From Pre-Clinical Studies to Clinical Trials: Generation of Novel Therapies for Pregnancy Complications

Complications of pregnancy represent a significant disease burden, with both immediate and lasting consequences for mother and baby. Two key pregnancy complications, fetal growth restriction (FGR) and preeclampsia (PE), together affect around 10%–15% of all pregnancies worldwide. Despite this high incidence, there are currently no therapies available to treat these pregnancy disorders. Early delivery remains the only intervention to reduce the risk of severe maternal complications and/or stillbirth of the baby; however early delivery itself is associated with increased risk of neonatal mortality and morbidity. As such, there is a pressing need to develop new and effective treatments that can prevent or treat FGR and PE. Animal models have been essential in identifying and screening potential new therapies in this field. In this review, we address recent progress that has been made in developing therapeutic strategies for pregnancy disorders, some of which are now entering clinical trials.     

The Role of Arachidonic and Linoleic Acid Derivatives in Pathological Pregnancies and the Human Reproduction Process

The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women’s ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies.     

Increased Placental Cell Senescence and Oxidative Stress in Women with Pre-Eclampsia and Normotensive Post-Term Pregnancies

Up to 11% of pregnancies extend to post-term with adverse obstetric events linked to pregnancies over 42 weeks. Oxidative stress and senescence (cells stop growing and dividing by irreversibly arresting their cell cycle and gradually ageing) can result in diminished cell function. There are no detailed studies of placental cell senescence markers across a range of gestational ages, although increased levels have been linked to pre-eclampsia before full term. This study aimed to determine placental senescence and oxidative markers across a range of gestational ages in women with uncomplicated pregnancies and those with a diagnosis of pre-eclampsia. Placentae were obtained from 37 women with uncomplicated pregnancies of 37–42 weeks and from 13 cases of pre-eclampsia of 31⁺²–41⁺² weeks. The expression of markers of senescence, oxidative stress, and antioxidant defence (tumour suppressor protein p16^INK4a, kinase inhibitor p21, interleukin-6 (IL-6), NADPH oxidase 4 (NOX4), glutathione peroxidases 1, 3, and 4 (GPx1, GPx3, and GPx4), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)) genes was measured (quantitative real-time PCR). Protein abundance of p16^INK4a, IL-6, NOX4, 8-hydroxy-2′-deoxy-guanosine (8-OHdG), and PlGF was assessed by immunocytochemistry. Placental NOX4 protein was higher in post-term than term deliveries and further increased by pre-eclampsia (p < 0.05 for all). P21 expression was higher in post-term placentae (p = 0.012) and in pre-eclampsia (p = 0.04), compared to term. Placental P16^INK4a protein expression was increased post-term, compared to term (p = 0.01). In normotensive women, gestational age at delivery was negatively associated with GPx4 and PlGF (mRNA and protein) (p < 0.05 for all), whereas a positive correlation was seen with placental P21, NOX4, and P16^INK4a (p < 0.05 for all) expression. Markers of placental oxidative stress and senescence appear to increase as gestational age increases, with antioxidant defences diminishing concomitantly. These observations increase our understanding of placental health and may contribute to assessment of the optimal gestational age for delivery.     

Irisin Protects the Human Placenta from Oxidative Stress and Apoptosis via Activation of the Akt Signaling Pathway

Irisin is a newly discovered exercise-mediated polypeptide hormone. Irisin levels increase during pregnancy however, women with preeclampsia (PE) have significantly lower levels of Irisin compared to women of healthy pregnancies. Even though many studies suggest a role of Irisin in pregnancy, its function in the human placenta is unclear. In the current study, we aimed to understand key roles of Irisin through its ability to protect against apoptosis is the preeclamptic placenta and in ex vivo and in vitro models of hypoxia/re-oxygenation (H/R) injury. Our studies show that Irisin prevents cell death by reducing pro-apoptotic signaling cascades, reducing cleavage of PARP to induce DNA repair pathways and reducing activity of Caspase 3. Irisin caused an increase in the levels of anti-apoptotic BCL2 to pro-apoptotic BAX and reduced ROS levels in an in vitro model of placental ischemia. Furthermore, we show that Irisin treatment acts through the Akt signaling pathway to prevent apoptosis and enhance cell survival. Our findings provide a novel understanding for the anti-apoptotic and pro-survival properties of Irisin in the human placenta under pathological conditions. This work yields new insights into placental development and disease and points towards intervention strategies for placental insufficiencies, such as PE, by protecting and maintaining placental function through inhibiting hypoxic ischemia-induced apoptosis.     

Type 1 Diabetes Mellitus and the First Trimester Placenta: Hyperglycemia-Induced Effects on Trophoblast Proliferation,Cell Cycle Regulators,and Invasion

Type 1 diabetes mellitus (T1DM) is associated with reduced fetal growth in early pregnancy, but a contributing role of the placenta has remained elusive. Thus, we investigated whether T1DM alters placental development in the first trimester. Using a protein array, the level of 60 cell-cycle-related proteins was determined in human first trimester placental tissue (gestational week 5–11) from control (n = 11) and T1DM pregnancies (n = 12). Primary trophoblasts (gestational week 7–12, n = 32) were incubated in the absence (control) or presence of hyperglycemia (25 mM D-glucose) and hyperosmolarity (5.5 mM D-glucose + 19.5 mM D-mannitol). We quantified the number of viable and dead trophoblasts (CASY Counter) and assessed cell cycle distribution (FACS) and trophoblast invasion using a transwell assay. T1DM was associated with a significant (p < 0.05) downregulation of Ki67 (−26%), chk1 (−25%), and p73 (−26%). The number of viable trophoblasts was reduced under hyperglycemia (−23%) and hyperosmolarity (−18%), whereas trophoblast invasion was increased only under hyperglycemia (+6%). Trophoblast cell death and cell cycle distribution remained unaffected. Collectively, our data demonstrate that hyperglycemia decreases trophoblast proliferation as a potential contributing factor to the reduced placental growth in T1DM in vivo.     

MicroRNA–mRNA Networks in Pregnancy Complications: A Comprehensive Downstream Analysis of Potential Biomarkers

Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans. The majority of pregnancy complications initiate due to abnormal placental development and function. During the last decade, the role of microRNAs (miRNAs) in regulating placental and fetal development has become evident. Dysregulation of miRNAs in the placenta not only affects placental development and function, but these miRNAs can also be exported to both maternal and fetal compartments and affect maternal physiology and fetal growth and development. Due to their differential expression in the placenta and maternal circulation during pregnancy complications, miRNAs can be used as diagnostic biomarkers. However, the differential expression of a miRNA in the placenta may not always be reflected in maternal circulation, which makes it difficult to find a reliable biomarker for placental dysfunction. In this review, we provide an overview of differentially expressed miRNAs in the placenta and/or maternal circulation during preeclampsia (PE) and intrauterine growth restriction (IUGR), which can potentially serve as biomarkers for prediction or diagnosis of pregnancy complications. Using different bioinformatics tools, we also identified potential target genes of miRNAs associated with PE and IUGR, and the role of miRNA-mRNA networks in the regulation of important signaling pathways and biological processes.     

Symptoms of Prenatal Depression Associated with Shorter Telomeres in Female Placenta

Background. Depression is a common mood disorder during pregnancy impacting one in every seven women. Children exposed to prenatal depression are more likely to be born at a low birth weight and develop chronic diseases later in life. A proposed hypothesis for this relationship between early exposure to adversity and poor outcomes is accelerated aging. Telomere length has been used as a biomarker of cellular aging. We used high-resolution telomere length analysis to examine the relationship between placental telomere length distributions and maternal mood symptoms in pregnancy. Methods. This study utilised samples from the longitudinal Grown in Wales (GiW) study. Women participating in this study were recruited at their presurgical appointment prior to a term elective caesarean section (ELCS). Women completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Telomere length distributions were generated using single telomere length analysis (STELA) in 109 term placenta (37–42 weeks). Multiple linear regression was performed to examine the relationship between maternally reported symptoms of depression and anxiety at term and mean placental telomere length. Results: Prenatal depression symptoms were significantly negatively associated with XpYp telomere length in female placenta (B = −0.098, p = 0.026, 95% CI −0.184, −0.012). There was no association between maternal depression symptoms and telomere length in male placenta (B = 0.022, p = 0.586, 95% CI −0.059, 0.103). There was no association with anxiety symptoms and telomere length for either sex. Conclusion: Maternal prenatal depression is associated with sex-specific differences in term placental telomeres. Telomere shortening in female placenta may indicate accelerated placental aging.     

Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum.     

Biological Functions of Thyroid Hormone in Placenta

The thyroid hormone, 3,3,5-triiodo-l-thyronine (T₃), modulates several physiological processes, including cellular growth, differentiation, metabolism, inflammation and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Infection and inflammation are critical processes in placental development and pregnancy-related diseases. In particular, infection is the leading cause of neonatal mortality and morbidity worldwide. However, to date, no successful approach has been developed for the effective diagnosis of infection in preterm infants. Pre-eclampsia (PE) is a serious disorder that adversely affects ~5% of human pregnancies. Recent studies identified a multiprotein complex, the inflammasome, including the Nod-like receptor (NLR) family of cytosolic pattern recognition receptors, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, which plays a vital role in the placenta. The thyroid hormone modulates inflammation processes and is additionally implicated in placental development and disease. Therefore, elucidation of thyroid hormone receptor-regulated inflammation-related molecules, and their underlying mechanisms in placenta, should facilitate the identification of novel predictive and therapeutic targets for placental disorders. This review provides a detailed summary of current knowledge with respect to identification of useful biomarkers and their physiological significance in placenta.     

Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis

Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%–2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk–based computational method named TM-rank to prioritize ectopic pregnancy–related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes.     

Insight into the Key Points of Preeclampsia Pathophysiology: Uterine Artery Remodeling and the Role of MicroRNAs

Preeclampsia affects about 3–8% of all pregnancies. It represents a complex and multifaceted syndrome with at least several potential pathways leading to the development of disease. The main dogma in preeclampsia is the two-stage model of disease. Stage 1 (placental stage) takes place in early pregnancy and is thought to be impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries that leads to reduced placental perfusion and release of numerous biological factors causing endothelial damage and development of acute maternal syndrome with systemic multiorgan failure (stage 2—the onset of maternal clinical symptoms, maternal stage). Recently, in the light of the vast body of evidence, two-stage model of preeclampsia has been updated with a few novel pathways leading to clinical manifestation in the second part of pregnancy. This paper reviews current state of knowledge about pathophysiology of preeclampsia and places particular focus on the recent advances in understanding of uterine artery remodeling alterations, as well as the role of microRNAs in preeclampsia.     

Megalin,Proton Pump Inhibitors and the Renin–Angiotensin System in Healthy and Pre-Eclamptic Placentas

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin–angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis.     

Role of the Macrophage Migration Inhibitory Factor in the Pathophysiology of Pre-Eclampsia

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE.     

Direct Analysis of hCGβcf Glycosylation in Normal and Aberrant Pregnancy by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry

The analysis of human chorionic gonadotropin (hCG) in clinical chemistry laboratories by specific immunoassay is well established. However, changes in glycosylation are not as easily assayed and yet alterations in hCG glycosylation is associated with abnormal pregnancy. hCGβ-core fragment (hCGβcf) was isolated from the urine of women, pregnant with normal, molar and hyperemesis gravidarum pregnancies. Each sample was subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis following dithiothreitol (DTT) reduction and fingerprint spectra of peptide hCGβ 6–40 were analyzed. Samples were variably glycosylated, where most structures were small, core and largely mono-antennary. Larger single bi-antennary and mixtures of larger mono-antennary and bi-antennary moieties were also observed in some samples. Larger glycoforms were more abundant in the abnormal pregnancies and tri-antennary carbohydrate moieties were only observed in the samples from molar and hyperemesis gravidarum pregnancies. Given that such spectral profiling differences may be characteristic, development of small sample preparation for mass spectral analysis of hCG may lead to a simpler and faster approach to glycostructural analysis and potentially a novel clinical diagnostic test.     

Mass Spectrometry-Based Proteomics for Pre-Eclampsia and Preterm Birth

Pregnancy-related complications such as pre-eclampsia and preterm birth now represent a notable burden of adverse health. Pre-eclampsia is a hypertensive disorder unique to pregnancy. It is an important cause of maternal death worldwide and a leading cause of fetal growth restriction and iatrogenic prematurity. Fifteen million infants are born preterm each year globally, but more than one million of those do not survive their first month of life. Currently there are no predictive tests available for diagnosis of these pregnancy-related complications and the biological mechanisms of the diseases have not been fully elucidated. Mass spectrometry-based proteomics have all the necessary attributes to provide the needed breakthrough in understanding the pathophysiology of complex human diseases thorough the discovery of biomarkers. The mass spectrometry methodologies employed in the studies for pregnancy-related complications are evaluated in this article. Top-down proteomic and peptidomic profiling by laser mass spectrometry, liquid chromatography or capillary electrophoresis coupled to mass spectrometry, and bottom-up quantitative proteomics and targeted proteomics by liquid chromatography mass spectrometry have been applied to elucidate protein biomarkers and biological mechanism of pregnancy-related complications. The proteomes of serum, urine, amniotic fluid, cervical-vaginal fluid, placental tissue, and cytotrophoblastic cells have all been investigated. Numerous biomarkers or biomarker candidates that could distinguish complicated pregnancies from healthy controls have been proposed. Nevertheless, questions as to the clinically utility and the capacity to elucidate the pathogenesis of the pre-eclampsia and preterm birth remain to be answered.     

Interaction between Metformin,Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B₁₂ deficiency and antifolate like activity. Vitamin B₁₂ and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B₁₂ imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B₁₂ and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B₁₂ balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.     

Pregnancy-Related Extracellular Vesicles Revisited

Extracellular vesicles (EVs) are small vesicles ranging from 20–200 nm to 10 μm in diameter that are discharged and taken in by many different types of cells. Depending on the nature and quantity of their content—which generally includes proteins, lipids as well as microRNAs (miRNAs), messenger-RNA (mRNA), and DNA—these particles can bring about functional modifications in the receiving cells. During pregnancy, placenta and/or fetal-derived EVs have recently been isolated, eliciting interest in discovering their clinical significance. To date, various studies have associated variations in the circulating levels of maternal and fetal EVs and their contents, with complications including gestational diabetes and preeclampsia, ultimately leading to adverse pregnancy outcomes. Furthermore, EVs have also been identified as messengers and important players in viral infections during pregnancy, as well as in various congenital malformations. Their presence can be detected in the maternal blood from the first trimester and their level increases towards term, thus acting as liquid biopsies that give invaluable insight into the status of the feto-placental unit. However, their exact roles in the metabolic and vascular adaptations associated with physiological and pathological pregnancy is still under investigation. Analyzing peer-reviewed journal articles available in online databases, the purpose of this review is to synthesize current knowledge regarding the utility of quantification of pregnancy related EVs in general and placental EVs in particular as non-invasive evidence of placental dysfunction and adverse pregnancy outcomes, and to develop the current understanding of these particles and their applicability in clinical practice.     

Maternal C-Peptide and Insulin Sensitivity,but Not BMI,Associate with Fatty Acids in the First Trimester of Pregnancy

Maternal obesity in pregnancy is a pro-inflammatory condition exposing the fetus to an adverse environment. Here, we tested associations of maternal obesity (primary exposures: BMI, leptin) and metabolic parameters (secondary exposures: glucose, C-peptide, and insulin sensitivity) with total serum concentrations of fatty acids in the first trimester of human pregnancy. This cross-sectional study included 123 non-smoking women with singleton pregnancy. In maternal serum, cotinine, leptin, and C-peptide (ELISA), glucose (hexokinase-based test) and fatty acids (gas chromatography) were quantified, and the insulin sensitivity index (IS_HOMA) was calculated. Concentrations of fatty acid classes and total fatty acids did not differ between BMI or leptin categories. However, n-3 polyunsaturated fatty acids (PUFA) were decreased in the category with the highest C-peptide concentration (n-3 PUFA: CI −35.82–−6.28, p < 0.006) and in the lowest IS_HOMA category (n-3 PUFA: CI −36.48–−5.61, p < 0.008). In a subcohort, in which fetal sex was determined (RT-qPCR of placental tissue), C-peptide was significantly associated with docosahexaenoic acid (DHA) in mothers bearing a female (n = 46), but not male (n = 37) fetus. In conclusion, pregnant women with high fasting C-peptide and low IS_HOMA had decreased n-3 PUFA, and DHA was lower with higher C-peptide only in mothers bearing a female fetus.