arguing against the stretch hypothesis. However, cord lengths in the ethanol-exposed fetuses plateaued in late gestation, suggesting possible adherence to a stretch hypothesis. This dichotomy is discussed emphasizing fetal growth and activity as well as intrauterine space.

Umbilical cord length has long been investigated as a potential marker of intrauterine events that may place the neonate at risk for future adverse developmental sequelae. Experimentally, significantly shortened cords have been reported in association with prenatal exposure to common drugs of abuse. This study in rats reports the time course of effects on umbilical cord length of a daily maternal ethanol gavage (3,200 mg/kg) from gestational day 6 through termination of pregnancy at either day 17, 18, 19, or 20. A total of 786 fetuses derived from 60 litters were examined. Control fetuses demonstrated a linear increase in umbilical cord length and body weight gain during late gestation, findings that support previous studies. The body weights of the ethanol-exposed fetuses were reduced significantly on all gestational days examined, indicating intrauterine growth retardation, a characteristic of fetal alcohol syndrome. Similarly, acute fetal akinesia as well as long-term sequelae stemming from impaired neurological development would result from the elevated blood ethanol levels achieved in this study. The umbilical cords of ethanol-exposed fetuses were significantly shorter on gestational days 19 and 20 in comparison to their controls, while cord lengths on days 17 and 18 were not shortened significantly. A stretch hypothesis has been proposed suggesting that the degree of fetal activity is the main determinant of umbilical cord length. In rats, there is a physiologic diminution of the volume of amniotic fluid (oligohydramnios) in late gestation (day 19 to term), which restricts fetal movements but does not appear to alter the linear relationships between gestational age and cord length in controls, thus arguing against the stretch hypothesis. However, cord lengths in the ethanol-exposed fetuses plateaued in late gestation, suggesting possible adherence to a stretch hypothesis. This dichotomy is discussed emphasizing fetal growth and activity as well as intrauterine space. Teratology 61:184–188, 2000. © 2000 Wiley-Liss, Inc.

Metronidazole is the primary antimicrobial drug for treating acute and chronic vaginal pathogens during pregnancy; however, there has been insufficient research on placental disorders, early pregnancy loss, and preterm birth. Here, the potential activity of metronidazole on pregnancy outcomes was investigated. 130 mg/kg body weight of metronidazole was orally given individually to pregnant rats on gestation days 0–7, 7–14, and 0–20. Pregnancy outcome evaluations were carried out on gestation day 20. It was demonstrated that metronidazole could induce maternal and fetal hepatotoxicity. There is a significant increase in the activities of maternal hepatic enzymes (ALT, AST, and ALP), total cholesterol, and triglycerides compared with the control. These biochemical findings were evidenced by maternal and fetal liver histopathological alterations. Furthermore, metronidazole caused a significant decrease in the number of implantation sites and fetal viability, whereas it caused an increase in fetal lethality and the number of fetal resorptions. In addition, a significant decrease in fetal weight, placental weight, and placental diameter was estimated. Macroscopical examination revealed placental discoloration and hypotrophy in the labyrinth zone and the degeneration of the basal zone. The fetal defects are related to exencephaly, visceral hernias, and tail defects. These findings suggest that the administration of metroniazole during gestation interferes with embryonic implantation and fetal organogenesis and enhances placental pathology. We can also conclude that metronidazole has potential maternal and fetal risks and is unsafe during pregnancy. Additionally, it should be strictly advised and prescribed, and further consideration should be given to the associated health risks.

Intrauterine growth restriction (IUGR) is one of the major problems of pregnancy. IUGR is associated with a 5- to 20-fold increase in perinatal mortality (McIntire et al. 1999; Berstein et al. 2000). In addition, 40–50% of IUGR babies require neonatal intensive care (Lackman et al. 2001). While there are many causes of IUGR, the underlying pathology is a failure of adequate placental transfer of nutrients from mother to fetus. In this issue of The Journal of Physiology, Jansson et al. (2006) address a basic question relating to the mechanisms underlying poor fetal growth that has intrigued researchers and clinicians for many years, namely, is there evidence for a failure of placental nutrient transport prior to the start of growth restriction or are decreases in placental function, particularly nutrient transfer, secondary to the slowing of fetal growth? To answer this question, the authors have studied placental amino acid and glucose transport in a well established model of low protein, isocaloric nutritional restriction in the pregnant rat that impairs fetal growth. While previous researchers have shown that protein restriction down-regulates the activity of transporters for both the system A and cationic amino acids (Malandro et al. 1996), Jansson et al. (2006) provide the first data to show that a decrease in placental amino acid transport precedes IUGR and hence is likely to be a contributing cause rather then merely a secondary consequence of it. They demonstrate decreased amino acid, but not glucose, transfer to the fetus at day 19 of gestation, prior to the development of IUGR at day 21. There are three placental subtypes of the system A amino acid transporter, SNAT1, SNAT2 and SNAT4, which mediate the transport of neutral amino acids. This system is regulated by key growth factors such as insulin, leptin, cortisol and IGF1. The strength of the present study is that it provides firm data for total placental amino acid and glucose transport in awake, chronically catheterized animals as well as evaluating mRNA expression for SNATs 1, 2 and 4, and protein expression of SNAT2. Such in vivo data are indispensable to a determination of the full phenotype. At 19 days of gestation there was no significant difference between the control and low protein pregnancies in litter size, fetal weight or placental weight. However, fetal and placental weights were decreased by 21 days of gestation. The relative placental transport of the inert amino acid methylaminoisobutyric acid measured in the chronically instrumented non-anaesthetized pregnant rat was decreased by 25% (P < 0.05) in the low protein pregnancies at 19 days of gestation compared with controls. The data indicate the reduction in placental system A transport precedes the development of IUGR in this model. There was some discrepancy in the expressed changes in mRNA and protein for SNAT2; the former was decreased in a low protein group on the 15th day of gestation while protein expression did not change until day 21. These discrepancies show how important it is to measure overall function rather than rely entirely on measures of intermediate activities in the pathways such as mRNA transcription or protein translation. In contrast to the changes demonstrated in amino acid uptake, glucose uptake was not altered as a result of a low protein diet. The authors hypothesize that the placenta, in addition to responding to regulatory growth factors, acts as a nutrient sensing organ. Their hypothesis is supported by a decrease in placental mTOR protein expression at 18 days of gestation. However, this decrease only approached significance, as the authors point out (P < 0.09). The suggestion that mTOR acts as a nutrient sensor is provocative and should stimulate further and more definitive studies. Pursuing histological approaches to determine relative changes in distribution of both mRNA and protein, as well as the study of molecular and activity determinations of other factors in the mTOR signalling pathway, such as S6 kinase, in the various cellular components of the placenta will be fruitful ways of determining the value of this interesting hypothesis as it relates to the multiple signalling pathways within the placenta. In the light of the finding of functional changes in amino acid transport in the absence of changes in SNAT2 protein, it will be of interest to determine changes in the trafficking of transporter protein to the plasma membrane of the syncytiotrophoblast with subsequent increase in activity without a change in protein measured by western analysis. Some degree of caution must be exercised since although data show a time relationship between decreased amino acid transport and the appearance of IUGR, temporal relationships do not prove a causal relationship. Development is proceeding so fast at this stage of gestation that it is still possible that the events that eventually lead to fetal growth reduction are already in place prior to the observed reduction in amino acid transport. The mechanisms underlying IUGR are complex and likely to differ according to the underlying cause, e.g. placental insufficiency, maternal diet, multiple pregnancy. However, by investigating activity at several levels these studies provide a clear indication of a potential component role for alterations in amino acid transport that play a causal role in the production of IUGR. Finally, changes in transport of other factors such as oxygen, lipids and micronutrients need to be considered as they may also play causative roles in the induction of IUGR.

Vigabatrin (VGB) administered during late gestation lowers maternal folate concentration and causes pregnancy loss, fetal growth restriction and skeletal hypoplasia in the mouse

Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and increased risk of lifelong disease, including neurodevelopmental impairment. Fatty acids (FA) are critical for normal brain development, although their transport across the placenta in IUGR pregnancies is poorly understood. The present study used a baboon model of IUGR (maternal nutrient restriction, MNR) to investigate placental expression of FA transport and binding proteins, and to determine gestational age-related changes in maternal and fetal plasma FA concentrations. We found MNR to be associated with increased placental expression of FA binding and transport proteins in late gestation, with fetal plasma FA concentrations that were similar to those of control animals. The present study is the first to report a profile of fetal and maternal plasma FA concentrations in a baboon model of growth restriction with data that suggest adaptation of placental transport to maintain delivery of critically needed FA. Intrauterine growth restriction (IUGR) is associated with specific changes in placental transport of amino acids, folate and ions. However, little is known about placental fatty acid (FA) transport in IUGR. We hypothesized that placental FA transport proteins (FATP) and FA binding proteins (FABP) are up-regulated and fetal plasma FA concentrations are decreased at term in a baboon model of IUGR. Pregnant baboons were fed control or maternal nutrient restricted (MNR) diet (70% of control calories) from gestation day (GD) 30 (term 184days). Plasma and placental samples were collected at GD120 (control n=8, MNR n=9), GD140 (control n=6, MNR n=7) and GD170 (control n=6, MNR n=6). Placentas were homogenized, and syncytiotrophoblast microvillous plasma membrane (MVM) and basal plasma membranes (BM) were isolated. Protein expression of FABP1, 3, 4 and 5 (homogenate) and FATP2, 4, and 6 (MVM, BM) was determined by Western blotting. FA content in maternal and umbilical vein plasma was measured by gas chromatography-mass spectrometry. Placental FABP1 and FABP5 expression was increased in MNR compared to controls at GD170, as was MVM FATP2 and FATP6 expression at GD140 and FATP2 expression at GD170. BM FATP4 and FATP6 expression was increased in MNR at GD140. Fetal plasma FA concentrations were similar in controls and MNR. These data suggest the adaptation of placental transport when aiming to maintain delivery of critically needed FAs for fetal growth and brain development.

An animal model of cigarette smoke-induced in utero growth retardation

Relationship between Nutritionally-Mediated Placental Growth Restriction and Fetal Growth, Body Composition and Endocrine Status During Late Gestation in Adolescent Sheep

Since deferiprone can be an effective chelating agent for the treatment of aluminum (Al) overload, in the present study we investigated whether this chelator could protect against Al-induced maternal and developmental toxicity in mice. A single oral dose of Al nitrate nonahydrate (1,327 mg/kg) was given on gestation day 12, the most sensitive time for Al-induced maternal and developmental toxic effects in mice. At 2, 24, 48, and 72 hr thereafter, deferiprone was given by gavage at 0 and 24 mg/kg. Cesarean sections were performed on day 18 of gestation and fetuses were examined for malformations and variations. Aluminum-induced maternal toxicity was evidenced by significant reductions in body weight gain, corrected body weight change, and food consumption. Developmental toxicity was evidenced by a significant decrease in fetal weight per litter and an increase in the total number of fetuses and litters showing bone retardation. No beneficial effects of deferiprone on these adverse effects could be observed. By contrast, a more pronounced decrease in maternal weight gain and corrected body weight change, as well as a higher number of litters with fetuses showing skeletal variations was noted in the group exposed to Al nitrate and treated with deferiprone at 24 mg/kg. According to the current results, deferiprone would not be effective to prevent Al-induced maternal and embryo/fetal toxicity in mice.

Background: Fetal growth restriction is associated with a greater risk of current wheeze or asthma. We explored the underlying mechanism for this association using a mouse model of maternal hypoxia-induced intrauterine growth restriction (IUGR). Aim: Examine the effects of IUGR on fetal ASM layer thickness. Methods: Pregnant mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-17.5 (IUGR). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). Body and lung weight was assessed: (i) at the end of the hypoxic insult (GD17.5); and (ii) 3-4 days after insult (day of birth). Lungs were fixed and sections stained with haematoxylin & eosin for planimetry, proliferating cell nuclear antigen to assess ASM proliferation, and TUNEL assay to assess ASM apoptosis. The ASM layer thickness was normalised to perimeter of epithelial basement membrane. Results: IUGR offspring were smaller (reduced weight and dimensions) at both ages compared with Control, however, airway size was comparable. At GD17.5, ASM thickness was increased in the IUGR group compared with the Control group and fetal body weight was inversely related to ASM thickness. The effect of maternal hypoxia on ASM thickness was not observed at birth, after the insult had subsided. There was no difference in ASM proliferation between the groups and ASM apoptosis was not detectable. Conclusion: Maternal hypoxia drove fetal growth restriction and this was accompanied by ASM thickening. Prenatal thickening of the ASM in growth restricted individuals may increase susceptibility to asthma.