Epigenomics: maternal high-fat diet exposure in utero disrupts peripheral circadian gene expression in nonhuman primates.

The effect of in utero exposure to a maternal high-fat diet on the peripheral circadian system of the fetus is unknown. Using mRNA copy number analysis, we report that the components of the peripheral circadian machinery are transcribed in the nonhuman primate fetal liver in an intact phase-antiphase fashion and that Npas2, a paralog of the Clock transcription factor, serves as the rate-limiting transcript by virtue of its relative low abundance (10- to 1000-fold lower). We show that exposure to a maternal high-fat diet in utero significantly alters the expression of fetal hepatic Npas2 (up to 7.1-fold, P<0.001) compared with that in control diet-exposed animals and is reversible in fetal offspring from obese dams reversed to a control diet (1.3-fold, P>0.05). Although the Npas2 promoter remains largely unmethylated, differential Npas2 promoter occupancy of acetylation of fetal histone H3 at lysine 14 (H3K14ac) occurs in response to maternal high-fat diet exposure compared with control diet-exposed animals. Furthermore, we find that disruption of Npas2 is consistent with high-fat diet exposure in juvenile animals, regardless of in utero diet exposure. In summary, the data suggest that peripheral Npas2 expression is uniquely vulnerable to diet exposure.

Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality.

Extracellular signal-regulated kinase 3 (Erk3) is an atypical member of the mitogen-activated protein (MAP) kinase family. No function has yet been ascribed to this MAP kinase. Here we show that targeted disruption of the Mapk6 gene (encoding Erk3) leads to intrauterine growth restriction, associated with marked pulmonary hypoplasia, and early neonatal death during the first day of life. Around 40% of Erk3(-/-) neonates die within minutes after birth from acute respiratory failure. Erk3-deficient mice have normal lung-branching morphogenesis, but show delayed lung maturation characterized by decreased sacculation, atelectasis, and defective type II pneumocyte differentiation. Interestingly, in utero administration of glucocorticoid promoted fetal lung maturity and rescued differentiation of type II cells, but failed to alter the neonatal lethality. We observed that loss of Erk3 retards intrauterine growth, as reflected by a marked reduction in fetal lung, heart, and liver weights, and by low body weight at birth. Importantly, we found that insulin-like growth factor (IGF)-2 levels are decreased in the serum of Erk3-deficient mice. Our findings reveal a critical role for Erk3 in the establishment of fetal growth potential and pulmonary function in the mouse.

Maternal tobacco use is associated with increased markers of oxidative stress in the placenta.

OBJECTIVE: We sought to extend our prior observations and histopathologically characterize key metabolic enzymes (CYP1A1) with markers of oxidative damage in the placental sections from smokers. STUDY DESIGN: Placental specimens were collected from term singleton deliveries from smokers (n = 10) and nonsmokers (n = 10) and subjected to a detailed histopathological examination. To quantify the extent of oxidative damage, masked score-graded (0-6) histopathology against 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxydeoxyguanisine (8-OHdG) was performed. Minimal significance (P < .05) was determined with a Fisher's exact and a 2-tailed Student t test as appropriate. RESULTS: We observed a significant increase in the presence of syncytial knots in placentas from smokers (70% vs 10%, P = .02). These gross observations were accompanied by a significant aberrant placental aromatic hydrocarbon metabolism (increased CYP1A1, 4.4 vs 2.1, P = .002) in addition to evidence of oxidative damage (4-HNE 3.4 vs 1.1, P = .00005; 8-OHdG 4.9 vs 3.1, P = .0038). CONCLUSION: We observed a strong association between maternal tobacco use and aberrant placental metabolism, syncytial knot formation, and multiple markers of oxidative damage.

Genome-wide array-based copy number profiling in human placentas from unexplained stillbirths.

OBJECTIVE: Accumulating evidence suggests that genomic structural variations, particularly copy number variations (CNV), are a common occurrence in humans that may bear phenotypic consequences for living individuals possessing the variant. While precise estimates vary, large-scale karyotypic abnormalities are present in 6-12% of stillbirths (SB). However, due to inherent limitations of conventional cytogenetics, the contribution of genomic aberrations to stillbirth is likely underrepresented. High-resolution copy number variant analysis by genomic array-based profiling may overcome such limitations. METHODS: Prospectively acquired SB cases > 22 weeks underwent classification of 'unexplained' stillbirth by Wigglesworth and Aberdeen criteria after extensive testing and rigorous multidisciplinary audit. Genome-wide analysis was conducted using high-resolution Illumina single nucleotide polymorphism (SNP) arrays (Human CNV370-Duo) on placental and fetal samples. Potential alternate detection methods were completed by one or more of three independent means (quantitative PCR, Illumina1M, or Agilent105K comparative genomic hybridization arrays). RESULTS: In our cohort of 54 stillbirths, 29 met strict unexplained criteria. Among these, we identified 24 putative novel CNVs. Subsequent interrogation detected 18 of 24 CNVs (75%) in placental samples, 8 of which were also confirmed in available fetal samples; none were present in maternal blood. CONCLUSION: We describe the potential of whole-genome placental profiling to identify small genomic imbalances, which might contribute to a small proportion of well-characterized, unexplained stillbirths.

Obstructive sleep apnea screening in pregnancy, perinatal outcomes, and impact of maternal obesity.

We employed accepted, validated symptom-based screening measures to discern attributable risk of obstructive sleep apnea (OSA) to adverse pregnancy outcomes, taking into account potential maternal confounders. Commonly employed OSA screening measures (Berlin and Epworth scales) were performed in the second and third trimesters; maternal and neonatal outcome data were thereafter obtained. The relationship between OSA and outcomes of interest were explored in stratified and multivariate models controlling for potential confounders. The overall prevalence of OSA was 25.4%. Given a nonlinear increase by body mass index (BMI) strata (8.9%, 46%; p < 0.0001), stratified multivariate analysis was subsequently performed. Among nonobese (BMI <30) gravidae, frequency of preeclampsia was significantly higher among women with OSA (adjusted odds ratio = 6.58, 95% confidence interval = 1.04, 38.51; p = 0.035). Among the obese (BMI ≥30) gravidae, infant birth weight ratio (or birth weight by gestational age) was higher with OSA + screening than OSA - (1.099 versus 1.035; p = 0.04), and this association remained significant after adjustment for potential confounders (p = 0.05). OSA prevalence increases significantly among obese gravidae, raising concerns for the overall validity of commonly employed screening measures in pregnancy. Nevertheless, OSA status continues to exert an independent influence, as obese and nonobese gravidae are at increased risk for a limited number of adverse perinatal outcomes in multivariate models.

Prospective trial on obstructive sleep apnea in pregnancy and fetal heart rate monitoring.

OBJECTIVE: Obstructive sleep apnea (OSA) involves episodic nocturnal apneas. Using polysomnography, we examined the predictive capacity of screening questionnaires (Berlin) in pregnancy. Incorporating simultaneous fetal heart rate monitoring (FHM), we examined the association of maternal apnea with FHM abnormalities. STUDY DESIGN: We enrolled 100 pregnant women at 26-39 weeks of gestation with OSA screening and baseline data ascertainment who underwent polysomnography and FHM for > or =3 hours. The relationship between maternal characteristics, OSA, and FHM was explored with multivariate analyses that were controlled for potential confounders. RESULTS: When compared with polysomnography, sensitivity and specificity by Berlin screening was 35% and 63.8%, respectively; the snoring component of the Berlin correlated better with oxygen desaturation <95% (P = .003). Body mass index was a significant confounder (r(s) = 0.44; P < .0001). No association was observed between FHM abnormalities and OSA parameters. CONCLUSION: In pregnancy, the Berlin questionnaire poorly predicts OSA. It is unclear whether fetal compromise during maternal apnea is a mechanism in OSA that is related to pregnancy outcome.

Influence of maternal BMI on genetic sonography in the FaSTER trial.

OBJECTIVE: We sought to evaluate the influence of maternal body mass index (BMI) on sonographic detection employing data from the FaSTER trial. METHOD: Unselected singleton pregnancies underwent detailed genetic sonogram to evaluate for structural fetal anomalies and soft markers for aneuploidy. BMI (kg/m(2)) were calculated from reported initial visit values. Sensitivity, specificity, false positive and false negative rates (FPR and FNR), likelihood ratio, detection rates, and a missed diagnosis rate (MDR: FNR + marker recorded as 'missing'/N) were calculated. RESULTS: Eight thousand five hundred and fifty-five patients with complete BMI information had detailed genetic sonography. A lower sensitivity with an elevated FNR and MDR was observed in obese women for multiple aneuploid markers (e.g. > or =2 markers 32% sensitivity with 68% FNR among BMI <25 vs 22% and 78% among BMI >30). Similarly, the detection rate for cardiac anomalies among women at BMI <25 was higher (21.6%) at a significantly lower FPR (78.4%; 95% CI 77.3-79.5%) in comparison to obese women (8.3% with FPR 91.7%; 95% CI 90.1-93.2%). In a logistic regression model, maternal obesity significantly decreased the likelihood of sonographic detection of common anomalies (adjusted OR 0.7; 95% CI 0.6-0.9; p = 0.001). CONCLUSION: The performance of second trimester genetic sonography is influenced by obesity, with a significantly higher MDR for multiple minor markers and lower likelihood for detecting common anomalies.

Pheochromocytoma and Von Hippel-Lindau in pregnancy.

Pheochromocytoma is an infrequent but well-acknowledged primary cause of malignant hypertension in pregnancy. Although the majority of pheochromocytomas are sporadic, those that present as bilateral or multifocal tumors may be a manifestation of a rare cancer susceptibility syndrome, such as Von Hippel-Lindau (VHL). Gravidae with unrecognized pheochromocytoma are at risk for recurrent paroxysmal hypertensive crises with ensuant maternal and fetal risks. To further illustrate the challenges of management of pheochromocytoma and VHL in pregnancy, we present two illustrative cases. In the first, a multigravida presented with an intrauterine fetal demise and malignant hypertension and a concurrent diagnosis of bilateral pheochromocytomas. A missense mutation in exon 3 of the VHL gene was identified, confirming the diagnosis of VHL type 2C. In the second case, a multigravida with a prior diagnosis of VHL syndrome but sporadic follow-up underwent renal and adrenal imaging surveillance as part of her prenatal care. Although she was normotensive and clinically asymptomatic, such imaging enabled the detection of bilateral pheochromocytomas. In summary, in this report we discuss our management in gravidae with pheochromocytoma and VHL, emphasizing current recommendations pertaining to obstetric management, genetic testing, and long-term follow-up.

Management of ornithine transcarbamylase deficiency in pregnancy.

Ornithine transcarbamylase (OTC) deficiency is the most common enzymatic deficiency in the urea cycle. In catabolic states, such as the intrapartum and immediate postpartum periods, hyperammonemic comas with permanent neurological damage and death can develop. We report six cases of OTC deficiency during pregnancy managed at our institution and review the literature on OTC deficiency during pregnancy. Using the patient database from our Metabolic Clinic, pregnant OTC deficiency carriers were identified. The antenatal, intrapartum, and postpartum periods were analyzed. Corresponding literature was reviewed and an extensive multidisciplinary management plan developed. All six pregnant women had favorable outcomes. No hyperammonemic episodes occurred, and intensive care unit admissions and hemodialysis were not required. Although risk to women with OTC deficiency during the intra- and postpartum period exists, multidisciplinary management and a coherent plan usually result in successful labor, delivery, and postpartum. A comprehensive plan for patients who develop hyperammonemia is recommended.

Genetic and epigenetic influences associated with intrauterine growth restriction due to in utero tobacco exposure.

While many fetuses are exposed to tobacco in utero, not all experience adverse outcomes as a result of this exposure. Mechanisms leading to the attenuation of fetal birth weight and adverse pregnancy outcomes are complex. Therefore many studies have begun to focus, not only on the contribution of maternal and fetal genes to phenotypic outcome, but also on epigenetic changes associated with exposure to maternal tobacco smoke. In this review, we detail the epidemiologic evidence associating an adverse pregnancy outcome to maternal tobacco use. We provide a brief summary of studies demonstrating an association between maternal and fetal gene polymorphisms with low birth weight in response to maternal tobacco exposure. We also review the literature showing epigenetic changes in the offspring associated with in utero tobacco exposure. The complex interplay of genomic and epigenomic factors may contribute to specific phenotypic outcomes and can help begin to elucidate the differential susceptibilities to tobacco smoke in utero.

A maternal high-fat diet is accompanied by alterations in the fetal primate metabolome.

OBJECTIVE: To characterize the serum metabolome of a primate model of in utero high-fat exposure. STUDY DESIGN: Serum from maternal and fetal (e130) macaque monkeys exposed to either a high-fat or control diet were analyzed by gas chromatography-mass spectrometry. Multivariate data analysis was performed to reduce the generated data set. Candidate metabolites were further analyzed for significance by using the analysis of variance and comparative t tests. RESULTS: Approximately 1300 chromatographic features were detected. Through multivariate data analysis this number was reduced to 60 possible metabolites. With the use of comparative t tests, 22 metabolites had statistical significance (P < .05) over the entire study. By virtue of maternal high-fat diet alone, fetal phenotypic differences are accompanied by altered metabolite concentrations of 7 metabolites (P < .05). CONCLUSION: In utero high-fat diet exposure is associated with an altered fetal epigenome and parlays a characteristic modification in the fetal metabolite profile.

Hyperemesis in pregnancy: an evaluation of treatment strategies with maternal and neonatal outcomes.

OBJECTIVE: The objective of the study was to evaluate the use of interventions such as a peripherally inserted central catheters (PICC) line or nasogastric (NG)/nasoduodenal (ND) tube with the use of medications alone in the management of pregnancies with hyperemesis. STUDY DESIGN: Subjects were identified with confirmed intrauterine pregnancy, admitted with hyperemesis gravidarum (HEG) between 1998 and 2004. Medical records were then abstracted for information with regard to therapy. Subjects were assigned on the basis of the management plan: medication alone, PICC line, or NG/ND tube. Outcomes were compared between groups. RESULTS: Ninety-four patients met study criteria and had complete outcome data available. Of those, 33 had a PICC line placed (35.1%), 19 had a NG/ND placed (20.2%), and 42 were managed with medication alone (44.7%). These groups were similar with respect to gestational age at delivery, Apgar score, and mean birthweight. Maternal complications were significantly higher among those with PICC lines. Of patients managed with PICC lines, 66.4% (P < .001) required treatment for infection, thromboembolism, or both. Adjusted odds ratio for a PICC line complication was 34.5 (5.09, 233.73). CONCLUSION: Maternal complications associated with PICC line placement are substantial despite no difference in neonatal outcomes, suggesting that the use of PICC lines for treatment of HEG patients should not be routinely used.

In utero tobacco exposure is associated with modified effects of maternal factors on fetal growth.

OBJECTIVE: The objective of the study was to evaluate whether maternal tobacco use is associated with an attenuation in fetal birthweight among women with nutritional and uteroplacental constraints. STUDY DESIGN: A population-based retrospective analysis of term (37 weeks or longer) singleton pregnancies delivered in Utah from 1991 to 2001. Birthweight (BW) and percent small for gestational age (SGA) (less than 10% for gestational age) among self-identified smokers and nonsmokers were compared. Adjusted odds ratios (ORs) were calculated to measure the association of maternal smoking with delivery of an SGA infant controlling for potential confounders across maternal strata. RESULTS: Among the 424,912 gestations, 37,076 occurred in self-identified smokers. Mean BW was significantly less and the prevalence of SGA infants was significantly greater in tobacco-exposed infants across all maternal BMI strata (P < .001) as well as pregnancies complicated by diabetes (P < .001) and hypertensive disorders (P < .001). In a multivariable logistic regression model, tobacco exposure remained the significant associative factor for SGA (OR 3.53, 95% confidence interval 2.61 to 4.79) after selecting for the first birth in the study interval (n = 283,916). CONCLUSION: Self-identified tobacco use increases the risk of a SGA infant at term across maternal strata.

Sample bias among women with retained DNA samples for future genetic studies.

OBJECTIVE: To evaluate whether women who agree to future use of their biologic specimens for genetic studies reflect the larger study population from which they are derived. METHODS: Women were questioned as to the future disposition of their maternal and fetal DNA samples upon enrollment in a multicenter, observational study originally designed to identify factor V Leiden mutation carriers and prospectively ascertain the estimated rate of pregnancy-related venous thromboembolism and adverse pregnancy outcome. Univariate and multivariate analyses was carried out on the 5,003 of 5,188 enrolled women who indicated their desire regarding future disposition of their DNA samples. RESULTS: Among these 5,003 women, 20.1% desired that their samples be discarded and not available for future genetic studies. Multivariate analysis demonstrated that women who agreed to subsequent use of samples were less likely African-American (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.4-0.7) or Hispanic (OR 0.4, 95% CI 0.3-0.5), and more likely to use tobacco (OR 1.2, 95% CI 1.0-1.6) than those who desired that their samples be discarded. CONCLUSION: Genetic samples from women agreeing to their use in a sample repository may not be representative of the index study cohort. This should be considered in their subsequent interpretation and generalizability. LEVEL OF EVIDENCE: III.

Factors associated with nonanomalous stillbirths: the Utah Stillbirth Database 1992-2002.

OBJECTIVE: This study was undertaken to characterize risk factors associated with nonanomalous stillborn (SB) infants and to ascribe the probability of fetal survival by gestational age among high-risk pregnancies. STUDY DESIGN: We compiled a database of all SB infants and an equivalent number of controls using information obtained from Utah Birth and Fetal Death Certificates during the years 1992 through 2002. Adjusted and unadjusted odds ratios for risk factors associated with SB were generated. Cox proportional hazard models were used to generate survival curves comparing pregnancies complicated by chronic hypertension or gestational hypertension with those of controls. RESULTS: Infants with major anomalies were eliminated from both cases and controls, to generate 1566 nonanomalous SBs and 2720 nonanomalous controls. In a logistic regression model controlling for multiple maternal and fetal factors, placental abruption, hydramnios, cord prolapse, and essential hypertension were associated with an increased risk of SB. In pregnancies complicated by essential hypertension, the survival curve diverged from that of controls at those gestational ages approaching term (hazard ratio 2.24; 95% CI 1.52-3.32). CONCLUSION: SB in nonanomalous infants in Utah is more common among pregnancies complicated by placental abruption, hydramnios, cord prolapse, and essential hypertension.

Preeclampsia and subsequent risk of cancer in Utah.

OBJECTIVE: The purpose of this study was to determine if preeclampsia is associated with a reduced risk of cancer later in life. STUDY DESIGN: We performed a cohort study where women with preeclampsia over the interval 1947 to 1999 were identified from the Utah Population Database. Preeclamptics (n = 17,432) were matched 1:3 with nonpreeclamptics (n = 52,296) on maternal age and birth year. Pregnancy, demographic, and cancer information was extracted from subjects and their offspring in linked datasets. Relative risk and hazard ratios were calculated. RESULTS: In a matched analysis using univariable random-effects Poisson regression, preeclampsia was protective against the development of cancer later in life (RR 0.91, 95% CI 0.84-0.99 with P = .027). In a multivariable clustered Cox regression model with the end point of cancer later in life, preeclampsia was associated with a lower risk of cancer (HR 0.92, 95% CI 0.85-0.99 with P = .039). These findings were supported by stratified and competing risk analyses. CONCLUSION: Women whose pregnancies were affected by preeclampsia have a decreased risk of developing cancer.

Immunology of normal pregnancy.

Since Medawar's initial contemplations in 1953 on the mechanisms of immune evasion allowing for the survival of the allogeneic conceptus in an immunologically competent mother, physicians and immunologists alike have struggled to understand the immunological paradox of pregnancy. Ultimately, our attempts to define the immunology of normal pregnancy have broadened our appreciation of the myriad mechanisms at play that enable the promotion of implantation and maintenance of pregnancy. In this review, we summarise what is known regarding the immunology of normal pregnancy, with special emphasis on the relation to common disorders of pregnancy.

Preterm premature rupture of membranes in human immunodeficiency virus-infected women: a novel case series.

OBJECTIVE: To evaluate the management and outcomes of a series of human immunodeficiency virus-(HIV-) infected women whose pregnancies were complicated by preterm premature rupture of membranes (PPROM). STUDY DESIGN: We conducted a retrospective chart review of all women with confirmed HIV infection who had a pregnancy complicated by PPROM remote from term. PPROM remote from term was defined as rupture of membranes prior to 32-week gestation. Collective cases from two centers (Hennepin County Medical Center and The University of Alabama at Birmingham) were reviewed and data on management and outcomes were abstracted. RESULTS: Of the HIV-positive women, we identified 291 pregnancies having occurred in the study interval from two institutions. Of these pregnancies, 7 (2.4%) developed PPROM remote from term with subsequent delivery from 25- to 32-week gestation. Vertical HIV transmission was noted in 2 of 6 children whose long-term followup status was confirmed (33%) of these cases. However, both of these cases occurred in women with either no antepartum/intrapartum antiviral therapy or where only zidovudine monotherapy was used. Importantly, in spite of expectant management, no cases of vertical HIV transmission occurred in women who were receiving either multidrug or highly active antiviral therapy (HAART) at the time of PPROM and who had a cesarean delivery in cases where the predelivery viral load > 1000 copies/mL. CONCLUSION: Our limited observations raise the question as to whether in the current era of multidrug therapy immediate delivery should be undertaken in HIV+ pregnancies complicated by PPROM at an early gestational age. This case series further suggests that in those pregnancies that lend themselves to expectant management, such a strategy may be considered appropriate.

Rate of wound complications with enoxaparin use among women at high risk for postpartum thrombosis.

OBJECTIVE: To estimate the rate of wound complications associated with protocol-driven postcesarean enoxaparin thromboprophylaxis. METHODS: After implementing an Institutional Clinical Practice Guideline for postoperative cesarean delivery thromboprophylaxis among at-risk gravid women (older than 35 years of age, body mass index greater than 30 kg/m2, or both), data on all cesarean deliveries over the first 23 months of guideline implementation were extracted and analyzed. Primary (wound hematoma, separation, or dehiscence) and secondary (venous thromboembolism) outcomes were compared in stratified and multivariable models controlling for potential confounders. RESULTS: Over 23 months, 2,509 cesarean deliveries were performed. A total of 1,677 (68%) gravid women met criteria for thromboprophylaxis; 653 received enoxaparin per protocol ("cases"), and, at the discretion of the ordering physician, 1,024 did not (at-risk, protocol-noncompliant "controls"). Cases differed significantly by virtue of maternal age, body mass index, and diabetic status. Univariable analysis subsequently revealed a higher rate of wound separation (6.8% compared with 3.6%, P=.003), rehospitalization (2.1% compared with 0.8%, P=.017) and composite score (8.9% compared with 4.8%, P=.002) among protocol-compliant cases, but no increased risk of wound hematoma (P>.06). In multivariable analysis, adjusted odds ratios continued to reveal an association between enoxaparin use and wound separation (OR 1.66, P=.04) as well as higher composite score (OR 1.69, P=.01). However, among the protocol-noncompliant controls, a nonsignificant increase in the rate of venous thromboembolism occurred. CONCLUSION: In our series, prophylactic enoxaparin use among at-risk gravid women undergoing cesarean delivery was accompanied by an increased risk of wound separation. LEVEL OF EVIDENCE: II.

Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression.

Several studies linking alterations in differential placental methylation with pregnancy disorders have implicated (de)regulation of the placental epigenome with fetal programming and later-in-life disease. We have previously demonstrated that maternal tobacco use is associated with alterations in promoter methylation of placental CYP1A1 and that these changes are correlated with CYP1A1 gene expression and fetal growth restriction. In this study we sought to expand our analysis of promoter methylation by correlating it to gene expression on a genome-wide scale. Employing side-by-side IlluminaHG-12 gene transcription with Infinium27K methylation arrays, we interrogated correlative changes in placental gene expression and DNA methylation associated with maternal tobacco smoke exposure at an epigenome-wide level and in consideration of signature gene pathways. We observed that the expression of 623 genes and the methylation of 1024 CpG dinucleotides are significantly altered among smokers, with only 38 CpGs showing significant differential methylation (differing by a methylation level of ≥10%). We identified a significant Pearson correlation (≥0.7 or ≤-0.7) between placental transcriptional regulation and differential CpG methylation in only 25 genes among non-smokers but in 438 genes among smokers (18-fold increase, p < 0.0001), with a dominant effect among oxidative stress pathways. Differential methylation at as few as 6 sites was attributed to maternal smoking-mediated birth weight reduction in linear regression models with Bonferroni correction (p < 1.8 × 10(-6)). These studies suggest that a common perinatal exposure (such as maternal smoking) deregulates placental methylation in a CpG site-specific manner that correlates with meaningful alterations in gene expression along signature pathways.