Interpregnancy Interval and Birth Outcomes: A Propensity Matching Study in the California Population.

INTRODUCTION: Previous studies that used traditional multivariable and sibling matched analyses to investigate interpregnancy interval (IPI) and birth outcomes have reached mixed conclusions about a minimum recommended IPI, raising concerns about confounding. Our objective was to isolate the contribution of interpregnancy interval to the risk for adverse birth outcomes using propensity score matching. METHODS: For this retrospective cohort study, data were drawn from a California Department of Health Care Access and Information database with linked vital records and hospital discharge records (2007-2012). We compared short IPIs of < 6, 6-11, and 12-17 months to a referent IPI of 18-23 months using 1:1 exact propensity score matching on 13 maternal sociodemographic and clinical factors. We used logistic regression to calculate the odds of preterm birth, early-term birth, and small for gestational age (SGA). RESULTS: Of 144,733 women, 73.6% had IPIs < 18 months, 5.5% delivered preterm, 27.0% delivered early-term, and 6.0% had SGA infants. In the propensity matched sample (n = 83,788), odds of preterm birth were increased among women with IPI < 6 and 6-11 months (OR 1.89, 95% CI 1.71-2.0; OR 1.22, 95% CI 1.13-1.31, respectively) and not with IPI 12-17 months (OR 1.01, 95% CI 0.94-1.09); a similar pattern emerged for early-term birth. The odds of SGA were slightly elevated only for intervals < 6 months (OR 1.10, 95% CI 1.00-1.20, p < .05). DISCUSSION: This study demonstrates a dose response association between short IPI and adverse birth outcomes, with no increased risk beyond 12 months. Findings suggest that longer IPI recommendations may be overly proscriptive.

Patient and provider perspectives on preterm birth risk assessment and communication.

OBJECTIVE: To describe and compare how obstetric patients and care providers view preterm birth risk assessment and communication. METHODS: We conducted eight focus groups with obstetric patients (n = 35) and 16 qualitative interviews with obstetric providers. Grounded theory was used to identify and analyze themes. RESULTS: Patients' knowledge about preterm birth varied greatly. Similar benefits and risks of preterm birth risk counseling were discussed by patients and providers with notable exceptions: patients cited preparedness as a benefit and providers cited maternal blame, patient alienation, and estimate uncertainty as potential risks. Most patients expressed a desire to know their personalized preterm birth risk during pregnancy. Providers differed in whether they offer universal versus selective, and quantitative versus qualitative, preterm birth risk counseling. Many providers expressed concern about discussing social and structural risk factors for preterm birth. CONCLUSION: While many patients desired knowing their personalized preterm birth risk, prenatal care providers' disclosure practices vary because of uncertainty of estimates, concerns about negative consequences and challenges of addressing systemic inequities and social determinants of health. PRACTICE IMPLICATIONS: Given the existing asymmetry of information about preterm birth risk, providers should consider patient preferences regarding and potential benefits and risks of such disclosure in their practice.

Racial and ethnic disparities in outcomes through 1 year of life in infants born prematurely: a population based study in California.

OBJECTIVES: To investigate racial/ethnic differences in rehospitalization and mortality rates among premature infants over the first year of life. STUDY DESIGN: A retrospective cohort study of infants born in California from 2011 to 2017 (n = 3,448,707) abstracted from a California Office of Statewide Health Planning and Development database. Unadjusted Kaplan-Meier tables and logistic regression controlling for health and sociodemographic characteristics were used to predict outcomes by race/ethnicity. RESULTS: Compared to White infants, Hispanic and Black early preterm infants were more likely to be readmitted; Black late/moderate preterm (LMPT) infants were more likely to be readmitted and to die after discharge; Hispanic and Black early preterm infants with BPD were more likely to be readmitted; Black LMPT infants with RDS were more likely to be readmitted and die after discharge. CONCLUSIONS: Racial/ethnic disparities in readmission and mortality rates exist for premature infants across several co-morbidities. Future studies are needed to improve equitability of outcomes.

Newborn metabolic vulnerability profile identifies preterm infants at risk for mortality and morbidity.

BACKGROUND: Identifying preterm infants at risk for mortality or major morbidity traditionally relies on gestational age, birth weight, and other clinical characteristics that offer underwhelming utility. We sought to determine whether a newborn metabolic vulnerability profile at birth can be used to evaluate risk for neonatal mortality and major morbidity in preterm infants. METHODS: This was a population-based retrospective cohort study of preterm infants born between 2005 and 2011 in California. We created a newborn metabolic vulnerability profile wherein maternal/infant characteristics along with routine newborn screening metabolites were evaluated for their association with neonatal mortality or major morbidity. RESULTS: Nine thousand six hundred and thirty-nine (9.2%) preterm infants experienced mortality or at least one complication. Six characteristics and 19 metabolites were included in the final metabolic vulnerability model. The model demonstrated exceptional performance for the composite outcome of mortality or any major morbidity (AUC 0.923 (95% CI: 0.917-0.929). Performance was maintained across mortality and morbidity subgroups (AUCs 0.893-0.979). CONCLUSIONS: Metabolites measured as part of routine newborn screening can be used to create a metabolic vulnerability profile. These findings lay the foundation for targeted clinical monitoring and further investigation of biological pathways that may increase the risk of neonatal death or major complications in infants born preterm. IMPACT: We built a newborn metabolic vulnerability profile that could identify preterm infants at risk for major morbidity and mortality. Identifying high-risk infants by this method is novel to the field and outperforms models currently in use that rely primarily on infant characteristics. Utilizing the newborn metabolic vulnerability profile for precision clinical monitoring and targeted investigation of etiologic pathways could lead to reductions in the incidence and severity of major morbidities associated with preterm birth.

Maternal cardiovascular disease risk factors as predictors of preterm birth in California: a case-control study.

OBJECTIVE: To determine whether maternal cardiovascular disease (CVD) risk factors predict preterm birth. DESIGN: Case control. SETTING: California hospitals. PARTICIPANTS: 868 mothers with linked demographic information and biospecimens who delivered singleton births from July 2009 to December 2010. METHODS: Logistic regression analysis was employed to calculate odds ratios for the associations between maternal CVD risk factors before and during pregnancy (including diabetes, hypertensive disorders and cholesterol levels) and preterm birth outcomes. PRIMARY OUTCOME: Preterm delivery status. RESULTS: Adjusting for the other maternal CVD risk factors of interest, all categories of hypertension led to increased odds of preterm birth, with the strongest magnitude observed in the pre-eclampsia group (adjusted OR (aOR), 13.49; 95% CI 6.01 to 30.27 for preterm birth; aOR, 10.62; 95% CI 4.58 to 24.60 for late preterm birth; aOR, 17.98; 95% CI 7.55 to 42.82 for early preterm birth) and chronic hypertension alone for early preterm birth (aOR, 4.58; 95% CI 1.40 to 15.05). Diabetes (types 1 and 2 and gestational) was also associated with threefold increased risk for preterm birth (aOR, 3.06; 95% CI 1.12 to 8.41). A significant and linear dose response was found between total and low-density lipoprotein (LDL) cholesterol and aORs for late and early preterm birth, with increasing cholesterol values associated with increased risk (likelihood χ2 differences of 8.422 and 8.019 for total cholesterol for late and early, and 9.169 and 10.896 for LDL for late and early, respectively). Receiver operating characteristic curves using these risk factors to predict late and early preterm birth produced C statistics of 0.601 and 0.686. CONCLUSION: Traditional CVD risk factors are significantly associated with an increased risk of preterm birth; these findings reinforce the clinical importance of integrating obstetric and cardiovascular risk assessment across the healthcare continuum in women.

Cohort study of respiratory hospital admissions, air quality and sociodemographic factors in preterm infants born in California.

BACKGROUND: Preterm infants suffer from respiratory morbidity especially during the first year of life. OBJECTIVE: To investigate the association of air quality and sociodemographic indicators on hospital admission rates for respiratory causes. METHODS: This is a retrospective cohort study. We identified all live-born preterm infants in California from 2007 to 2012 in a population-based administrative data set and linked them to a data set measuring several air quality and sociodemographic indicators at the census tract level. All sociodemographic and air quality predictors were divided into quartiles (first quartile most favourable to the fourth quartile least favourable). Mixed effect logistic models to account for clustering at the census tract level were used to investigate associations between chronic air quality and sociodemographic indicators respiratory hospital admission during the first year of life. RESULTS: Of 205 178 preterm infants, 5.9% (n = 12 033) were admitted to the hospital for respiratory causes during the first year. In the univariate analysis, comparing the first to the fourth quartile of chronic ozone (risk ratio [RR] 1.29, 95% confidence interval [CI] 1.21, 1.37), diesel (RR 1.10, 95% CI 1.02, 1.17) and particulate matter 2.5 (RR 1.07, 95% CI 1.01, 1.14) exposure were associated with hospital admission during the first year. Following adjustment for confounders, the risk ratios for hospital admission during the first year were 1.53 (95% CI 1.37, 1.72) in relation to educational attainment (per cent of the population over age 25 with less than a high school education) and 1.23 (95% CI 1.09, 1.38) for poverty (per cent of the population living below two times the federal poverty level). CONCLUSIONS: Among preterm infants, respiratory hospital admissions in the first year in California are associated with socioeconomic characteristics of the neighbourhood an individual is living in.

Exposures to structural racism and racial discrimination among pregnant and early post-partum Black women living in Oakland, California.

Research supports that exposure to stressors (e.g., perceived stress and racism) during pregnancy can negatively impact the immune system, which may lead to infection and ultimately increases the risk for having a preterm or low-birthweight infant. It is well known that Black women report higher levels of stressors at multiple timepoints across pregnancy compared with women of all other racial and ethnic groups. This study addresses gaps in the literature by describing pregnant and early post-partum Black women's exposures to structural racism and self-reported experiences of racial discrimination, and the extent to which these factors are related. We used a cross-sectional study design to collect data related to exposures to racism from pregnant and early post-partum Black women residing in Oakland, California, from January 2016 to December 2017. Comparative analysis revealed that living in highly deprived race + income neighborhoods was associated with experiencing racial discrimination in three or more situational domains (p = .01). Findings show that Black women are exposed to high levels of racism that may have negative impacts on maternal health outcomes.

Mediation of Adverse Pregnancy Outcomes in Autoimmune Conditions by Pregnancy Complications: A Mediation Analysis of Autoimmune Conditions and Adverse Pregnancy Outcomes.

OBJECTIVE: Autoimmune conditions are associated with an increased risk of adverse pregnancy complications and outcomes, suggesting that pregnancy complications may mediate the excess risk. We performed a causal mediation analysis to quantify the mediated effects of autoimmune conditions on adverse pregnancy outcomes. METHODS: We queried a California birth cohort created from linked birth certificates and hospital discharge summaries. From 2,963,888 births, we identified women with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel disease (IBD). Pregnancy complications included preeclampsia/hypertension, gestational diabetes mellitus, and infection in pregnancy. Adverse pregnancy outcomes were preterm birth, cesarean delivery, and small for gestational age. We performed a mediation analysis to estimate the total effects of each autoimmune condition and adverse pregnancy outcome and the indirect effects through pregnancy complications. RESULTS: All 4 autoimmune conditions were associated with preterm birth and cesarean delivery, and RA, SLE, and IBD were associated with offspring that were small for gestational age. The strongest mediator of RA, SLE, and psoriasis was preeclampsia/hypertension, accounting for 20-33% of the excess risk of preterm births and 10-19% of excess cesarean deliveries. Gestational diabetes mellitus and infections generally mediated <10% of excess adverse pregnancy outcomes. Of the 4 autoimmune conditions, selected pregnancy complications mediated the least number of adverse pregnancy outcomes among women with IBD. CONCLUSION: We found evidence that some excess risk of adverse pregnancy outcomes is mediated through pregnancy complications, particularly preeclampsia/hypertension. Quantifying excess risk and associated pathways provides insight into the underlying etiologies of adverse pregnancy outcomes and can inform intervention strategies.

Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life.

OBJECTIVE: To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies and severities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverse clinical outcomes. STUDY DESIGN: This was a population-based study using an administrative dataset linking birth and death certificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants ≥34 weeks' gestational age with International Classification of Diseases,9th edition, codes consistent with PPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first year of life. Crude and adjusted risk ratio (aRR) with 95% CIs were calculated to quantify the risk for the primary outcome and to identify risk factors. RESULTS: Infants with PPHN (n = 7847) had an aRR of 3.5 (95% CI, 3.3-3.7) for the primary outcome compared with infants without PPHN (n = 3 974 536), and infants with only mild PPHN (n = 2477) had an aRR of 2.2 (95% CI, 2.0-2.5). Infants with congenital diaphragmatic hernia as the etiology for PPHN had an aRR of 8.2 (95% CI, 6.7-10.2) and infants with meconium aspiration syndrome had an aRR of 4.2 (95% CI, 3.7-4.6) compared with infants without PPHN. Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primary outcome. CONCLUSIONS: The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infants with mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable. These data could inform counseling of parents.

Socioeconomic Status, Preeclampsia Risk and Gestational Length in Black and White Women.

BACKGROUND: Higher socioeconomic status (SES) has less impact on cardio-metabolic disease and preterm birth risk among Black women compared to White women, an effect called "diminishing returns." No studies have tested whether this also occurs for pregnancy cardio-metabolic disease, specifically preeclampsia, or whether preeclampsia risk could account for race-by-SES disparities in birth timing. METHODS: A sample of 718,604 Black and White women was drawn from a population-based California cohort of singleton births. Education, public health insurance status, gestational length, and preeclampsia diagnosis were extracted from a State-maintained birth cohort database. Age, prenatal care, diabetes diagnosis, smoking during pregnancy, and pre-pregnancy body mass index were covariates. RESULTS: In logistic regression models predicting preeclampsia risk, the race-by-SES interaction (for both education and insurance status) was significant. White women were at lower risk for preeclampsia, and higher SES further reduced risk. Black women were at higher risk for preeclampsia, and SES did not attenuate risk. In pathway analyses predicting gestational length, an indirect effect of the race-by-SES interaction was observed. Among White women, higher SES predicted lower preeclampsia risk, which in turn predicted longer gestation. The same was not observed for Black women. CONCLUSIONS: Compared to White women, Black women had increased preeclampsia risk. Higher SES attenuated risk for preeclampsia among White women, but not for Black women. Similarly, higher SES indirectly predicted longer gestational length via reduced preeclampsia risk among White women, but not for Black women. These findings are consistent with diminishing returns of higher SES for Black women with respect to preeclampsia.

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

OBJECTIVE: Inflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia. STUDY DESIGN: A sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios. RESULTS: Higher 5-α-pregnan-3ß,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia. CONCLUSIONS: Among women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth.

Associations between unstable housing, obstetric outcomes, and perinatal health care utilization.

BACKGROUND: While there is a growing interest in addressing social determinants of health in clinical settings, there are limited data on the relationship between unstable housing and both obstetric outcomes and health care utilization. OBJECTIVE: The objective of the study was to investigate the relationship between unstable housing, obstetric outcomes, and health care utilization after birth. STUDY DESIGN: This was a retrospective cohort study. Data were drawn from a database of liveborn neonates linked to their mothers' hospital discharge records (2007-2012) maintained by the California Office of Statewide Health Planning and Development. The analytic sample included singleton pregnancies with both maternal and infant data available, restricted to births between the gestational age of 20 and 44 weeks, who presented at a hospital that documented at least 1 woman as having unstable housing using the International Classification of Diseases, ninth edition, codes (n = 2,898,035). Infants with chromosomal abnormalities and major birth defects were excluded. Women with unstable housing (lack of housing or inadequate housing) were identified using International Classification of Diseases, ninth edition, codes from clinical records. Outcomes of interest included preterm birth (<37 weeks' gestational age), early term birth (37-38 weeks gestational age), preterm labor, preeclampsia, chorioamnionitis, small for gestational age, long birth hospitalization length of stay after delivery (vaginal birth, >2 days; cesarean delivery, >4 days), emergency department visit within 3 months and 1 year after delivery, and readmission within 3 months and 1 year after delivery. We used exact propensity score matching without replacement to select a reference population to compare with the sample of women with unstable housing using a one-to-one ratio, matching for maternal age, race/ethnicity, parity, prior preterm birth, body mass index, tobacco use during pregnancy, drug/alcohol abuse during pregnancy, hypertension, diabetes, mental health condition during pregnancy, adequacy of prenatal care, education, and type of hospital. Odds of an adverse obstetric outcome were estimated using logistic regression. RESULTS: Of 2794 women with unstable housing identified, 83.0% (n = 2318) had an exact propensity score-matched control. Women with an unstable housing code had higher odds of preterm birth (odds ratio, 1.2, 95% confidence interval, 1.0-1.4, P < .05), preterm labor (odds ratio, 1.4, 95% confidence interval, 1.2-1.6, P < .001), long length of stay (odds ratio, 1.6, 95% confidence interval, 1.4-1.8, P < .001), emergency department visits within 3 months (odds ratio, 2.4, 95% confidence interval, 2.1-2.8, P < .001) and 1 year after birth (odds ratio, 2.7, 95% confidence interval, 2.4-3.0, P < .001), and readmission within 3 months (odds ratio, 2.7, 95% confidence interval, 2.2-3.4, P < .0014) and 1 year after birth (odds ratio, 2.6, 95% confidence interval, 2.2-3.0, P < .001). CONCLUSION: Unstable housing documentation is associated with adverse obstetric outcomes and high health care utilization. Housing and supplemental income for pregnant women should be explored as a potential intervention to prevent preterm birth and prevent increased health care utilization.

Maternal dyslipidemia and risk for preterm birth.

Maternal lipid profiles during pregnancy are associated with risk for preterm birth. This study investigates the association between maternal dyslipidemia and subsequent preterm birth among pregnant women in the state of California. Births were identified from California birth certificate and hospital discharge records from 2007-2012 (N = 2,865,987). Preterm birth was defined as <37 weeks completed gestation and dyslipidemia was defined by diagnostic codes. Subtypes of preterm birth were classified as preterm premature rupture of membranes (PPROM), spontaneous labor, and medically indicated, according to birth certificate data and diagnostic codes. The association between dyslipidemia and preterm birth was tested with logistic regression. Models were adjusted for maternal age at delivery, race/ethnicity, hypertension, pre-pregnancy body mass index, insurance type, and education. Maternal dyslipidemia was significantly associated with increased odds of preterm birth (adjusted OR: 1.49, 95%CI: 1.39, 1.59). This finding was consistent across all subtypes of preterm birth, including PPROM (adjusted OR: 1.54, 95%CI: 1.34, 1.76), spontaneous (adjusted OR: 1.51, 95%CI: 1.39, 1.65), and medically indicated (adjusted OR: 1.454, 95%CI: 1.282, 1.649). This study suggests that maternal dyslipidemia is associated with increased risk for all types of preterm birth.

Effect of Fetal Growth on 1-Year Mortality in Neonates With Critical Congenital Heart Disease.

Background Infants with critical congenital heart disease ( CCHD ) are more likely to be small for gestational age (GA). It is unclear how this affects mortality. The authors investigated the effect of birth weight Z score on 1-year mortality separately in preterm (GA <37 weeks), early-term (GA 37-38 weeks), and full-term (GA 39-42 weeks) infants with CCHD . Methods and Results Live-born infants with CCHD and GA 22 to 42 weeks born in California 2007-2012 were included in the analysis. The primary predictor was Z score for birth weight and the primary outcome was 1-year mortality. Multivariable logistic regression was used. Results are presented as adjusted odds ratios and 95% confidence intervals ( CIs ). The authors identified 6903 infants with CCHD . For preterm and full-term infants, only a Z score for birth weight <-2 was associated with increased mortality compared with the reference group ( Z score 0-0.5, adjusted odds ratio, 2.15 [95% CI , 1.1-4.21] and adjusted odds ratio, 3.93 [95% CI , 2.32-6.68], respectively). In contrast, in early-term infants, the adjusted odds ratios for Z scores <-2, -2 to -1, and -1 to -0.5 were 3.42 (95% CI , 1.93-6.04), 1.78 (95% CI , 1.12-2.83), and 2.03 (95% CI , 1.27-3.23), respectively, versus the reference group. Conclusions GA seems to modify the effect of birth weight Z score on mortality in infants with CCHD . In preterm and full-term infants, only the most severe small-for-GA infants ( Z score <-2) were at increased risk for mortality, while, in early-term infants, the risk extended to mild to moderate small-for-GA infants ( Z score <-0.5). This information helps to identify high-risk infants and is useful for surgical planning.

Second trimester serum cortisol and preterm birth: an analysis by timing and subtype.

OBJECTIVE: We hypothesized second trimester serum cortisol would be higher in spontaneous preterm births compared to provider-initiated (previously termed 'medically indicated') preterm births. STUDY DESIGN: We used a nested case-control design with a sample of 993 women with live births. Cortisol was measured from serum samples collected as part of routine prenatal screening. We tested whether mean-adjusted cortisol fold-change differed by gestational age at delivery or preterm birth subtype using multivariable linear regression. RESULT: An inverse association between cortisol and gestational age category (trend p = 0.09) was observed. Among deliveries prior to 37 weeks, the mean-adjusted cortisol fold-change values were highest for preterm premature rupture of the membranes (1.10), followed by premature labor (1.03) and provider-initiated preterm birth (1.01), although they did not differ statistically. CONCLUSION: Cortisol continues to be of interest as a marker of future preterm birth. Augmentation with additional biomarkers should be explored.

Sexually dimorphic effect of in vitro fertilization (IVF) on adult mouse fat and liver metabolomes.

The preimplantation embryo is particularly vulnerable to environmental perturbation, such that nutritional and in vitro stresses restricted exclusively to this stage may alter growth and affect long-term metabolic health. This is particularly relevant to the over 5 million children conceived by in vitro fertilization (IVF). We previously reported that even optimized IVF conditions reprogram mouse postnatal growth, fat deposition, and glucose homeostasis in a sexually dimorphic fashion. To more clearly interrogate the metabolic changes associated with IVF in adulthood, we used nontargeted mass spectrometry to globally profile adult IVF- and in vivo-conceived liver and gonadal adipose tissues. There was a sex- and tissue-specific effect of IVF on adult metabolite signatures indicative of metabolic reprogramming and oxidative stress and reflective of the observed phenotypes. Additionally, we observed a striking effect of IVF on adult sexual dimorphism. Male-female differences in metabolite concentration were exaggerated in hepatic IVF tissue and significantly reduced in IVF adipose tissue, with the majority of changes affecting amino acid and lipid metabolites. We also observed female-specific changes in markers of oxidative stress and adipogenesis, including reduced glutathione, cysteine glutathione disulfide, ophthalmate, urate, and corticosterone. In summary, embryo manipulation and early developmental experiences can affect adult patterns of sexual dimorphism and metabolic physiology.

Comparative intrauterine development and placental function of ART concepti: implications for human reproductive medicine and animal breeding.

BACKGROUND: The number of children conceived using assisted reproductive technologies (ART) has reached >5 million worldwide and continues to increase. Although the great majority of ART children are healthy, many reports suggest a forthcoming risk of metabolic complications, which is further supported by the Developmental Origins of Health and Disease hypothesis of suboptimal embryo/fetal conditions predisposing adult cardiometabolic pathologies. Accumulating evidence suggests that fetal and placental growth kinetics are important features predicting post-natal health, but the relationship between ART and intrauterine growth has not been systematically reviewed. METHODS: Relevant studies describing fetoplacental intrauterine phenotypes of concepti generated by in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and somatic cell nuclear transfer (SCNT) in the mouse, bovine and human were comprehensively researched using PubMed and Google Scholar. Intrauterine growth plots were created from tabular formatted data available in selected reports. RESULTS: ART pregnancies display minor but noticeable alterations in fetal and placental growth curves across mammalian species. In all species, there is evidence of fetal growth restriction in the earlier stages of pregnancy, followed by significant increases in placental size and accelerated fetal growth toward the end of gestation. However, there is a species-specific effect of ART on birthweights, that additionally vary in a culture condition-, strain-, and/or stage at transfer-specific manner. We discuss the potential mechanisms that underlie these changes, and how they are affected by specific components of ART procedures. CONCLUSIONS: ART may promote measurable alterations to intrauterine growth trajectory and placental function. Key findings include evidence that birthweight is not a reliable marker of fetal stress, and that increases in embryo manipulation result in more deviant fetal growth curves. Because growth kinetics in early life are particularly relevant to adult metabolic physiology, we advise more rigorous assessment of fetal growth and placental function in human ART pregnancies, as well as continued follow-up of ART offspring throughout post-natal life. Finally, strategies to minimize embryo manipulations should be adopted whenever possible.

Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis.

The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases such as diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response, as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression is associated with enrichment for H4 acetylation at the Txnip promoter that persists from the blastocyst stage through adulthood in adipose tissue. Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.

Extreme HOT regions are CpG-dense promoters in C. elegans and humans.

Most vertebrate promoters lie in unmethylated CpG-dense islands, whereas methylation of the more sparsely distributed CpGs in the remainder of the genome is thought to contribute to transcriptional repression. Nonmethylated CG dinucleotides are recognized by CXXC finger protein 1 (CXXC1, also known as CFP1), which recruits SETD1A (also known as Set1) methyltransferase for trimethylation of histone H3 lysine 4, an active promoter mark. Genomic regions enriched for CpGs are thought to be either absent or irrelevant in invertebrates that lack DNA methylation, such as C. elegans; however, a CXXC1 ortholog (CFP-1) is present. Here we demonstrate that C. elegans CFP-1 targets promoters with high CpG density, and these promoters are marked by high levels of H3K4me3. Furthermore, as for mammalian promoters, high CpG content is associated with nucleosome depletion irrespective of transcriptional activity. We further show that highly occupied target (HOT) regions identified by the binding of a large number of transcription factors are CpG-rich promoters in C. elegans and human genomes, suggesting that the unusually high factor association at HOT regions may be a consequence of CpG-linked chromatin accessibility. Our results indicate that nonmethylated CpG-dense sequence is a conserved genomic signal that promotes an open chromatin state, targeting by a CXXC1 ortholog, and H3K4me3 modification in both C. elegans and human genomes.