Trajectories of brain and behaviour development in the womb, at birth and through infancy.

Birth is often seen as the starting point for studying effects of the environment on human development, with much research focused on the capacities of young infants. However, recent imaging advances have revealed that the complex behaviours of the fetus and the uterine environment exert influence. Birth is now viewed as a punctuate event along a developmental pathway of increasing autonomy of the child from their mother. Here we highlight (1) increasing physiological autonomy and perceptual sensitivity in the fetus, (2) physiological and neurochemical processes associated with birth that influence future behaviour, (3) the recalibration of motor and sensory systems in the newborn to adapt to the world outside the womb and (4) the effect of the prenatal environment on later infant behaviours and brain function. Taken together, these lines of evidence move us beyond nature-nurture issues to a developmental human lifespan view beginning within the womb.

Fetal brain growth and infant autistic traits.

BACKGROUND: Structural differences exist in the brains of autistic individuals. To date only a few studies have explored the relationship between fetal brain growth and later infant autistic traits, and some have used fetal head circumference (HC) as a proxy for brain development. These findings have been inconsistent. Here we investigate whether fetal subregional brain measurements correlate with autistic traits in toddlers. METHODS: A total of 219 singleton pregnancies (104 males and 115 females) were recruited at the Rosie Hospital, Cambridge, UK. 2D ultrasound was performed at 12-, 20- and between 26 and 30 weeks of pregnancy, measuring head circumference (HC), ventricular atrium (VA) and transcerebellar diameter (TCD). A total of 179 infants were followed up at 18-20 months of age and completed the quantitative checklist for autism in toddlers (Q-CHAT) to measure autistic traits. RESULTS: Q-CHAT scores at 18-20 months of age were positively associated with TCD size at 20 weeks and with HC at 28 weeks, in univariate analyses, and in multiple regression models which controlled for sex, maternal age and birth weight. LIMITATIONS: Due to the nature and location of the study, ascertainment bias could also have contributed to the recruitment of volunteer mothers with a higher than typical range of autistic traits and/or with a significant interest in the neurodevelopment of their children. CONCLUSION: Prenatal brain growth is associated with toddler autistic traits and this can be ascertained via ultrasound starting at 20 weeks gestation.

Is the association between mothers' autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?

BACKGROUND: Previous studies showed that there is a positive association between mothers' and children's autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). METHOD: The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). RESULT: Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; ßadjusted = 0.20, p < 0.01), in early childhood (Generation R; ßadjusted = 0.19, p < 0.01), and in early adolescence (Generation R; ßadjusted = 0.16, p < 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (ßadjusted = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. CONCLUSION: We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Importance: Few translational human studies have assessed the association of prenatal maternal immune activation with altered brain development and psychiatric risk in newborn offspring. Objective: To identify the effects of maternal immune activation during the 2nd and 3rd trimesters of pregnancy on newborn brain metabolite concentrations, tissue microstructure, and longitudinal motor development. Design: Prospective longitudinal cohort study conducted from 2012 - 2017. Setting: Columbia University Irving Medical Center and Weill Cornell Medical College. Participants: 76 nulliparous pregnant women, aged 14 to 19 years, were recruited in their 2nd trimester, and their children were followed through 14 months of age. Exposure: Maternal immune activation indexed by maternal interleukin-6 and C-reactive protein in the 2nd and 3rd trimesters of pregnancy. Main Outcomes and Measures: The main outcomes included (1) newborn metabolite concentrations, measured as N-acetylaspartate, creatine, and choline using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity measured using Diffusion Tensor Imaging; and (3) indices of motor development assessed prenatally and postnatally at ages 4- and 14-months. Results: Maternal interleukin-6 and C-reactive protein levels in the 2nd or 3rd trimester were significantly positively associated with the N-acetylaspartate, creatine, and choline concentrations in the putamen, thalamus, insula, and anterior limb of the internal capsule. Maternal interleukin-6 was associated with fractional anisotropy in the putamen, insula, thalamus, precuneus, and caudate, and with mean diffusivity in the inferior parietal and middle temporal gyrus. C-reactive protein was associated with fractional anisotropy in the thalamus, insula, and putamen. Regional commonalities were found across imaging modalities, though the direction of the associations differed by immune marker. In addition, a significant positive association was observed between offspring motor development and both maternal interleukin-6 and C-reactive protein (in both trimesters) prenatally and 4- and 14-months of age. Conclusions and Relevance: Using a healthy sample, these findings demonstrate that levels of maternal immune activation in mid- to late pregnancy associate with tissue characteristics in newborn brain regions primarily supporting motor integration/coordination and behavioral regulation and may lead to alterations in motor development.

Mini-puberty testosterone and infant autistic traits.

Background: Levels of steroid hormones in the first three months of life, a period referred to as 'mini-puberty', are one of the earliest physiological differences between typical males and females postnatally. Autistic traits also show consistent typical sex differences in later infancy, after the 18th month of life. Previous studies have shown prenatal testosterone is associated with later levels of autistic traits. Studies testing if postnatal testosterone levels are associated with autistic traits have reported null results. No studies to date have investigated mini-puberty longitudinally or tested for interactions with baseline sex differences or familial likelihood of autism. Methods: The 'Cambridge Human Imaging and Longitudinal Development Study' (CHILD) is a prospective enriched cohort study in Cambridge, UK. It includes physiological measurements in early infancy, as well as neurodevelopmental follow-ups over the first two years of life. A subset of the cohort also includes children with a family history of autism (a diagnosed parent or sibling). Salivary testosterone levels were assessed at two time-points, just after the 2nd and 6th month of life. Autistic traits were measured using the Quantitative Checklist of Autism in Toddlers (Q-CHAT) when the children were 18 months of age. Results: Salivary testosterone levels were significantly higher during 'mini-puberty' in the 2nd and 3rd month of life, compared to after the 6th month of life, in both males and females. There was no significant sex difference at either time-point. Log-transformed testosterone levels were not associated with autistic traits (Q-CHAT). There was no interaction effect with infant sex, autism family history or baseline testosterone levels after mini-puberty (at >6 months of age). Conclusion: Both male and female infants have elevated levels of salivary testosterone during mini-puberty but in this relatively small sample this was not associated with their later autistic traits at 18 months or their family history of autism. This suggests that prenatal rather than postnatal testosterone levels are more relevant for understanding the causes of autism. Future studies should test these relationships in larger samples.

A qualitative exploration of autistic mothers' experiences I: Pregnancy experiences.

LAY ABSTRACT: Little is known about how autistic people experience pregnancy. We interviewed 24 autistic and 21 non-autistic women during pregnancy to find out about their experiences. Autistic participants had more physical difficulties, such as nausea and pain, during pregnancy than non-autistic participants. They also sometimes felt that healthcare professionals, such as midwives, did not have a good understanding of autism and they did not always feel comfortable telling professionals about their autism diagnosis. Autistic participants told us that they needed professionals to communicate with them clearly and to make changes during appointments such as dimming lights. This research shows that autistic people would benefit from changes to pregnancy appointments and that more training about autism would help maternity care professionals to support autistic people during pregnancy.

Digit ratio (2D:4D) and maternal testosterone-to-estradiol ratio measured in early pregnancy.

The ratio of index to ring finger (2D:4D) has been hypothesised to indicate prenatal androgen exposure, yet evidence for its validity is lacking. We report the first pre-registered study to investigate mothers' early pregnancy sex hormone concentrations in relation to their children's digit ratios measured at 18-22-month follow-up. Although the testosterone (T) to estradiol (E) ratio correlated negatively with right hand digit ratio (R2D:4D) and directional asymmetry (right-minus-left) in digit ratio (D[R-L]), neither effect remained statistically significant once demographic and obstetric covariates were controlled for. Nevertheless, the multivariate level of analysis did reveal that T correlated positively with left hand digit ratio (L2D:4D) and negatively with D[R-L]. However, the first of these effects is in the opposite direction to that predicted by theory. Taken together, the results of our study suggest research with larger samples is required to determine whether digit ratios are valid proxies for maternal sex hormone exposure.

COVID-19 in the context of pregnancy, infancy and parenting (CoCoPIP) study: protocol for a longitudinal study of parental mental health, social interactions, physical growth and cognitive development of infants during the pandemic.

INTRODUCTION: While the secondary impact of the COVID-19 pandemic on the psychological well-being of pregnant women and parents has become apparent over the past year, the impact of these changes on early social interactions, physical growth and cognitive development of their infants is unknown, as is the way in which a range of COVID-19-related changes have mediated this impact. This study (CoCoPIP) will investigate: (1) how parent's experiences of the social, medical and financial changes during the pandemic have impacted prenatal and postnatal parental mental health and parent-infant social interaction; and (2) the extent to which these COVID-19-related changes in parental prenatal and postnatal mental health and social interaction are associated with fetal and infant development. METHODS AND ANALYSIS: The CoCoPIP study is a national online survey initiated in July 2020. This ongoing study (n=1700 families currently enrolled as of 6 May 2021) involves both quantitative and qualitative data being collected across pregnancy and infancy. It is designed to identify the longitudinal impact of the pandemic from pregnancy to 2 years of age as assessed using a range of parent- and self-report measures, with the aim of identifying if stress-associated moderators (ie, loss of income, COVID-19 illness, access to ante/postnatal support) appear to impact parental mental health, and in turn, infant development. In addition, we aim to document individual differences in social and cognitive development in toddlers who were born during restrictions intended to mitigate COVID-19 spread (eg, social distancing, national lockdowns). ETHICS AND DISSEMINATION: Ethical approval was given by the University of Cambridge, Psychology Research Ethics Committee (PRE.2020.077). Findings will be made available via community engagement, public forums (eg, social media,) and to national (eg, NHS England) and local (Cambridge Universities Hospitals NHS Foundation Trust) healthcare partners. Results will be submitted for publication in peer-reviews journals.

Expectant parents' perceptions of healthcare and support during COVID-19 in the UK: a thematic analysis.

BACKGROUND: In response to the COVID-19 pandemic, expectant parents experienced changes in the availability and uptake of both National Health Service (NHS) community and hospital-based healthcare. OBJECTIVE: To examine how COVID-19 and its societal related restrictions have impacted the provision of healthcare support for pregnant women during the COVID-19 pandemic. METHOD: A thematic analysis using an inductive approach was undertaken using data from open-ended responses to the national COVID in Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study online survey (n = 507 families). FINDINGS: The overarching theme identified was the way in which the changes to healthcare provision increased parents' anxiety levels, and feelings of not being supported. Five sub-themes, associated with the first wave of the pandemic, were identified: (1) rushed and/or fewer antenatal appointments, (2) lack of sympathy from healthcare workers, (3) lack of face-to-face appointments, (4) requirement to attend appointments without a partner, and (5) requirement to use PPE. A sentiment analysis, that used quantitative techniques, revealed participant responses to be predominantly negative (50.1%), with a smaller proportion of positive (21.8%) and neutral (28.1%) responses found. CONCLUSION: This study provides evidence indicating that the changes to healthcare services for pregnant women during the pandemic increased feelings of anxiety and have left women feeling inadequately supported. Our findings highlight the need for compensatory social and emotional support for new and expectant parents while COVID-19 related restrictions continue to impact on family life and society.

Giving birth in a pandemic: women's birth experiences in England during COVID-19.

BACKGROUND: Expectant parents worldwide have experienced changes in the way they give birth as a result of COVID-19, including restrictions relating to access to birthing units and the presence of birthing partners during the birth, and changes to birth plans. This paper reports the experiences of women in England. METHODS: Data were obtained from both closed- and open-ended responses collected as part of the national COVID in Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study online survey (n = 477 families) between 15th July 2020 - 29th March 2021. Frequency data are presented alongside the results of a sentiment analysis; the open-ended data was analysed thematically. RESULTS: Two-thirds of expectant women reported giving birth via spontaneous vaginal delivery (SVD) (66.1%) and a third via caesarean section (CS) (32.6%) or 'other' (1.3%). Just under half (49.7%) of the CS were reported to have been elective/planned, with 47.7% being emergencies. A third (37.4%) of participants reported having no changes to their birth (as set out in their birthing plan), with a further 25% reporting COVID-related changes, and 37.4% reporting non-COVID related changes (e.g., changes as a result of birthing complications). One quarter of the sample reported COVID-related changes to their birth plan, including limited birthing options and reduced feelings of control; difficulties accessing pain-relief and assistance, and feelings of distress and anxiety. Under half of the respondents reported not knowing whether there could be someone present at the birth (44.8%), with 2.3% of respondents reporting no birthing partner being present due to COVID-related restrictions. Parental experiences of communication and advice provided by the hospital prior to delivery were mixed, with significant stress and anxiety being reported in relation to both the fluctuating guidance and lack of certainty regarding the presence of birthing partners at the birth. The sentiment analysis revealed that participant experiences of giving birth during the pandemic were predominately negative (46.9%) particularly in relation to the first national lockdown, with a smaller proportion of positive (33.2%) and neutral responses (19.9%). CONCLUSION: The proportion of parents reporting birthing interventions (i.e., emergency CS) was higher than previously reported, as were uncertainties related to the birth, and poor communication, leading to increased feelings of anxiety and high levels of negative emotions. The implications of these findings are discussed.

An ode to fetal, infant, and toddler neuroimaging: Chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field.

Fetal, infant, and toddler neuroimaging is commonly thought of as a development of modern times (last two decades). Yet, this field mobilized shortly after the discovery and implementation of MRI technology. Here, we provide a review of the parallel advancements in the fields of fetal, infant, and toddler neuroimaging, noting the shifts from clinical to research use, and the ongoing challenges in this fast-growing field. We chronicle the pioneering science of fetal, infant, and toddler neuroimaging, highlighting the early studies that set the stage for modern advances in imaging during this developmental period, and the large-scale multi-site efforts which ultimately led to the explosion of interest in the field today. Lastly, we consider the growing pains of the community and the need for an academic society that bridges expertise in developmental neuroscience, clinical science, as well as computational and biomedical engineering, to ensure special consideration of the vulnerable mother-offspring dyad (especially during pregnancy), data quality, and image processing tools that are created, rather than adapted, for the young brain.

Autistic mothers' perinatal well-being and parenting styles.

LAY ABSTRACT: Autistic people can have difficulties during pregnancy and after giving birth, such as difficulty getting health care that meets their needs. Autistic people may therefore have lower well-being than non-autistic people during this time. We asked autistic and non-autistic people to fill in questionnaires measuring stress, depression, anxiety and satisfaction with life. They were asked to do this once during pregnancy, once 2 to 3 months after giving birth and once 6 months after giving birth. At 6 months after giving birth, they also filled in questionnaires about parenting. The autistic parents had higher stress, depression and anxiety scores than the non-autistic parents. For both groups, scores for anxiety went down over time. There were no differences between the groups on satisfaction with their life or how confident they were as a parent. There were no differences between the groups on most areas of parenting style, although autistic parents scored lower on parenting discipline. This study suggests that autistic people may be more stressed, depressed and anxious than non-autistic people during pregnancy and after giving birth. Autistic people therefore need good quality support during this time. This study also suggests that autistic and non-autistic parents may be just as likely to parent in positive ways such as being sensitive to their baby's needs.

A qualitative exploration of autistic mothers' experiences II: Childbirth and postnatal experiences.

LAY ABSTRACT: Very little research has looked at how autistic people experience childbirth and the first few months of parenthood. We interviewed 21 autistic and 25 non-autistic women 2-3 months after their baby was born, to find out how they experienced giving birth and being a parent. Some autistic participants found sensory aspects of giving birth difficult, such as noise and being touched. They also wanted healthcare professionals to give them clear information while giving birth. Participants sometimes thought that healthcare professionals did not know enough about autism. Autistic and non-autistic participants both found parenthood difficult at times and autistic parents sometimes had extra difficulties, such as with planning and organising. Autistic participants also felt good at understanding their baby's needs. This research suggests that autistic people would benefit from changes to childbirth and postnatal healthcare such as being communicated with more clearly. It also indicates that healthcare professionals should receive more training about autism.

Generation COVID-19 - Should the foetus be worried?

AIM: The aim of this narrative review was to evaluate the risks, both direct and indirect, to the foetus from the COVID-19 pandemic. METHODS: Direct and indirect risks were defined as (a) vertical infection (congenital or intrapartum), (b) maternal infection and its sequelae, and (c) sources of maternal stress during lockdown, including social isolation and altered healthcare provision. RESULTS: Early studies suggest that vertical viral transmission is low; however, there may be an important effect of maternal infection on foetal growth and development. The impact of various degrees of lockdown on prospective mothers' health, habits and healthcare provision is of concern. In particular, increased maternal stress has been shown to have a significant effect on foetal brain development increasing the risk of mental health, and cognitive and behavioural disorders in later life. CONCLUSION: From the evidence available to date, direct risks to the foetus from the SARS-CoV-2 virus are low. Indirect effects of the pandemic, particularly resulting from the effect of maternal stress on the developing brain, can have lifelong detrimental impacts for this generation of children.

Digit ratio (2D:4D) and congenital adrenal hyperplasia (CAH): Systematic literature review and meta-analysis.

The ratio of length between the second and fourth fingers (2D:4D) is commonly used as an indicator of prenatal sex hormone exposure. Several approaches have been used to try to validate the measure, including examining 2D:4D in people with congenital adrenal hyperplasia (CAH), a suite of conditions characterised by elevated adrenal androgen production secondary to defective steroidogenesis. We present a systematic review and meta-analysis that examines the relationship between these two variables. Twelve articles relating to nine CAH cohorts were identified, and 2D:4D comparisons have been made between cases and controls in eight of these cohorts. Altogether, at least one 2D:4D variable has been compared between n = 251 females with CAH and n = 358 unaffected females, and between n = 108 males with CAH and n = 204 unaffected males. A previous meta-analysis (Hönekopp and Watson, 2010) reported lower right hand (R2D:4D) and left hand (L2D:4D) digit ratios in patients with CAH relative to sex-matched controls. Our meta-analysis showed the same pattern, with medium effect sizes for R2D:4D and small effect sizes for L2D:4D. Differences of small magnitude were also observed for M2D:4D, and no significant effects were observed for D[R-L]. Notably, the only effects that remained statistically significant when stratified by sex were R2D:4D in males and L2D:4D in females, and the average effect size had reduced by 46.70% since the meta-analysis of Hönekopp and Watson (2010). We also found that individual comparisons in this literature were considerably underpowered, and that patterns of sexual dimorphism in 2D:4D were similar in CAH samples as in typically developing populations. Findings are discussed in relation to the prenatal androgen hypothesis as well as alternative explanations.

Fetal anogenital distance using ultrasound.

OBJECTIVE: This study measured anogenital distance (AGD) during late second/early third trimester of pregnancy to confirm previous findings that AGD can be measured noninvasively in the fetus using ultrasound and further showed differences in reference ranges between populations. METHOD: Two hundred ten singleton pregnancies were recruited at the Rosie Hospital, Cambridge, UK. A 2D ultrasound was performed between 26 and 30 weeks of pregnancy. AGD was measured from the centre of the anus to the base of the scrotum in males and to the posterior convergence of the fourchette in females. RESULTS: A significant difference in AGD between males and females (P < .0001) was found, replicating previous results with a significant correlation between estimated fetal weight (EFW) and AGD in males only (P = .006). A comparison of AGD using reference data from an Israeli sample (n = 118) and our UK sample (n = 208) showed a significant difference (P < .0001) in both males and females, after controlling for gestational age (GA). CONCLUSION: Our results confirm that AGD measurement in utero using ultrasound is feasible. In addition, there are strong sex differences, consistent with previous suggestions that AGD is influenced by prenatal androgen exposure. AGD lengths differ between the UK and Israel; therefore, population-specific normative values may be required for accurate clinical assessments.

Laterality of foetal self-touch in relation to maternal stress.

This longitudinal observational study investigated whether foetuses change their hand preference with gestational age, and also examined the effects of maternal stress on lateralized foetal self-touch. Following ethical approval, fifteen healthy foetuses (eight girls and seven boys) were scanned four times from 24 to 36 weeks gestation. Self-touch behaviours which resulted in a touch of the foetal face/head were coded in 60 scans for 10 min and analysed in terms of frequency of the foetuses using left and right hands to touch their face. The joint effects of foetal age, stress and sex on laterality were assessed. We modelled the proportion of right self-touches for each foetal scan using a generalized linear mixed model, taking account of the repeated measures design. There was substantial variability in hand preference between foetuses. However, there was no significant increase in the proportion of right-handed touches with foetal age. No sex differences in handedness were identified. However, maternally reported stress level was significantly positively related to foetal left-handed self-touches (odds ratio 0.915; p < .0001). This longitudinal study provides important new insights into the effect of recent maternal stress on foetal predominant hand use during self-touch.