Paternal involvement in infant care and developmental milestone outcomes at age 3 years: the Japan Environment and Children's Study (JECS).

BACKGROUND: In developed countries, the time fathers spend on childcare has increased steadily in recent decades. However, studies on the relationship between paternal care and child outcomes remain scarce. Thus, we examined the association between paternal involvement in childcare and children's developmental outcomes. METHODS: We used Japan's largest birth cohort data, the Japan Environment and Children's Study, to examine the relationship between paternal involvement in childcare at the child's age of 6 months and developmental milestone outcomes at the child's age of 3 years (n = 28,050). Developmental delays were assessed with Ages and Stages Questionnaire. Potential mediation by maternal parenting stress at the child's age of 1.5 years was also examined. We used log-binomial regression analyses to estimate risk ratios. RESULTS: Fathers' high involvement in childcare was associated with a lower risk of developmental delay in gross-motor, fine-motor, problem solving, and personal-social domains compared with low involvement, adjusting for potential confounders. For example, the risk ratio with 95% confidence intervals was 0.76 [0.67, 0.86] for the gross-motor domain. We also observed that the associations were partially mediated by maternal parenting stress. CONCLUSIONS: Fathers' active involvement in childcare during infancy may promote young children's development, partially by reducing maternal parenting stress. IMPACT: Using Japan's largest birth cohort data (Japan Environment and Children's Study), we showed that paternal involvement in infant care might benefit young children's development. Fathers' active involvement in infant care was associated with a lower risk of developmental delays in gross-motor, fine-motor, problem solving, and personal-social domains. Maternal parenting stress may mediate the association between paternal involvement in infant care and child development outcomes at 3 years.

Open-ended movements structure sensorimotor information in early human development.

Human behaviors, with whole-body coordination, involve large-scale sensorimotor interaction. Spontaneous bodily movements in the early developmental stage potentially lead toward acquisition of such coordinated behavior. These movements presumably contribute to the structuration of sensorimotor interaction, providing specific regularities in bidirectional information among muscle activities and proprioception. Whether and how spontaneous movements, despite being task-free, structure and organize sensorimotor interactions in the entire body during early development remain unknown. Herein, to address these issues, we gained insights into the structuration process of the sensorimotor interaction in neonates and 3-mo-old infants. By combining detailed motion capture and musculoskeletal simulation, sensorimotor information flows among muscle activities and proprioception throughout the body were obtained. Subsequently, we extracted spatial modules and temporal state in sensorimotor information flows. Our approach demonstrated that early spontaneous movements elicited body-dependent sensorimotor modules, revealing age-related changes in them, depending on the combination or direction. The sensorimotor interactions also displayed temporal non-random fluctuations analogous to those seen in spontaneous activities in the cerebral cortex and spinal cord. Furthermore, we found recurring state sequence patterns across multiple participants, characterized by a substantial increase in infants compared to the patterns in neonates. Therefore, early spontaneous movements induce the spatiotemporal structuration in sensorimotor interactions and subsequent developmental changes. These results implicated that early open-ended movements, emerging from a certain neural substrate, regulate the sensorimotor interactions through embodiment and contribute to subsequent coordinated behaviors. Our findings also provide a conceptual linkage between early spontaneous movements and spontaneous neuronal activity in terms of spatiotemporal characteristics.

Glucocorticoid Receptor Expression Pattern in Very Low Birth Weight Infants Changes Drastically within the First Week of Life.

INTRODUCTION: We herein examined changes in expression levels of the glucocorticoid receptor subtypes GRα and GRß in very low birth weight (VLBW) and term infants to clarify time-dependent changes in glucocorticoid sensitivity after birth. METHODS: Whole blood samples were collected at birth and on postnatal days 4-7, and the mRNA expression levels of GRα and GRß were measured using RT-qPCR. The relative gene expression levels of GRα and GRß as the target genes normalized to actin beta as the endogenous control were calculated by the comparative cycle threshold method. RESULTS: The GRα/GRß expression ratio at birth was significantly lower in 32 VLBW cesarean section (CS) infants than in term planned CS infants (median [IQR], 1.5 [1.1-1.8]- and 1.1 [0.7-1.6]-fold change, p < 0.05). Furthermore, the GRα/GRß expression ratio increased from day 0 to days 4-7 (1.0 [0.6-1.4]- and 1.7 [0.6-1.4]-fold change, p < 0.01) in 43 VLBW infants. DISCUSSION/CONCLUSION: The present results suggest that glucocorticoid sensitivity in VLBW infants increases after birth and this rapid change may play a role in surviving critical postnatal events.

Comparison of two methods measuring serum alkaline phosphatase in neonates.

BACKGROUND: Serum alkaline phosphatase (ALP) is a useful bone turnover marker to diagnose metabolic bone disease in preterm infants. In Japan, serum ALP levels were generally measured using the Japan Society of Clinical Chemistry (JSCC) method. It is problematic that ALP levels measured using the JSCC method tend to be higher in people with blood types B and O regardless of the disease. For international standardization, since 2020, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) method has been used as a reference method for ALP measurement instead of the JSCC method. However, no report has investigated the correlation between these two methods in neonates. We therefore aimed to compare the JSCC and IFCC methods and demonstrate a conversion formula in neonates. METHODS: In this retrospective study, we used a total of 402 samples in 49 preterm and 38 term infants. Serum ALP levels were measured using the JSCC and IFCC methods. RESULTS: Alkaline phosphatase measured using the JSCC method strongly correlated with that measured using the IFCC method in all blood types in preterm and term infants (P < 0.01 for all). CONCLUSIONS: We found that the serum ALP levels measured using the IFCC method could be calculated as 0.34 times the ALP levels measured using the JSCC method in preterm and term infants with any blood type: ALP levels (IFCC method) = 0.34 × ALP levels (JSCC method).

Effect of doxapram on the electrical activity of the diaphragm waveform pattern of preterm infants.

OBJECTIVE: This study aimed to evaluate the change in the waveform pattern of the electrical activity of the diaphragm (Edi) following the administration of doxapram in extremely preterm infants ventilated with neurally adjusted ventilatory assist (NAVA). STUDY DESIGN: We conducted this retrospective cohort study in our neonatal intensive care unit between November 2019 and September 2021. The study participants were extremely preterm infants under the gestational age of 28 weeks who were ventilated with NAVA and administered doxapram. We collected the data of the Edi waveform pattern and calculated the proportion. To analyze the change in the proportion of the Edi waveform pattern, we compared the proportion of the data for 1 h before and after doxapram administration. RESULTS: Ten extremely preterm infants were included. Almost all the patients' respiratory condition improved after doxapram administration. The ventilatory parameters-Edi peak, Edi minimum, peak inspiratory pressure, time in backup ventilation, and number of switches to backup ventilation-did not change significantly. However, the proportion of phasic pattern significantly increased (before: 46% vs. after: 72%; p < 0.05), whereas the central apnea pattern significantly decreased after doxapram administration (before: 31% vs. after: 8.3%; p < 0.05). The proportion of irregular low-voltage patterns tended to decrease, albeit with no significant changes. CONCLUSION: Our results indicated that the proportion of Edi waveform patterns changed following doxapram administration. Edi waveform pattern analysis could be a sensitive indicator of effect with other intervention for respiratory conditions.

Cognitive flexibility in 12-month-old preterm and term infants is associated with neurobehavioural development in 18-month-olds.

There is growing evidence that preterm children are at an increased risk of poor executive functioning, which underlies behavioural and attention problems. Previous studies have suggested that early cognitive flexibility is a possible predictor of later executive function; however, how it develops in infancy and relates to the later neurobehavioural outcomes is still unclear in the preterm population. Here, we conducted a longitudinal study to investigate oculomotor response shifting in 27 preterm and 25 term infants at 12 months and its relationship with general cognitive development and effortful control, which is a temperamental aspect closely associated with executive function, at 18 months. We found that moderate to late preterm and term infants significantly inhibited previously rewarded look responses, while very preterm infants did not show significant inhibition of perseverative looking at 12 months. Moreover, lower inhibition of perseverative looking was significantly associated with lower general cognitive development and attentional shifting at 18 months. These findings suggest that the early atypical patterns of oculomotor response shifting may be a behavioural marker for predicting a higher risk of negative neurobehavioural outcomes, including attention-related problems in preterm children.

Longitudinal assessment of social attention in preterm and term infants: Its relation to social communication and language outcome.

Preterm birth has been reported to be associated with an increased risk of social communication and language problems. Recently, we found that preterm infants showed atypical patterns of social attention compared with term infants. However, it is still unknown how social attention develops and whether the individual differences are associated with developmental outcomes for social communication and language in preterm infants. The social attention of preterm and term infants at 6, 12, and 18 months was investigated using two types of social attention tasks (human-geometric preference task and gaze-following task). The Modified Checklist for Autism in Toddlers (M-CHAT) and the MacArthur Communicative Development Inventory adapted for Japanese were measured at 18 months. We found that compared with term infants, preterm infants spent less time looking toward dynamic human images and followed another's gaze directions less frequently through 6, 12, and 18 months. Moreover, hierarchical multiple regression analysis revealed that less preference for dynamic human images and gaze-following abilities was associated with high M-CHAT and low language scores in preterm and term infants, respectively. These findings suggest that birth status affects development of social attention through 18 months and individual differences in social attention reflect differences in social communication and language outcomes.

Effect of electrical activity of the diaphragm waveform patterns on SpO2 for extremely preterm infants ventilated with neurally adjusted ventilatory assist.

OBJECTIVE: This study aimed to evaluate the association between electrical activity of the diaphragm (Edi) waveform patterns and peripheral oxygen saturation (SpO2 ) in extremely preterm infants who are ventilated with neurally adjusted ventilatory assist (NAVA). STUDY DESIGN: We conducted a retrospective cohort study at a level III neonatal intensive care unit. Extremely preterm infants born at our hospital between November 2019 and November 2020 and ventilated with NAVA were included. We collected Edi waveform data and classified them into four Edi waveform patterns, including the phasic pattern, central apnea pattern, irregular low-voltage pattern, and tonic burst pattern. We analyzed the Edi waveform pattern for the first 15 h of collectable data in each patient. To investigate the association between Edi waveform patterns and SpO2 , we analyzed the dataset every 5 min as one data unit. We compared the proportion of each waveform pattern between the desaturation (Desat [+]) and non-desaturation (Desat [-]) groups. RESULTS: We analyzed collected data for 105 h (1260 data units). The proportion of the phasic pattern in the Desat (+) group was significantly lower than that in the Desat (-) group (p < .001). However, the proportions of the central apnea, irregular low-voltage, and tonic burst patterns in the Desat (+) group were significantly higher than those in the Desat (-) group (all p < .05). CONCLUSION: Our results indicate that proportions of Edi waveform patterns have an effect on desaturation of SpO2 in extremely preterm infants who are ventilated with NAVA.

Antenatal Glucocorticoids Reduce the Incidence of Refractory Hypotension in Low Birthweight Infants during the Early Neonatal Period, but Do Not Affect It beyond This Time.

OBJECTIVE: This study aimed to clarify the effect of antenatal glucocorticoids (AGs) on the incidence of refractory hypotension (RH) in very low birthweight (VLBW) infants after the first week of life. STUDY DESIGN: We included VLBW infants born at a gestational age of <30 weeks and divided them into three groups: the complete group (born within 7 days of completing a single course [two doses] of AGs), the incomplete group (born without complete course), and the late delivery group (born at ≥8 days after a single course). We compared the incidence and period of onset of RH among the three groups. RESULTS: A total of 115 infants were enrolled. The incidence of RH in the first week of life was significantly lower in the complete group than in the other groups. However, there was no significant difference in the incidence of RH after the first week of life among the groups. CONCLUSION: AGs contribute to circulatory stabilization during the first week of life, but this effect does not last after 1 or 2 weeks of administration. In infants who receive AGs, physicians should consider that the risk of RH after the first week of life is not low.

Effects of passage through the digestive tract on incretin secretion: Before and after birth.

AIMS/INTRODUCTION: It was reported that fetuses secrete endogenous incretin; however, the stimulants of fetal incretin secretion are not fully understood. To investigate the association between the passage of amniotic fluid through the intestinal tract and fetal secretion of incretin, we analyzed umbilical cord incretin levels of infants with duodenum atresia. MATERIALS AND METHODS: Infants born from July 2017 to July 2019 (infants with duodenum atresia and normal term or preterm infants) were enrolled. We measured and compared the concentrations of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP) in the umbilical vein and preprandial blood samples after birth. RESULTS: A total of 98 infants (47 term, 46 preterm and 5 with duodenum atresia) were included. In patients with duodenum atresia, umbilical vein GLP-1 and GIP levels were the same as those in normal infants. In postnatal samples, there were positive correlations between the amount of enteral feeding and preprandial serum concentrations of GLP-1 (r = 0.47) or GIP (r = 0.49). CONCLUSIONS: Our results show that enteral feeding is important for secretion of GLP-1 and GIP in postnatal infants, whereas the passage of amniotic fluid is not important for fetal secretion of GLP-1 and GIP. The effect of ingested material passing through the digestive tract on incretin secretion might change before and after birth. Other factors might stimulate secretion of GLP-1 and GIP during the fetal period.

Appropriate Phosphorus Intake by Parenteral Nutrition Prevents Metabolic Bone Disease of Prematurity in Extremely Low-Birth-Weight Infants.

BACKGROUND: Metabolic bone disease (MBD) is a common disorder in extremely low-birth-weight (ELBW) infants. However, no studies have investigated whether high-dose calcium (Ca) and phosphorus (P) supplementation by parenteral nutrition (PN) prevents MBD in ELBW infants. This study aimed to identify the effect of PN on MBD in ELBW infants. METHODS: We retrospectively analyzed ELBW infants who were admitted between April 2011 and March 2017. ELBW infants were divided into the low-P group (n = 22) and the high-P group (n = 26) according to the dose of parenteral P supply. Biochemical and radiological markers of MBD and treatments were analyzed. RESULTS: Mean daily parenteral intake of Ca and P in the first week was significantly higher in the high-P group than in the low-P group (both P ≤ .001). Serum alkaline phosphatase (ALP) levels were significantly higher in the low-P group than in the high-P group in the first month. ELBW infants in the low-P group received alfacalcidol much more frequently than those in the high-P group. There was a trend of a higher rate of x-ray changes in the low-P group than in the high-P group. No infants developed bone fractures. CONCLUSION: Appropriate P intake by PN is required to ensure high Ca intake, reduce ALP levels in the first month, and prevent MBD from hyperparathyroidism and does not worsen x-ray findings in ELBW infants.

Antenatal corticosteroids for threatened labour facilitate thyroid maturation among preterm neonates.

OBJECTIVE: To examine the effect of antenatal corticosteroids (ANS) on the maturation of thyroid function in the preterm infants. CONTEXT: ANS reduce mortality and morbidities in preterm neonates. Organ maturation by the glucocorticoids is the key, at least in part. However, the effect of ANS on thyroid is controversial. PATIENTS: A study group of 99 very low birthweight neonates (<34 weeks' gestational age) with the exception of those born more than 7 days after ANS administration were divided into a complete group (n = 49) whose mothers completed two doses of betamethasone and who were born more than 24 hours after the completion of ANS administration, and an incomplete group (n = 50) who were not exposed to any ANS or were born within 24 hours after the completion of ANS administration. Serum-free thyroxine and thyroid-stimulating hormone (TSH) levels were measured, and thyrotropin-releasing hormone (TRH) stimulation tests were performed at about 2 weeks of age. RESULTS: The incidence of hyperthyrotropinaemia (TSH > 15 mIU/L) in the complete group was significantly lower than in the incomplete group (6% vs 22%, P = .023). Exaggerated responses to TRH tests were more frequent in the incomplete group (17% vs 44%; P = .053). TSH30 was significantly lower in the complete group, (P = .046). Multivariate logistic regression analysis showed that the incidence of hyperthyrotropinaemia was associated with complete ANS administration (adjusted odds ratios 0.39). CONCLUSIONS: ANS administration might facilitate thyroid maturation in preterm neonates.

Response of preterm infants with transient hypothyroxinaemia of prematurity to the thyrotropin-releasing hormone stimulation test is characterized by a delayed decrease in thyroid-stimulating hormone after the peak.

OBJECTIVES: We evaluated the response to the thyrotropin-releasing hormone (TRH) stimulation test in very low-birth weight (VLBW) infants to elucidate the aetiology of transient hypothyroxinaemia of prematurity (THOP). DESIGN AND METHODS: We performed TRH stimulation tests on 43 VLBW infants. Subjects were divided into two groups; a THOP group (N = 11; basal TSH < 15 mU/L and basal FT4 ≤ 0.8 ng/dL) and a non-THOP group (N = 32; basal TSH < 15 mU/L and basal FT4 > 0.8 ng/dL). Basal FT4 and FT3 were measured before, and TSH (0, 30, 60, 90, 120 and 180 minutes) was measured after, the administration of TRH (7 µg/kg). We calculated the ratio of TSH 180 minutes to THS 0 minute as the primary outcome. We also collected data on T3 and rT3 in this study. RESULTS: In both groups, TSH 30 minutes values were the highest. However, the ratios of TSH 180 minutes to THS 0 minutes in the non-THOP group and the THOP group were (median [IQR]) 1.3 [1.0-1.7] and 3.0 [1.5-5.3] (P < .01). No significant differences were observed in T3 (1.0 [0.8-1.3] and 0.7 [0.4-0.7] ng/mL, P = .06). However, in the THOP group, rT3 was significantly lower than that of the non-THOP group (168.0 [148.1-197.0] and 92.9 [74.7-101.6] pg/mL, P < .01). CONCLUSIONS: The delayed decrease in the TSH concentration after the peak for the TRH tests and decreased levels of rT3 suggest that the main aetiology for THOP is suppression at the level of the hypothalamus, but not inactivation of peripheral thyroid hormone metabolism.

Audiovisual speech perception and language acquisition in preterm infants: A longitudinal study.

BACKGROUND: Preterm infants have a higher risk of language delay throughout childhood. The ability to integrate audiovisual speech information is associated with language acquisition in term infants; however, the relation is still unclear in preterm infant. AIM AND METHODS: This study longitudinally investigated visual preference for audiovisual congruent and incongruent speech during a preferential looking task using eye-tracking in preterm and term infants at 6, 12, and 18 months of corrected age. The infants' receptive and expressive vocabulary at 12 and 18 months were obtained by parent report, using the Japanese MacArthur Communicative Development Inventory. RESULTS: We found that preterm infants did not clearly show visual preference for the congruent audiovisual display at any age, whereas term infants looked at the congruent audiovisual display longer than the incongruent audiovisual display at 6 and 18 months. Preterm infants' receptive and expressive vocabulary scores were lower than those of term infants at 12 and 18 months. Furthermore, the proportion of looking time toward the congruent audiovisual display at 6 months was positively correlated with receptive vocabulary scores at 12 and 18 months for both groups. CONCLUSIONS: These findings suggest that better audiovisual speech perception abilities are one factor that results in better language acquisition in preterm as well as term infants. Early identification of behaviors associated with later language in preterm infants may contribute to planning intervention for developmental problems.

Corticotrophin-releasing hormone stimulation tests for the infants with relative adrenal insufficiency.

BACKGROUND: Very low birthweight (VLBW) infants are considered to be vulnerable to relative adrenal insufficiency (RAI); however, diagnosis is difficult in some clinical settings. Considering this background, it is necessary to establish a diagnosis of RAI in preterm infants. OBJECTIVE: In this study, we attempted to clarify the difference in response to CRH stimulation tests for preterm infants with or without RAI. METHODS: Between June 2009 and December 2015, we performed CRH stimulation tests for preterm infants born at a gestational age of <30 weeks at around 2 weeks of age. Retrospectively, subjects were classified into two groups: infants with RAI (n = 9) or without RAI (n = 17) based on the clinical symptoms and responsiveness to hydrocortisone. RESULTS: We found no difference in base or peak serum cortisol levels related to CRH stimulation tests between the two groups; however, delta cortisol levels and responsive ratio (peak-to-base ratio) were significantly reduced in infants with RAI. 140 nmol/L for delta cortisol or 1.5 times for peak-to-base ratio may be cut-off levels in preterm infants. CONCLUSION: This study provides evidence that base cortisol levels of preterm infants with RAI were not different from those without RAI; however, CRH stimulation tests may be a useful tool for the diagnosis of RAI in preterm infants.

Preference for Dynamic Human Images and Gaze-Following Abilities in Preterm Infants at 6 and 12 Months of Age: An Eye-Tracking Study.

Preterm children are reported to be at higher risk of social communication problems such as autism spectrum disorder compared with full-term infants. Although previous studies have suggested that preference for social stimuli in infancy is a possible indicator of later social communication development, little is known about this relation in preterm infants. We examined the gaze behavior of low-risk preterm and full-term infants at 6 and 12 months' corrected ages using two types of eye-tracking tasks, which measured 1) preference for social stimuli by biological motion and human geometric preference and 2) ability to follow another's gaze direction. We found that preterm (compared with full-term) infants at both 6 and 12 months of age spent less time looking toward dynamic human images, followed another's gaze less frequently, and looked for a shorter time at an object cued by another. Moreover, we found a positive correlation between looking time toward dynamic human images and frequency of gaze following at 12 months of age in full-term, but not preterm, infants. We discuss the relation between the atypical patterns of gaze behavior in preterm infants and their higher risk of later social communication problems.

Fundamental Frequency Variation of Neonatal Spontaneous Crying Predicts Language Acquisition in Preterm and Term Infants.

Spontaneous cries of infants exhibit rich melodic features (i.e., time variation of fundamental frequency [F0 ]) even during the neonatal period, and the development of these characteristics might provide an essential base for later expressive prosody in language. However, little is known about the melodic features of spontaneous cries in preterm infants, who have a higher risk of later language-related problems. Thus, the present study investigated how preterm birth influenced melodic features of spontaneous crying at term-equivalent age as well as how these melodic features related to language outcomes at 18 months of corrected age in preterm and term infants. At term, moderate-to-late preterm (MLP) infants showed spontaneous cries with significantly higher F0 variation and melody complexity than term infants, while there were no significant differences between very preterm (VP) and term infants. Furthermore, larger F0 variation within cry series at term was significantly related to better language and cognitive outcomes, particularly expressive language skills, at 18 months. On the other hand, no other melodic features at term predicted any developmental outcomes at 18 months. The present results suggest that the additional postnatal vocal experience of MLP preterm infants increased F0 variation and the complexity of spontaneous cries at term. Additionally, the increases in F0 variation may partly reflect the development of voluntary vocal control, which, in turn, contributes to expressive language in infancy.

Associations between respiratory arrhythmia and fundamental frequency of spontaneous crying in preterm and term infants at term-equivalent age.

This study investigated whether lower vagal function in preterm infants is associated with increased fundamental frequency (F0 ; frequency of vocal fold vibration) of their spontaneous cries. We assessed respiratory sinus arrhythmia (RSA) during quiet sleep as a measure of vagal function, and its relationship with the F0 of spontaneous cries in healthy preterm and term infants at term-equivalent age. The results showed that preterm infants have significantly lower RSA, and higher overall F0 than term infants. Moreover, lower RSA was associated with higher overall F0 in preterm infants, whereas higher RSA was positively associated with mean and maximum F0 , and a larger F0 range in term infants. These results suggest that individual differences in vagal function may be associated with the F0 of spontaneous cries via modulation of vocal fold tension in infants at an early developmental stage. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 58:724-733, 2016.

Fetal growth restriction but not preterm birth is a risk factor for severe hypospadias.

BACKGROUND: Hypospadias has multifactorial causes and occurs at a high frequency among very low-birthweight infants. Placental insufficiency is hypothesized to be one cause of hypospadias; that is, decreased human chorionic gonadotropin (hCG) secretion caused by placental insufficiency is suspected to result in abnormal male external genitalia, but there is little direct evidence to support this. The aim of this study was therefore to identify the features of hypospadias and to clarify the male genital abnormalities caused by fetal growth restriction (FGR). METHODS: We reviewed the clinical data of boys who underwent hypospadias repair between 2005 and 2011 at Kyoto University Hospital. RESULTS: Twenty boys were included in this study. Fifteen (75%) of the subjects were preterm or low-birthweight infants. Thirteen (65%) had FGR, 60% of whom had severe hypospadias regardless of gestational age. In addition, 92% of the FGR infants also had other genital anomalies, such as cryptorchidism, bifid scrotum, or micropenis. In contrast, only 14% and 43% of the non-FGR infants had severe hypospadias or genital anomalies other than hypospadias, respectively. Placental histopathology was available in eight FGR infants, in seven of whom it was suggestive of blood flow deficiency such as infarction and single umbilical artery. CONCLUSIONS: Infants with FGR have a high incidence of hypospadias. FGR caused by placental dysfunction, but not low birthweight, is a risk factor for severe hypospadias associated with multiple genital anomalies.