Social cognition is a broad construct that refers to the fundamental abilities to perceive, store, analyze, process, categorize, reason with, and behave towards other conspecifics (Pelphrey & Carter, 2008). Two important aspects of social cognition are the ability to perceive and interpret body movements (biological motion perception) and the ability to infer the mental states of others (theory of mind reasoning) (Allison, Puce & McCarthy, 2000). In my thesis, these and other aspects of social cognition are explored in a group known to be at high risk for poor social outcomes, namely children born prematurely at very low birth weight (VLBW: < 1500 grams). Results showed that 8-11 year old VLBW children had difficulties processing both realistic and stylized life motion displays. These impairments were associated with increased evidence of autistic-like traits. Finally, poor performance on tests requiring life motion perception was linked to complications related to premature birth. These results could inform the development of screening, diagnostic, and intervention tools.

The fetal component of the human placenta is comprised of cells termed trophoblasts and the proper differentiation of these cells is pivotal for maintaining maternal and fetal health throughout pregnancy. The placental syncytiotrophoblast layer is a key secretory portion of the placenta and is produced through fusion of underlying progenitor cytotrophoblast cells with the multinucleated syncytiotrophoblast layer. The MacPhee laboratory has previously established that fusion or syncytialization of cytotrophoblasts is aided by expression of integrin-linked kinase (ILK), a cytoplasmic adapter protein. Nuclear enzyme Poly ADP-ribose Polymerase-1 (PARP-1) and the transcriptional repressor Snail-1 work with ILK to downregulate epithelial cell-cell adhesion. This process would also be necessary for proper trophoblast syncytialization. Thus, it was hypothesized that PARP-1 would be an important mediator of syncytiotrophoblast development. To test this hypothesis, immunofluorescence analysis of PARP-1 and Snail expression in human chorionic villi from first and second trimester as well as from term pregnancy was conducted. Furthermore, co-localization between PARP-1 and Snail-1 were evaluated. Lastly, human PARP-1 was overexpressed in the BeWo trophoblast derived cell line, under fusion promoting conditions, to directly test the ability of PARP-1 to regulate trophoblast fusion. Throughout the first and second trimester, PARP-1 and Snail were highly expressed and co-localized in villous cytotrophoblast nuclei. In contrast, PARP-1 was rarely detectable in syncytiotrophoblast nuclei, while Snail was highly expressed. Upon transient overexpression of PARP-1 in BeWo cells, fusion was robustly promoted. Furthermore, the mean number of nuclei per syncytium was markedly higher in PARP-overexpressing cells compared to control cells. However, PARP-1 overexpression did not regulate trophoblast hormonal differentiation. In conclusion, PARP-1 does appear to be a key enzyme in the process of trophoblast syncytialization. Lastly, a comparative analysis of PARP-1 was conducted in the mouse placenta. It was found that PARP-1 was highly detectable in nuclei of mononuclear trophoblast as well as the nuclei in the syncytiotrophoblast bilayer of the mouse labyrinth. Additionally, PARP-1 was localized to the nuclei of other trophoblast populations, including spongiotrophoblasts, trophoblast giant cell, and glycogen trophoblast giant cells, which are involved in the invasive pathway of trophoblast differentiation.

Prior studies have shown that the low-level microbiome in the placenta is most similar to the non-pregnant oral microbiome, suggesting a hematogenous route of bacterial transmission. Based on these studies, we theorized that a disruption of the normal balance of pathogenic and commensal microorganisms in the oral cavity will lead to conditions that favor colonization of the placenta and amniotic cavity, leading to inflammation and preterm birth. We hypothesized that an altered oral microbiome profile will promote preterm birth. Our study aimed to compare metagenomic profiles of saliva and tongue in women delivering preterm to those of women delivering at term. Unstimulated saliva and tongue brushings were collected according to an IRB-approved protocol from patients who delivered preterm, and from age and race-matched patients who delivered at term. Exclusion criteria included obvious risk factors for preterm birth or other major complications (multiple gestation; history of or current cervical cerclage; history of hypertension or diabetes; prior history of preterm birth or preeclampsia; age less than 16 or greater than 45) as well as immunologic problems (HIV, organ transplant, etc). Oral samples were collected within 24-48 hours after delivery. Samples were analyzed using 16S rDNA-based sequencing, where the DNA was extracted and then amplified by PCR using 16S rDNA primers. Data was processed using the UPARSE/SINTAX pipeline, and differentially abundant taxa were determined using the LEfSe method and MaAsLin2. The parent study enrolled 100 patients who delivered preterm and 205 patients who delivered at term. A subset of patients had oral samples collected, and 95 saliva and 70 tongue samples were analyzed using 16S rDNA-based sequencing. Communities from tongue and saliva were significantly different between women who delivered preterm and those who delivered at term, although not between those delivering low birthweight versus normal birthweight infants. When assessing beta diversity using the unweighted unifrac metric, patients who delivered very preterm (VPT, < 32 weeks) had a tongue microbiome that was consistently and statistically different from the tongue microbiome of patients who delivered both term (T, > 37 weeks) and late preterm (LPT, 32-<37). Differences remained significant after controlling for tobacco use. In a three-way comparison of saliva samples between the groups using MaAsLin2, the genus Lachnoanaerobaculum was significantly less abundant in the VPT group. Our studies suggest a tongue and salivary microbiome that differs between women delivering term and late preterm versus very preterm. Future studies are required to prospectively confirm differences and may yield data to design noninvasive tests to predict preterm birth risk. / 2021-06-12T00:00:00Z

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Definition of neurodevelopmental outcome from early brain imaging remains a priority for survivors of very preterm (VPT) birth given their persistently high rates of cognitive and motor difficulties. Volumes of the deep grey matter (DGM) structures were measured longitudinally using magnetic resonance imaging from 96 VPT infants studied within 2 weeks of birth and 70 at term-equivalent age. At 4 years of age, 36 children returned for neuropsychological assessments evaluating IQ, language function, and visual motor integration. Multiple hierarchical regressions examined associations of DGM growth with neuropsychological measures. Overall DGM growth, primarily attributed to the caudate and thalamus, predicted Full Scale IQ, core language and VMI scores after controlling for sex and total brain volume. Thalamic growth was additionally associated with measures of neonatal clinical severity, bronchopulmonary dysplasia, and white matter lesions. Longitudinal growth of the DGM, particularly the caudate and thalamus were established as early markers of long-term outcomes.

Definition of neurodevelopmental outcome from early brain imaging remains a priority for survivors of very preterm (VPT) birth given their persistently high rates of cognitive and motor difficulties. Volumes of the deep grey matter (DGM) structures were measured longitudinally using magnetic resonance imaging from 96 VPT infants studied within 2 weeks of birth and 70 at term-equivalent age. At 4 years of age, 36 children returned for neuropsychological assessments evaluating IQ, language function, and visual motor integration. Multiple hierarchical regressions examined associations of DGM growth with neuropsychological measures. Overall DGM growth, primarily attributed to the caudate and thalamus, predicted Full Scale IQ, core language and VMI scores after controlling for sex and total brain volume. Thalamic growth was additionally associated with measures of neonatal clinical severity, bronchopulmonary dysplasia, and white matter lesions. Longitudinal growth of the DGM, particularly the caudate and thalamus were established as early markers of long-term outcomes.

Background Preterm birth is a leading cause of perinatal morbidity and mortality worldwide, resulting in a pressing need to identify risk factors leading to effective interventions. Limited evidence suggests potential relationships between maternal sleep or vital exhaustion and preterm birth, yet the literature is generally inconclusive. Methods We examined the relationship between maternal sleep duration and vital exhaustion in the first six months of pregnancy and spontaneous (non-medically indicated) preterm birth among 479 Peruvian women who delivered a preterm singleton infant (<37 weeks gestation) and 480 term controls who delivered a singleton infant at term (≥37 weeks gestation). Maternal nightly sleep and reports of vital exhaustion were ascertained through in-person interviews. Spontaneous preterm birth cases were further categorized as those following either spontaneous preterm labor or preterm premature rupture of membranes. In addition, cases were categorized as very (<32 weeks), moderate (32–33 weeks), and late (34- <37 weeks) preterm birth for additional analyses. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Results After adjusting for confounders, we found that short sleep duration (≤6 hours) was significantly associated with preterm birth (aOR = 1.56; 95% CI 1.11-2.19) compared to 7–8 hours of sleep. Vital exhaustion was also associated with increased odds of preterm birth (aOR = 2.41; 95% CI 1.79-3.23) compared to no exhaustion (Ptrend <0.001). These associations remained significant for spontaneous preterm labor and preterm premature rupture of membranes. We also found evidence of joint effects of sleep duration and vital exhaustion on the odds of spontaneous preterm birth. Conclusions The results of this case–control study suggest maternal sleep duration, particularly short sleep duration, and vital exhaustion may be risk factors for spontaneous preterm birth. These findings call for increased clinical attention to maternal sleep and the study of potential intervention strategies to improve sleep in early pregnancy with the aim of decreasing risk of preterm birth.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Antepartum suicidal behaviors are a leading cause of maternal injury and death. Previous research has not investigated associations between antepartum suicidal ideation and perinatal complications. Our study objective was to evaluate the relationship of antepartum suicidal ideation with low infant birthweight, small for gestational age, and preterm birth. A cohort study was conducted among 1,108 women receiving prenatal care in Peru. Suicidal ideation was measured using the Patient Health Questionnaire-9 during pregnancy. Birth outcomes were extracted from medical records. Linear regressions and multivariable logistic regressions were used to estimate were used to investigate associations between suicidal ideation and pregnancy outcomes. The prevalence of suicidal ideation was 8.7%, preterm delivery was 5.7%, low birthweight was 4.4%, and small for gestational age was 3.4%. In an adjusted model, infant birthweight was 94.2 grams lower for mothers with antepartum suicidal ideation (95% CI: −183.0, −5.5, p = 0.037) compared with those without suicidal ideation. After adjusting for confounders including depression, participants with suicidal ideation had a nearly four-fold increased odds of delivering a small for gestational age infant (OR: 3.73; 95% CI: 1.59–8.74). These findings suggest suicidal ideation during pregnancy is associated with adverse perinatal outcomes, especially low infant birthweight. / Revisión por pares

Preterm birth (PTB) is a global public health problem that has significant adverse effects on neonatal mortality and morbidity. Progress in understanding the pathological mechanisms underlying PTB has been greatly hampered by the complex and polygenic nature of the disease. As a result, a multifaceted approach may hold promise for identifying true causal factors. The main objective of this thesis is to identify genes that play a role in the etiology of PTB using experimental data derived from different molecular levels (genome, transcriptome, and epigenome). To achieve this goal, we performed association studies using a candidate gene approach to identify genetic factors contributing to PTB. Our analysis of genetic variants in three OXT pathway genes (oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP)) revealed several common polymorphisms in LNPEP that show significant association with prematurity. Large-scale sequence analysis of the OXTR gene identified several novel rare coding variants that might be of etiologic importance. Our results suggest that these variants, in aggregate, appear to make some contribution to susceptibility to PTB. We also examined the gene expression profiles in the human placenta to identify, at the transcriptomic level, candidate genes for PTB. Using splicing-sensitive microarray and deep sequencing technologies, we identified transcriptome signatures that differ between term (with and without labor) and preterm placental tissues and between placental and other human tissues. The transcriptome data were analyzed not only at the gene-level, but also at the exon-level, enabling the detection of alternative splicing events. The exon-level analysis revealed more frequent disruption of alternative splicing in preterm than term placental tissues, indicating that alternative splicing may represent one possible mechanism contributing to PTB. Our study at the epigenomic level was pursued through investigation of placental DNA methylation profiles. We, using a genome-wide approach, detected a panel of genes showing labor- and gestational age-associated methylation differences. Selected genes were validated using bisulfite sequencing and methylation-specific PCR. SLC30A3, a validated differentially methylated gene between term labor and preterm labor amnion tissues, for instance, may potentially play a role in the pathogenesis of PTB. Taken together, this thesis work provides a valuable source of novel candidate genes for PTB, and future research using integrative systems biology approaches may shed light on the molecular mechanisms underlying this complex, heterogeneous disease.

This dissertation examined the relationship between maternal stressful life events and urogenital infection in preterm birth. A systematic literature review revealed ambivalent findings concerning the relationship between maternal stress and infection during pregnancy; the effects of this relationship on pregnancy outcome were not examined in the reviewed studies. The current study employed a biobehavioral model consisting of maternal stressful life events (illness among family members, divorced, moved, became homeless, partner lost job, mom lost job, argued with partner more than usual, partner did not want the child, inability to pay bills, got in a physical fight, partner went to jail, close friend/relative had a bad problem with drinking or drug use, and close friend/relative died) and urogenital infection (genital warts, herpes, chlamydia, gonorrhea, pelvic inflammatory disease, syphilis, Group B streptococcus, bacterial vaginosis, trichomoniasis, yeast infection, urinary tract infection, and other infection) to examine the relationship between these variables in preterm birth. Data from 1,647 respondents of the 2005 Florida Pregnancy Risk Assessment Monitoring System survey were analyzed using descriptive statistics, chi-square and student t- tests, analysis of variance, and structural equation modeling (SEM). Of the respondents, 42% were White, 37.8% had preterm deliveries, and the mean age was 27.1 years. White mothers who became homeless (p = 0.021) or had a partner in jail (p = 0.041) during the 12 months prior to delivery had more preterm deliveries as compared to full-term deliveries. Other non-White mothers who had an ill family member (p = 0.010) had fewer preterm deliveries. In general, mothers diagnosed with Group B streptococcus during pregnancy (p = 0.031) had fewer preterm deliveries. Black mothers diagnosed with herpes (p = 0.006) had fewer preterm deliveries. SEM revealed a significant relationship between maternal stress and infection, in general (p < 0.001), and among White (p < 0.001), Black (p < 0.001), and Hispanic (p < 0.001) mothers. The interaction between these variables was not significant, in general, or among racial/ethnic groups. Results of this study indicate that culturally tailored prevention programs designed to help women cope with multiple risk factors may prove beneficial in reducing preterm birth rates.