Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications.

Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management.

GABA in the medial prefrontal cortex regulates anxiety-like behavior during the postpartum period.

The postpartum period is commonly accompanied by emotional changes, which for many new mothers includes a reduction in anxiety. Previous research in rodents has shown that the postpartum attenuation in anxiety is dependent on offspring contact and has further implicated enhanced GABAergic neurotransmission as an underlying mechanism. However, the specific brain regions where GABA acts to regulate the offspring-induced reduction in postpartum anxiety requires further investigation. Here, we test the hypothesis that offspring interactions suppress anxiety-like behavior in postpartum female rats via GABA signaling in the medial prefrontal cortex (mPFC). Our results show a postpartum reduction in anxiety-like behavior, an effect which was abolished by localized infusion of the GABAA receptor antagonist bicuculline in the mPFC. We also show that activation of GABAA receptors in the mPFC by the agonist muscimol was effective in restoring anxiolyisis in mothers separated from their pups. Lastly, we show that heightened anxiety-like behavior in pup-separated mothers was accompanied by a lower number and percentage of activated GABAergic neurons within the mPFC. Together, these results suggest that mother-offspring interactions reduce anxiety-like behavior in postpartum females via GABAA neurotransmission in the mPFC and in doing so provide insight into mechanisms that may become dysfunctional in mothers who experience high postpartum anxiety.

Association of taurine with ovarian follicular steroids and postpartum anestrus condition in Murrah buffaloes.

Taurine is an abundant intracellular beta-amino acid majorly synthesized in the liver and transported through plasma. In mammals, taurine was reported to be involved in various physiological functions, including the enhancement of testosterone levels, the major estradiol precursor. Therefore, we hypothesize that taurine levels are associated with ovarian follicular steroids as well as with a reproductive problem called postpartum anestrus (PPA) in dairy buffaloes. To understand the taurine levels and its possible role in buffalo ovarian follicles, a correlation was established among taurine, estradiol, and testosterone levels in the ovarian follicular fluid. For this purpose, buffalo ovaries were obtained from the slaughterhouse, and follicular fluid samples were collected from small (<4 mm), medium (4-8 mm) and large (>8 mm) follicles. Taurine and steroid levels in the follicular fluid were analyzed by TLC and ELISA, respectively. Taurine and testosterone levels were significantly (P < 0.05) higher in the follicular fluid of small and medium follicles than large follicles, whereas the estradiol levels were significantly (P < 0.001) higher in the large follicles. Thus, taurine showed a positive correlation (r = 0.75) with testosterone and a negative correlation (r = -0.77) with estradiol in buffalo follicular fluid, indicating its possible role in testosterone function during follicular development. Interestingly, significantly (P < 0.001) lower plasma taurine levels in PPA (n = 50) than normal cyclic (n = 50) buffaloes represented its association with PPA. Therefore, our present study recommends the need for future nutrition studies on taurine supplementation to PPA buffaloes.

Thyroid dysfunction following pregnancy and implications for breastfeeding.

Subclinical autoimmune thyroiditis exacerbates after delivery through immune rebound mechanisms and results in 5 types of thyroid dysfunction. The prevalence of postpartum thyroid dysfunction is around 5% in mothers in the general population. Typically, an exacerbation induces destructive thyrotoxicosis followed by transient hypothyroidism, known as postpartum thyroiditis. Late development of permanent hypothyroidism is found frequently and patients should be followed up once every one to two years. Destructive thyrotoxicosis in postpartum thyroiditis should carefully be differentiated from post-partum Graves' disease. Postpartum thyroiditis typically occurs 1-4 months after parturition whereas Graves' disease develops at 4-12 months postpartum. Anti-TSH receptor antibodies (TRAb) are typically positive and thyroid blood flow is high in Graves' disease, whereas these features are absent in postpartum thyroiditis. Postpartum Graves' disease should be treated with antithyroid drugs.

Gestational hypothyroidism elicits more pronounced lipid dysregulation in mice than pre-pregnant hypothyroidism.

Thyroid hormone is crucial for regulating lipid and glucose metabolism, which plays essential role in maintaining the health of pregnant women and their offspring. However, the current literature is just focusing on the development of offspring born to the untreated mothers with hypothyroidism, rather than mothers themselves. Additionally, the interaction between hypothyroidism and pregnancy, and its impact on the women's health are still elusive. Therefore, this study was designed to compare the metabolic differences in dams with hypothyroidism starting before pregnancy and after pregnancy. Pre-pregnant hypothyroidism was generated in 5-week-old female C57/BL/6J mice using iodine-deficient diet containing 0.15% propylthiouracil for 4 weeks, and the hypothyroidism was maintained until delivery. Gestational hypothyroidism was induced in dams after mating, using the same diet intervention until delivery. Compared with normal control, gestational hypothyroidism exhibited more prominent increase than pre-pregnant hypothyroidism in plasma total cholesterol and low-density lipoprotein cholesterol, and caused hepatic triglycerides accumulation. Similarly, more significant elevations of protein expressions of SREBP1c and p-ACL, while more dramatic inhibition of CPT1A and LDL-R levels were also observed in murine livers with gestational hypothyroidism than those with pre-pregnant hypothyroidism. Moreover, the murine hepatic levels of total cholesterol and gluconeogenesis were dramatically and equally enhanced in two hypothyroid groups, while plasma triglycerides and protein expressions of p-AKT, p-FoxO1 and APOC3 were reduced substantially in two hypothyroid groups. Taken together, our current study illuminated that gestational hypothyroidism may elicit more pronounced lipid dysregulation in dams than dose the pre-pregnant hypothyroidism.

Biological stress response in women at risk of postpartum psychosis: The role of life events and inflammation.

BACKGROUND: Postpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high in women with a history of bipolar disorder, schizoaffective disorder or in those who have suffered previous episodes of PP. While studies in patients with psychosis not related to the puerperium have demonstrated that abnormalities in stress response are important risk factors for psychosis, it remains unknown whether this is also the case for PP. METHODS: This study includes 30 postpartum women, assessed, on average, at postpartum week 14.8 ± 10.1 either with a current episode of PP (n = 14), or at-risk of PP because of a history of bipolar/schizoaffective disorder but who were well (n = 16), and a group of healthy women (n = 26). Details about recent stressful life events were obtained using the List of Threatening Experiences questionnaire, while perceived stress was evaluated using the Perceived Stress Scale. We estimated hypothalamic-pituitary adrenal (HPA) activity by measuring salivary cortisol at awakening; at 15, 30, and 60 min after awakening; at noon; and at 8 pm. An Area Under the Curve analysis was performed to assess the awakening response (AUCi) and cortisol levels during the day (AUCg). Immune markers, including high sensitivity C-Reactive Protein (hs-CRP) and Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, Tumor Necrosis Factor (TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF) were evaluated from peripheral blood samples. RESULTS: Women with current PP reported more frequent recent stressful life events, and higher perceived stress than healthy women. They also showed an activation of the stress and immune response, with higher levels of cortisol AUCg and hs-CRP (but not of other inflammatory markers) than healthy controls. Women at-risk of PP who remained well had values on these measures that were intermediate between those of women with a current episode of PP and those of healthy women. Stress measures and markers of stress and immune response explained 78 % of the variance of in group status between PP and healthy women, and 46 % of variance of in group status between women at-risk and healthy women. CONCLUSION: These findings suggest that an immune-HPA axis dysregulation, together with current stress may represent an important underlying pathophysiological mechanism in the onset of psychosis after childbirth in vulnerable women.

Association between blood loss at delivery and fatigue in the puerperium: a prospective longitudinal study.

Objective: The objective was to investigate the association between blood loss at delivery and physical and mental fatigue during the first 12 weeks postpartum. We also investigated the association between hemoglobin and postpartum fatigue.Methods: We performed a single center prospective longitudinal study of healthy women with a singleton delivery. Women completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale at 3 and 7 d, 3, 8 and 12 weeks postpartum. The hemoglobin level was measured at inclusion (baseline).Results: A total of 196 women with blood loss at delivery ranging from 100 to 2800 mL were included in the study. At 12 weeks follow-up the response rate was 92% (n = 181). We found a significant association between blood loss and scores of physical and mental fatigue within the first week postpartum. When adjusted for bleeding, hemoglobin measured at inclusion was not associated with fatigue at any given time point.Conclusions: The amount of measured blood loss was significantly associated with increased physical and mental fatigue in the first week postpartum. When adjusted for bleeding, baseline hemoglobin was no longer associated with physical and mental fatigue.

Characterization of circulating plasma proteins in dairy cows with cytological endometritis.

Early diagnosis of endometritis in dairy cattle is currently requires invasive techniques and specialist expertise. The goal of this study is to utilize a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without. Blood samples were collected from cows (N = 112) seven days postpartum (DPP). Plasma samples from a cohort of 20 animals with cytological endometritis (n = 10) and without (n = 10) as classified 21 DPP were selected for proteomic analysis. Differential abundances of proteins between the two animal groups were determined using both fold change (≥1.5 fold change) and statistical significance threshold (p < .05). A total of 181 non-redundant proteins were quantified, and 25 proteins were found with differential abundance. These include 4 binding protein alpha and mannose binding lectin 2 involved in immune responses. Differentially abundant proteins between the animals were then processed using PANTHER for gene ontology. Gene ontology included associations with innate immune processes, acute phase responses and immune regulation. A potential marker for disease identified here is the "uncharacterized protein G5E513," a protein previously defined by RNA-transcripts. These proteins may form the basis for endometritis prognosis, the development of which is proceeded by systemic changes in immune function. SIGNIFICANCE: Endometritis is a costly reproductive disease of lactating dairy cows that warrants timely diagnosis. We utilized a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without, for the characterization of changes in the proteomic profile associated with uterine disease postpartum. Furthermore, we compared the plasma proteome of healthy and affected cows in the same physiological status of production to better understand the relationship between changes in expression of circulating proteins and to unravel essential biological mechanisms involved in bovine cytological endometritis.

Elevated bradykinin receptor type 1 expression in postpartum acute myometritis: Possible involvement in augmented interstitial edema of the atonic gravid uterus.

AIM: Uterine atony is a major cause of postpartum hemorrhage. We recently proposed a new concept for the histopathophysiology of refractory uterine atony, postpartum acute myometritis (PAM), characterized by acute inflammatory changes with massive stromal edema, increased numbers of complement C5a receptors and diffuse mast cell activation in the myometrium. We herein focused on the possible involvement of the kinin-kallikrein system in the rapid development of interstitial edema in PAM, particularly bradykinin receptor type 1 (B1R), which is up-regulated under inflammatory conditions. The present study investigated B1R expression with uterine interstitial edema in PAM. METHODS: Our institution plays an important role in a Japanese amniotic fluid embolism registry project. We selected PAM cases from uterine samples delivered to us for further analyses between 2012 and 2017. Control tissues were collected during cesarean section and planned hysterectomy. B1R expression was semi-quantitatively measured by immunohistochemistry, while uterine interstitial edema was estimated by semi-quantitative measurements of the alpha smooth muscle actin-negative area using immunohistochemistry. RESULTS: There were 36 and 8 cases in the PAM and control groups, respectively. The alpha smooth muscle actin-negative area was increased in the PAM group, concomitant with the significant up-regulation of B1R expression in uterine smooth muscle cells, vascular endothelial cells, and neutrophils. A positive correlation was observed between these two factors. CONCLUSION: We demonstrated the up-regulated expression of B1R in the myometrium and its positive correlation with histologically estimated interstitial edema, suggesting the contribution of the kinin-kallikrein-B1R system to the development of interstitial edema in PAM cases.

The DiPEP study: an observational study of the diagnostic accuracy of clinical assessment, D-dimer and chest x-ray for suspected pulmonary embolism in pregnancy and postpartum.

OBJECTIVE: To identify clinical features associated with pulmonary embolism (PE) diagnosis and determine the accuracy of decision rules and D-dimer for diagnosing suspected PE in pregnant/postpartum women DESIGN: Observational cohort study augmented with additional cases. SETTING: Emergency departments and maternity units at eleven prospectively recruiting sites and maternity units in the United Kingdom Obstetric Surveillance System (UKOSS) POPULATION: 324 pregnant/postpartum women with suspected PE and 198 pregnant/postpartum women with diagnosed PE METHODS: We recorded clinical features, elements of clinical decision rules, D-dimer measurements, imaging results, treatments and adverse outcomes up to 30 days MAIN OUTCOME MEASURES: Women were classified as having PE on the basis of imaging, treatment and adverse outcomes by assessors blind to clinical features and D-dimer. Primary analysis was limited to women with conclusive imaging to avoid work-up bias. Secondary analyses included women with clinically diagnosed or ruled out PE. RESULTS: The only clinical features associated with PE on multivariate analysis were age (odds ratio 1.06; 95% confidence interval 1.01-1.11), previous thrombosis (3.07; 1.05-8.99), family history of thrombosis (0.35; 0.14-0.90), temperature (2.22; 1.26-3.91), systolic blood pressure (0.96; 0.93-0.99), oxygen saturation (0.87; 0.78-0.97) and PE-related chest x-ray abnormality (13.4; 1.39-130.2). Clinical decision rules had areas under the receiver-operator characteristic curve ranging from 0.577 to 0.732 and no clinically useful threshold for decision-making. Sensitivities and specificities of D-dimer were 88.4% and 8.8% using a standard threshold and 69.8% and 32.8% using a pregnancy-specific threshold. CONCLUSIONS: Clinical decision rules and D-dimer should not be used to select pregnant or postpartum women with suspected PE for further investigation. Clinical features and chest x-ray appearances may have counter-intuitive associations with PE in this context. TWEETABLE ABSTRACT: Clinical decision rules and D-dimer are not helpful for diagnosing pregnant/postpartum women with suspected PE.

Oral vs intravenous iron therapy for postpartum anemia: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review of randomized trials comparing oral vs intravenous (IV) iron therapy to treat postpartum anemia. DATA SOURCES: Data sources were as follows: PubMed (1972-2017); Cochrane Central Register of Controlled Trials, CENTRAL (1972-2017); CINAHL (1972-2017); Web of Science; Excerpta Medica Database, and EMBASE (1972-2017). STUDY ELIGIBILITY CRITERIA: We included randomized trials comparing oral vs IV iron monotherapy to treat postpartum anemia (classified as a hemoglobin <12 g/dL). STUDY APPRAISAL AND SYNTHESIS METHODS: Study quality was assessed with the Cochrane risk of bias assessment tool. The primary outcome was hemoglobin concentration at 6 weeks postpartum. Secondary outcomes included hemoglobin concentration at 1-5 weeks postpartum, ferritin concentration at 1-6 weeks postpartum, and maternal adverse outcomes. For meta-analysis, mean differences and odds ratios using a random effects model were calculated. Risk of heterogeneity was reported as I2. RESULTS: A total of 15 randomized trials met our inclusion criteria (n = 1001 and 1 181 women receiving oral iron and IV iron, respectively); 4 studies reported data for our primary outcome. We observed higher postpartum week 6 hemoglobin concentrations in the IV iron group compared to the oral iron group (mean difference, 0.9 g/dL; 95% confidence interval (CI), 0.4-1.3; P = .0003). Compared to oral iron, women receiving IV iron had higher hemoglobin concentrations at postpartum weeks 1, 2, and 3; higher ferritin concentrations at postpartum weeks 1, 2, 4, and 6; an increased likelihood of skin flushing (odds ratio [OR], 6.95; 95% CI, 1.56-31.03; P = .01; I2 = 0%); and a decreased likelihood of constipation (OR, 0.08; 95% CI, 0.03-0.21; P < .00001, I2 = 27%) and dyspepsia (OR, 0.07; 95% confidence interval, 0.01-0.42; P = .004; I2 = 0%). The reported event rate for anaphylaxis among women receiving IV iron was 0.6%. CONCLUSION: In this systematic review, among women with postpartum anemia, hemoglobin concentrations at 6 weeks postpartum were almost 1 g/dL higher in women who received IV iron compared to oral iron. The safety profile of IV iron was also reassuring. Given the weaker hemoglobin response and higher risk of gastrointestinal side effects with oral iron use, our findings suggest that IV iron be considered as a viable treatment option for postpartum iron deficiency anemia.

Do Defective Immune System-Mediated Myelination Processes Increase Postpartum Psychosis Risk?

Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets.

Inflammatory status and its relationships with different patterns of postpartum luteal activity and reproductive performance in early lactating Holstein cows.

This study was undertaken to determine the effect of inflammatory status on different patterns of postpartum luteal activity and reproductive performance of Holstein cows during early lactation. The cows (n = 75) averaged 3.4 ±â€¯1.2 (mean ±â€¯SEM) in parity and 3.1 ±â€¯0.2 (mean ±â€¯SEM) in body condition score at calving. Transrectal ultrasonography was performed twice weekly from day 10-60 postpartum to consider ovarian dynamics. Plasma concentrations of progesterone (P4) and estradiol (E2) were measured twice weekly and plasma levels of tumor necrosis factor alpha (TNF-α) and lipopolysacchride binding protein (LBP) were measured weekly (week 3-6 postpartum). Based on plasma P4 and E2 results, 34 (45.3%) cows had normal luteal activity (NLA), whereas 19 (25.3%), 12 (16.0%), 7 (9.3%) and 3 (4.0%) cows had prolonged luteal phase (PLP), delayed first ovulation (DO), anovulation (AO) and short luteal phase (SLP), respectively. Plasma TNF-α and LBP concentrations were affected by postpartum luteal activity (NLA, SLP and PLP), ovulatory status (DO and AO) and number of weeks postpartum (P < .05). These concentrations were greater in cows with PLP (P < .05) as compared to NLA cows, and in cows that had delayed ovulation or anovulation compared to ovulated cows (P < .05). Cows with PLP had greater open days and lower conception rate as compared to NLA cows (P < .05). Healthy cows had a larger CL and greater plasma estradiol and progesterone concentrations at first and second cycle postpartum compared to inflamed cows and followed it with greater fertility (P < .05). In conclusion, inflammatory statuses were different in high-producing dairy cows showing PLP, AO and DO in comparison with the postpartum normal luteal activity (NLA) cows that influenced reproduction outcomes.

The psychoneuroimmunology of pregnancy.

Pregnancy is associated with a number of significant changes in maternal physiology. Perhaps one of the more notable changes is the significant alteration in immune function that occurs during pregnancy. This change in immune function is necessary to support a successful pregnancy, but also creates a unique period of life during which a female is susceptible to disease and, as we'll speculate here, may also contribute to mental health disorders associated with pregnancy and the postpartum period. Here, we review the known changes in peripheral immune function that occur during pregnancy and the postpartum period, while highlighting the impact of hormones during these times on immune function, brain or neural function, as well as behavior. We also discuss the known and possible impact of pregnancy-induced immune changes on neural function during this time and briefly discuss how these changes might be a risk factor for perinatal anxiety or mood disorders.

A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.

Postpartum psychosis (PP) is a severe psychiatric disorder affecting a small proportion of new mothers shortly after childbirth. The molecular pathophysiology underlying the disorder is currently poorly understood, and there are no amenable animal models for the condition; maternal deficiency for the enzyme steroid sulfatase has been proposed as a potential risk mechanism. Here we show that inhibition of steroid sulfatase with 667-COUMATE (10mg/kg p.o.) in new mouse mothers results in behavioural abnormalities that can be partially alleviated by the administration of the clinically-efficacious antipsychotic ziprasidone (0.3-1.0mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21-23cM on chromosome 15; of the 17 genes within this chromosomal interval, only one (Nov/Ccn3) was significantly differentially expressed in the brains of vehicle and 667-COUMATE-treated mice. Two additional members of the Ccn family (Ccn2/Ctgf and Ccn4/Wisp1) were also significantly differentially expressed between the two groups, as were three further genes co-expressed with Nov/Ccn3 in brain (Arhgdig) or previously implicated in disorder risk by clinical studies (Adcy8 and Ccl2). The expression of Nov/Ccn3, but not of the other differentially-expressed genes, could be normalised by ziprasidone administration (1.0mg/kg). NOV/CCN3 lies directly under a linkage peak for PP risk at 8q24, and the associated protein possesses numerous characteristics that make it an excellent candidate mediator of PP risk. Our data suggest the 667-COUMATE-treated mouse as a model for PP with some degree of face, construct, and predictive validity, and implicate a novel, and biologically-plausible, molecular risk pathway for PP.

Reproductive Steroid Regulation of Mood and Behavior.

In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e.

The effect of puerperal uterine disease on histopathologic findings and mRNA expression of proinflammatory cytokines of the endometrium in dairy cows.

The aim of this study was to investigate the effect of puerperal uterine disease on histopathologic findings and gene expression of proinflammatory cytokines in the endometrium of postpuerperal dairy cows; 49 lactating Holstein-Friesian cows were divided into two groups, one without (UD-; n = 29) and one with uterine disease (UD+; n = 21), defined as retained fetal membranes and/or clinical metritis. General clinical examination, vaginoscopy, transrectal palpation, and transrectal B-mode sonography were conducted on days 8, 11, 18, and 25 and then every 10 days until Day 65 (Day 0 = day of calving). The first endometrial sampling (ES1; swab and biopsy) was done during estrus around Day 42 and the second endometrial sampling (ES2) during the estrus after synchronization (cloprostenol between days 55 and 60 and GnRH 2 days later). The prevalence of histopathologic evidence of endometritis, according to the categories used here, and positive bacteriologic cultures was not affected by group (P > 0.05), but cows with uterine disease had a higher prevalence of chronic purulent endometritis (ES1; P = 0.07) and angiosclerosis (ES2; P ≤ 0.05) than healthy cows. Endometrial gene expression of IL1α (ES2), IL1ß (ES2), and TNFα (ES1 and ES2) was higher (P ≤ 0.05) in the UD+ group than in the UD- group. In conclusion, puerperal uterine disease had an effect on histopathologic parameters and on gene expression of proinflammatory cytokines in the endometrium of postpuerperal cows, indicating impaired clearance of uterine inflammation in cows with puerperal uterine disease.

Tryptophan pathway alterations in the postpartum period and in acute postpartum psychosis and depression.

OBJECTIVES: Women are at very high risk for the first onset of acute and severe mood disorders the first weeks after delivery. Tryptophan breakdown is increased as a physiological phenomenon of the postpartum period and might lead to vulnerability for affective psychosis (PP) and severe depression (PD). The aim of the current study was to investigate alterations in tryptophan breakdown in the physiological postpartum period compared to patients with severe postpartum mood disorders. METHODS: We included 52 patients (29 with PP, 23 with PD), 52 matched healthy postpartum women and 29 healthy non-postpartum women. Analyzes of serum tryptophan metabolites were performed using LC-MS/MS system for tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid and 5-hydroxyindoleacetic acid. RESULTS: The first two months of the physiological postpartum period were characterized by low tryptophan levels, increased breakdown towards kynurenine and a downstream shift toward the 3-OH-kynurenine arm, away from the kynurenic acid arm. Kynurenine was significantly lower in patients with PP and PD as compared to healthy postpartum women (p=0.011 and p=0.001); the remaining tryptophan metabolites demonstrated few differences between patients and healthy postpartum women. LIMITATION: Low prevalence of the investigated disorders and strict exclusion criteria to obtain homogenous groups, resulted in relatively small sample sizes. CONCLUSION: The high kynurenine levels and increased tryptophan breakdown as a phenomenon of the physiological postpartum period was not present in patients with severe postpartum mood disorders. No differences were observed in the levels of the 'neurotoxic' 3-OH-kynurenine and the 'neuroprotective' kynurenic acid arms between patients and healthy postpartum women.