Mid-gestational sevoflurane exposure inhibits fetal neural stem cell proliferation and impairs postnatal learning and memory function in a dose-dependent manner.

Advancements in fetal intervention procedures have led to increases in the number of pregnant women undergoing general anesthesia during the second trimester-a period characterized by extensive proliferation of fetal neural stem cells (NSCs). However, few studies have investigated the effects of mid-gestational sevoflurane exposure on fetal NSC proliferation or postnatal learning and memory function. In the present study, pregnant rats were randomly assigned to a control group (C group), a low sevoflurane concentration group (2%; L group), a high sevoflurane concentration group (3.5%; H group), a high sevoflurane concentration plus lithium chloride group (H + Li group), and a lithium chloride group (Li group) at gestational day 14. Rats received different concentrations of sevoflurane anesthesia for 2 h. The offspring rats were weaned at 28 days for behavioral testing (i.e., Morris Water Maze [MWM]), and fetal brains or postnatal hippocampal tissues were harvested for immunofluorescence staining, real-time PCR, and Western blotting analyses in order to determine the effect of sevoflurane exposure on NSC proliferation and the Wnt/ß-catenin signaling pathway. Our results indicated that maternal exposure to 3.5% sevoflurane (H group) during the mid-gestational period impaired the performance of offspring rats in the MWM test, reduced NSC proliferation, and increased protein levels of fetal glycogen synthase kinase-3 beta (GSK-3ß). Such treatment also decreased levels of ß-catenin protein, CD44 RNA, and Cyclin D1 RNA relative to those observed in the C group. However, these effects were transiently attenuated by treatment with lithium chloride. Conversely, maternal exposure to 2% sevoflurane (L group) did not influence NSC proliferation or the Wnt signaling pathway. Our results suggest that sevoflurane exposure during the second trimester inhibits fetal NSC proliferation via the Wnt/ß-catenin pathway and impairs postnatal learning and memory function in a dose-dependent manner.

Fetal Surgery Decreases Anesthesia-Induced Neuroapoptosis in the Mid-Gestational Fetal Ovine Brain.

BACKGROUND: Studies demonstrating an association between anesthesia and brain cell death (neuroapoptosis) in young animals were performed without accompanying surgery. This study tests the hypothesis that fetal surgery decreases anesthesia-induced neuroapoptosis. MATERIALS AND METHODS: Seventy-day-pregnant ewes received 2% isoflurane for 1 h (low dose [LD]) or 4% for 3 h (high dose [HD]) with or without fetal surgery (S). Unexposed fetuses served as controls (C). Fetal brains were processed for neuroapoptosis using anti-caspase-3 antibodies. Data were analyzed using ANOVA. RESULTS: Twenty-eight fetal sheep were evaluated. Dentate gyrus neuroapoptosis was lower in the HD+S group (13.1 ± 3.76 × 105/mm3) than in the HD (19.1 ± 1.40 × 105/mm3, p = 0.012) and C groups (18.3 ± 3.55 × 105/mm3, p = 0.035). In the pyramidal layer of the hippocampus, neuroapoptosis was lower in the HD+S group (8.11 ± 4.88 × 105/mm3) than in the HD (14.8 ± 2.82 × 105/mm3, p = 0.006) and C groups (14.1 ± 4.54 × 105/mm3, p = 0.019). The LD+S group showed a trend towards a significant decrease in neuroapoptosis in the pyramidal layer (LD+S 7.51 ± 1.48 vs. LD 13.5 ± 1.87 vs. C 14.1 ± 4.54 × 105/mm3, p = 0.07) but not in the dentate gyrus. Fetal surgery did not affect neuroapoptosis in the frontal cortex or endplate. CONCLUSIONS: Fetal surgery decreases isoflurane-induced neuroapoptosis in the dentate gyrus and the pyramidal layer of mid-gestational fetal sheep. Long-term effects of these observations on memory and learning deserve further exploration.

Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice.

Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483 expression is dependent on Igf2 transcription and the regulation of the Igf2/H19 imprinting control region. Transgenic Mir483 overexpression in utero causes fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483 post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483 as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19 transcriptional region to limit excessive tissue growth through repression of IGF signaling.

Litters of Various-Sized Mummies (LVSM) and Stillborns after Porcine Reproductive and Respiratory Syndrome Virus Type 1 Infection-A Case Report.

Diverse origins and causes are described for papyraceous mummifications of porcine foetuses, but the porcine reproductive and respiratory syndrome virus (PRRSV) is not one of them. In contrast, PRRSV is unlikely to cause mid-term placental transmission but may cause late-term abortions and weakness of piglets. This case report describes a sudden occurrence of mummified foetuses of various sizes and stillborns and delayed birth (>115 days) in more than 50% of sows from one farrowing batch, while newborn piglets were mostly vital. Neither increased embryonic death nor infertility was reported. Three litters with mummies, autolysed piglets and stillborn piglets were investigated, and infections with porcine parvoviruses, porcine teschoviruses, porcine circoviruses, encephalomyocarditis virus, Leptospira spp. and Chlamydia spp. were excluded. Instead, high viral loads of PRRSV were detected in the thymus pools of piglets at all developmental stages, even in piglets with a crown-rump length between 80 and 150 mm, suggesting a potential mid-term in utero transmission of the virus. Genomic regions encoding structural proteins (ORF2-7) of the virus were sequenced and identified the virulent PRRSV-1 strain AUT15-33 as the closest relative. This case report confirms the diversity of PRRSV and its potential involvement in foetal death in mid-gestation.

Midgestational pre-labor spontaneous uterine rupture: a systematic review.

OBJECTIVE: Second and early third-trimester uterine rupture in a non-laboring woman is a very rare and life-threatening condition for both mothers and newborns. However, there are scant epidemiologic data on this event. STUDY DESIGN: Literature searches using Medical Subject Headings (MeSH) and non-MeSH terms were conducted in the PubMed/MEDLINE, Google Scholar and Embase databases from 1988 to 2020. Abstracts were reviewed and selected if they reported on uterine rupture in the second and third trimester. Uterine rupture was characterized as a full-thickness uterine wall defect. A total of 80 singleton intrauterine pregnancies between gestational ages of 14 and 34 weeks' gestation were included. RESULTS: The mean gestational age at diagnosis of uterine rupture was 22.4 ± 5.4 weeks. The associated events in obstetric history for uterine rupture were: ≥1 previous cesarean section (45%; 36/80 of the cases), previous uterine rupture (10%; 8/80), previous classical uterine incision (7.5%; 6/80), myomectomy (25%; 20/80) and congenital uterine malformations (16.3%; 13/80 of the cases). Uterine ruptures were associated with a short IP interval in 13.7% (11/80) and 43.7% (35/80) were associated with abnormal placentation: placenta accreta spectrum (PAS) disorders (n = 26), placenta previa (n = 2) and placenta previa and PAS (n = 7). The rate of related prenatal ultrasound findings was 67.5%. Cesarean hysterectomy was performed in 27% of the cases. Maternal death was reported in 2.5% (2/80). For the neonates delivered ≥24 weeks' gestation (n = 27) peripartum fetal death was reported in 33.3% (9/27). CONCLUSIONS: Midgestational pre-labor spontaneous uterine rupture is not an anecdotal event and may follow the worldwide increasing rate of cesarean sections. Health care providers should be familiar with the associated factors, presenting symptoms and complications of this obstetric emergency.

Nutrient Transporter Gene Expression in the Early Conceptus-Implications From Two Mouse Models of Diabetic Pregnancy.

Maternal diabetes in early pregnancy increases the risk for birth defects in the offspring, particularly heart, and neural tube defects. While elevated glucose levels are characteristic for diabetic pregnancies, these are also accompanied by hyperlipidemia, indicating altered nutrient availability. We therefore investigated whether changes in the expression of nutrient transporters at the conception site or in the early post-implantation embryo could account for increased birth defect incidence at later developmental stages. Focusing on glucose and fatty acid transporters, we measured their expression by RT-PCR in the spontaneously diabetic non-obese mouse strain NOD, and in pregnant FVB/N mouse strain dams with Streptozotocin-induced diabetes. Sites of expression in the deciduum, extra-embryonic, and embryonic tissues were determined by RNAscope in situ hybridization. While maternal diabetes had no apparent effects on levels or cellular profiles of expression, we detected striking cell-type specificity of particular nutrient transporters. For examples, Slc2a2/Glut2 expression was restricted to the endodermal cells of the visceral yolk sac, while Slc2a1/Glut1 expression was limited to the mesodermal compartment; Slc27a4/Fatp4 and Slc27a3/Fatp3 also exhibited reciprocally exclusive expression in the endodermal and mesodermal compartments of the yolk sac, respectively. These findings not only highlight the significance of nutrient transporters in the intrauterine environment, but also raise important implications for the etiology of birth defects in diabetic pregnancies, and for strategies aimed at reducing birth defects risk by nutrient supplementation.

The nutritive value of soybean meal from different sources for sows during mid- and late gestation.

A precise understanding of the nutritive value of soybean meal (SBM) for pregnant sow is required for accurate feeding. Hence, we evaluated the nutritive value of 11 SBM samples from different sources for sows during mid and late gestation. In total, 24 mid-gestating sows (parity three; 230.3 ± 12.0 kg on day 37 of gestation) and 24 late-gestating sows (parity three; 238.8 ± 20.9 kg on day 72 of gestation) were assigned to a replicated 12 × 3 Youden square design with 12 diets and 3 periods. The 12 diets included a corn-based diet and 11 diets containing 25.50% SBMs from different sources. After 5-d adaptation, urine and feces were collected for 5 d. Although the chemical characteristics of SBM varied between samples, no differences were observed in digestible energy (DE), metabolizable energy (ME), apparent total tract digestibility (ATTD) of dry matter, gross energy, crude fiber, and neutral detergent fiber values in SBMs fed to both animal groups. However, de-hulled SBM 4 from Brazil displayed greater ATTD for nitrogen (N) in late-gestating sows (P < 0.05); animals displayed significantly (P < 0.01) greater ME, ME:DE ratio, and N net utilization values when compared with mid-gestating sows. The chemical composition of SBMs can be used to predict DE and ME values. In conclusion, ME, ME:DE ratio, and N net utilization SBM values for late-gestating sows were greater than in mid-gestating sows. Therefore, we should consider differences in ME values for SBMs when formulating diets for sows in mid and late gestation periods.

Soybean meal (SBM) is the most commonly used protein source in swine diets, with high available energy. Sows have crucial roles in the pig industry, therefore precise knowledge of actual SBM nutritive values at different gestation stages is vital for efficient livestock production and management. In our study, we evaluated the nutritive value of SBMs from different sources in mid- and late-gestating sows, and generated prediction equations for digestible energy (DE) and metabolizable energy (ME) values. We identified no differences in DE and ME values in SBMs from different sources when fed to sows during mid- and late gestation. However, regardless of the pregnancy stage, DE and ME SBM values for sows, identified in this study, were greater than values published by NRC (2012). Also, ME, ME:DE ratio, and nitrogen (N) net utilization SBM values for late-gestating sows were greater than in mid-gestating sows. The chemical composition of SBMs can be used to predict DE and ME values. Our study data can be used to accurately formulate diets for pregnant sows.

Skeletal Muscle Development in Postnatal Beef Cattle Resulting from Maternal Protein Restriction during Mid-Gestation.

We aimed to investigate the effects of maternal protein restriction during mid-gestation on the skeletal muscle composition of the offspring. In the restriction treatment (RES, n = 9), cows were fed a basal diet, while in the control (CON, n = 9) group cows received the same RES diet plus the protein supplement during mid-gestation (100-200d). Samples of Longissimus dorsi muscle were collected from the offspring at 30d and 450d postnatal. Muscle fiber number was found to be decreased as a result of maternal protein restriction and persisted throughout the offspring's life (p < 0.01). The collagen content was enhanced (p < 0.05) due to maternal protein restriction at 30d. MHC2X mRNA expression tended to be higher (p = 0.08) in RES 30d offspring, however, no difference (p > 0.05) was found among treatments at 450d. Taken together, our results suggest that maternal protein restriction during mid-gestation has major and persistent effects by reducing muscle fiber formation and may slightly increase collagen accumulation in the skeletal muscle of the offspring. Although maternal protein restriction may alter the muscle fiber metabolism by favoring the establishment of a predominant glycolytic metabolism, the postnatal environment may be a determinant factor that establishes the different proportion of muscle fiber types.

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus.

Zika virus (ZIKV) is an arbovirus that causes birth defects, persistent male infection, and sexual transmission in humans. The purpose of this study was to continue the development of an ovine ZIKV infection model; thus, two experiments were undertaken. In the first experiment, we built on previous pregnant sheep experiments by developing a mid-gestation model of ZIKV infection. Four pregnant sheep were challenged with ZIKV at 57-64 days gestation; two animals served as controls. After 13-15 days (corresponding with 70-79 days of gestation), one control and two infected animals were euthanized; the remaining animals were euthanized at 20-22 days post-infection (corresponding with 77-86 days of gestation). In the second experiment, six sexually mature, intact, male sheep were challenged with ZIKV and two animals served as controls. Infected animals were serially euthanized on days 2-6 and day 9 post-infection with the goal of isolating ZIKV from the male reproductive tract. In the mid-gestation study, virus was detected in maternal placenta and spleen, and in fetal organs, including the brains, spleens/liver, and umbilicus of infected fetuses. Fetuses from infected animals had visibly misshapen heads and morphometrics revealed significantly smaller head sizes in infected fetuses when compared to controls. Placental pathology was evident in infected dams. In the male experiment, ZIKV was detected in the spleen, liver, testes/epididymides, and accessory sex glands of infected animals. Results from both experiments indicate that mid-gestation ewes can be infected with ZIKV with subsequent disruption of fetal development and that intact male sheep are susceptible to ZIKV infection and viral dissemination and replication occurs in highly vascular tissues (including those of the male reproductive tract).

Development of the human accessory olivary nuclei: A morphometric and computerized 3D-reconstruction study.

INTRODUCTION: This study described the prenatal development of the accessory olivary nuclei (AO) in humans. MATERIALS/METHODS: Serial brain sections from ten pre- and full term infants aged 21-43 postmenstrual weeks (PW) were stained using the Klüver-Barrera method. A computerized 3D-reconstruction technique and morphometry were adopted for the study. RESULTS: The medial AO (MAO) and dorsal AO (DAO) were identified at 21 PW. The dorsal cap was clearly differentiated from the main body (MB) of the MAO in neuronal cytoarchitecture. Pyknotic neurons were diffusely observed in the AO at 21 PW and were most concentrated in the MB. These neurons became infrequent from 28 PW onward. Neuronal nests existed in clusters between the AO and the medial lemniscus at 21 PW, which reduced progressively in size and number with age. The 3D-reconstructions showed that the AO are separated into caudal and rostral parts, and that this separation is achieved by mid-gestation in the DAO. Nuclear volume increased exponentially with age in the AO, although the rate of increase was half that of the principal nucleus (PO). Neuronal numerical density decreased rapidly 21-28 PW. The total neuronal number showed a weak correlation with age. The mean neuronal profile area increased linearly with age. CONCLUSION: The human AO are separated into caudal and rostral parts in the fetal period. The nuclear volume and neuronal profile areas increase with age, although the rate of this increase is lower than in the PO. Natural neuronal death may occur at mid-gestation in the AO.

Maternal glycemia during pregnancy and offspring abdominal adiposity measured by MRI in the neonatal period and preschool years: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective mother-offspring birth cohort study.

BACKGROUND: Gestational diabetes is associated with unfavorable body fat distribution in offspring. However, less is known about the effects across the range of maternal gestational glycemia on offspring abdominal adiposity (AA) in infancy and early childhood. OBJECTIVES: This study determined the association between gestational glycemia and offspring AA measured by MRI in the neonatal period and during the preschool years. METHODS: Participants were mother-offspring pairs from the GUSTO (Growing Up in Singapore Towards healthy Outcomes) prospective cohort study. Children who underwent MRI within 2 wk postdelivery (n = 305) and/or at preschool age, 4.5 y (n = 273), and whose mothers had a 2-h 75-g oral-glucose-tolerance test (OGTT) at 26-28 weeks of gestation were included. AA measured by adipose tissue compartment volumes-abdominal superficial (sSAT), deep subcutaneous (dSAT), and internal (IAT) adipose tissue-was quantified from MRI images. RESULTS: Adjusting for potential confounders including maternal prepregnancy BMI, each 1-mmol/L increase in maternal fasting glucose was associated with higher SD scores for sSAT (0.66; 95% CI: 0.45, 0.86), dSAT (0.65; 95% CI: 0.44, 0.87), and IAT (0.64; 95% CI: 0.42, 0.86) in neonates. Similarly, each 1-mmol/L increase in 2-h OGTT glucose was associated with higher neonatal sSAT (0.11; 95% CI: 0.03, 0.19) and dSAT (0.09; 95% CI: 0.00, 0.17). These associations were stronger in female neonates but only persisted in girls between fasting glucose, and sSAT and dSAT at 4.5 y. CONCLUSIONS: A positive association between maternal glycemia and neonatal AA was observed across the whole range of maternal mid-gestation glucose concentrations. These findings may lend further support to efforts toward optimizing maternal hyperglycemia during pregnancy. The study also provides suggestive evidence on sex differences in the impact of maternal glycemia, which merits further confirmation in other studies.This trial was registered at clinicaltrials.gov as NCT01174875.

Development of the human principal inferior olivary nucleus: A morphometric and computerized 3D-reconstruction study.

INTRODUCTION: This study describes the prenatal development of the principal inferior olivary nucleus (PO) in humans. MATERIAL/METHODS: Ten brains were obtained from preterm infants aged 21-43 postmenstrual weeks (PW). After fixation, the brains were processed into 30-µm serial sections, which were stained using the Klüver-Barrera method. RESULTS: At mid-gestation, the dorsal and ventral lamellae were distinguishable. The dorsal lamella (DL) was composed of ballooned and folded portions, with many neurons peripherally gathered in the ballooned portion, and neurons densely packed in the folded portion. Clusters of pyknotic neurons were observed in the lateral portion of the PO at 21PW. The PO acquired thin complicated folds by 28-29 PW. Then, it regained the width of a nuclear band, and further elaborated the folds. The 3D-reconstruction models showed that the basic pattern of folding like in adults was attained at 28-29PW, and that the rostro-medial region of DL was microgyric. The nuclear volume increased exponentially with age. The total surface area increased progressively, while the surface density varied in a biphasic manner, wherein it increased initially and then decreased. The neuronal profile area increased uniformly. The total neuronal number increased uniformly, while the numerical density decreased rapidly during 21-29 PW. CONCLUSION: After mid-gestation, the period of 21-29 PW may be critical, because the PO undergoes extensive folding after massive neuronal death.

Development of the human lateral geniculate nucleus: A morphometric and computerized 3D-reconstruction study.

INTRODUCTION: The lateral geniculate nucleus (LGN) is the major relay center of the visual pathway in humans. There are few quantitative data on the morphology of LGN in prenatal infants. In this study, using serial brain sections, the author investigated the morphology of this nucleus during the second half of fetal period. MATERIAL AND METHODS: Eleven human brains were obtained at routine autopsy from preterm infants aged 20-39 postmenstrual weeks. After fixation, the brain was embedded en bloc in celloidin and cut serially at 30 µm in the horizontal plane. The sections were stained at regular intervals using the Klüver-Barrera method. RESULTS: At 20-21 weeks, the long axis of LGN declined obliquely from the vertical to horizontal plane, while a deep groove was noted on the ventro-lateral surface of the superior half. At this time, an arcuate cell-sparse zone appeared in the dorso-medial region, indicating the beginning of lamination. From 25 weeks onwards, the magnocellular and parvocellular layers were distinguishable, and the characteristic six-layered structure was recognized. The magnocellular layer covered most of the dorsal surface, and parts of the medial, lateral, and inferior surfaces but not the ventral and superior surfaces. Nuclear volume increased exponentially with age during 20-39 weeks, while the mean neuronal profile area increased linearly during 25-39 weeks. CONCLUSION: Human LGN develops a deep groove on the ventro-lateral surface at around mid-gestation, when the initial lamination is recognized in the prospective magnocellular layer. Thereafter, the nuclear volume increases with age in an exponential function.

The mid-gestation triple test profile among women diagnosed with vasa previa.

PURPOSE: To assess the mid-trimester triple test biomarkers among women diagnosed with vasa previa (VP). METHODS: The study included 43 singleton pregnancies diagnosed with vasa previa between the years 1988 and 2011. The mid-gestation screening test for Down syndrome was calculated from the combination of triple serum markers and maternal age, and expressed as a multiple of the gestation specific normal mean (MoM). Reference MoM values were calculated from the local population. The levels of mid-gestation maternal serum alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3) of patients with VP were compared with control reference group. RESULTS: The mean hCG and αFP levels of women diagnosed with VP was significantly higher compared to control reference group (1.42 versus 0.99 MoM; p < .002 and 1.24 versus1.01 MoM; p < .001, respectively). In contrast, there was no significant difference in uE3 levels between these two groups (0.99 versus 0.98 MoM; p = .71). CONCLUSIONS: Our findings suggest that increased mid-gestation hCG and AFP were found among pregnancies complicated with VP. Clinicians should consider targeted scanning of pregnant women with risk factors for VP, including unexplained high maternal levels of hCG and αFP of the triple test, while conducting mid-gestation anomaly scan.

Maternal and foetal cytokine production in dams naturally and experimentally infected with Neospora caninum on gestation day 110.

In the present study, IFN-γ (Th1), IL-17A (Th17) and IL-4 (Th2) concentrations in response to concanavalin (ConA) and Neospora caninum antigen (Nc-1) stimulation were determined in cultures of cells from control uninfected (n=4), naturally N. caninum-infected (n=3) and experimentally N. caninum-infected (n=6) pregnant dams and their foetuses. Experimental animals were infected at 110days of gestation and euthanized 6weeks post-infection. In culture supernatants from the dams, significantly higher IFN-γ and IL-4 levels were found in the experimentally-infected animals compared to the control or naturally-infected dams. However, among the experimentally-infected dams no significant differences in IFN-γ production were observed regardless of the incidence of live or aborted/dead foetuses, though spleen cultures of dams carrying live foetuses showed the highest levels of IFN-γ. IL-17A production was very low and occasional in the dams infected with N. caninum and did not seem to be a major regulator of IFN-γ production in this model. Experimentally infected dams with live foetuses showed higher IL-4 levels and accordingly IFN-γ/IL-4 ratios were significantly lower than ratios recorded for cows with aborted/dead foetuses. In the infected foetuses of these dams, only spleen cultures showed high levels of IFN-γ and IL-4 after Nc-1 antigen and ConA stimulation, respectively. No IL-17A was detected in the foetuses. As conclusion, although we could not clearly relate a protective immune response against N. caninum abortion only to IFN-γ levels in cell cultures, our results highlight the important role of an inverse IFN-γ/IL-4 balance in conferring protection against abortion induced by this parasite.

In utero Head Circumference is Associated with Childhood Allergy.

BACKGROUND: Altered fetal growth is known to be associated with allergic disease. Specifically, increased head circumference at birth has been linked to asthma and elevated IgE. However, few studies have examined a link between early fetal anthropometry and allergic disease. The aim of this study was to examine head circumference at mid-gestation in children diagnosed with allergy. METHODS: This was a retrospective cohort study, comprising pregnancies delivered between 10/2006 and 9/2010 at Nepean Hospital, Australia. Exclusion criteria were illegal drug use, alcohol consumption, gestation <35 weeks, and gestational hypertension. Pregnancy data were sourced from the Nepean Obstetric Database. Atopic diseases (asthma, atopic dermatitis, and IgE-mediated food allergy) were assessed by questionnaire at age 1-5 years. Infants from pregnancies with completed questionnaires, who also had a mid-gestation ultrasound scan, were included (N = 121). Multiple logistic regression techniques were used to model head circumference against the development of allergies. RESULTS: Smaller head circumference at mid-gestation was associated with increased odds of allergic disease in children aged 1-5 years. A 1 mm smaller head circumference was associated with a 7% increased chance of allergies being later diagnosed, adjusted for gestation (95% CI: 1-14%, p = 0.036). Head circumference at mid-gestation was also inversely correlated with the presence of multiple atopic disease. CONCLUSION: Smaller mid-gestational head circumference is associated with early childhood allergic disease, which suggests that fetal programing of allergic disease occurs before mid-gestation. This suggests that mediators such as brain-derived neurotrophic factor may be dysregulated early in utero in a milieu, which also predisposes to atopic disease.