"Navigating in a maze without a map". Partners' experiences of hyperemesis gravidarum- a qualitative study.

OBJECTIVE: A supportive environment for women with Hyperemesis Gravidarum is crucial but not always provided. There is a lack of research regarding Hyperemesis Gravidarum, its impact on the family, and the partner's perception of supporting their spouse. Thus, this study aims to explore partners' experiences of Hyperemesis Gravidarum during their spousés pregnancy. METHODS: Data were gathered through 13 individual, semi-structured, in-depth, digital interviews with partners of women who had experienced Hyperemesis Gravidarum and analysed with Qualitative Content Analysis. The partners were recruited through advertisement on a social media platform and were exclusively males, representing 8 of 21 Swedish regions. The mean age was 34, and they had, on average, 1 previous child. The mean time from the experience to the interview was 12 months. FINDINGS: The main theme, "Navigating in a maze without a map", explains partners' situation as stressful and demanding when their spouse suffers from Hyperemesis Gravidarum, with insufficient support and guidance from healthcare providers. The analysis resulted in three themes: "Standing alone with a demanding responsibility", "Being in a lottery when facing healthcare", and "Climbing the mountain together." The themes display challenges within everyday life and healthcare, as well as strained relations within the family. CONCLUSION: Partners experience a need to support their spouse in every aspect of daily life and advocate for adequate healthcare. Healthcare professionals must support and acknowledge the partners' struggles during the demanding situation with Hyperemesis Gravidarum.

Treatments for hyperemesis gravidarum: A systematic review.

INTRODUCTION: Hyperemesis gravidarum affects 0.3%-3% of pregnant women each year and is the leading cause of hospitalization in early pregnancy. Previous systematic reviews of available treatments have found a lack of consistent evidence, and few studies of high quality. Since 2016, no systematic review has been conducted and an up-to date review is requested. In a recent James Lind Alliance collaboration, it was clear that research on effective treatments is a high priority for both patients and clinicians. MATERIAL AND METHODS: Searches without time limits were performed in the AMED, CINAHL, Cochrane Library, EMBASE, Medline, PsycINFO, and Scopus databases until June 26, 2023. Studies published before October 1, 2014 were identified from the review by O'Donnell et al., 2016. Selection criteria were randomized clinical trials and non-randomized studies of interventions comparing treatment of hyperemesis gravidarum with another treatment or placebo. Outcome variables included were: degree of nausea; vomiting; inability to tolerate oral fluids or food; hospital treatment; health-related quality of life, small-for-gestational-age infant; and preterm birth. Abstracts and full texts were screened, and risk of bias of the studies was assessed independently by two authors. Synthesis without meta-analysis was performed, and certainty of evidence was assessed using the GRADE approach. PROSPERO (CRD42022303150). RESULTS: Twenty treatments were included in 25 studies with low or moderate risk of bias. The certainty of evidence was very low for all treatments except for acupressure in addition to standard care, which showed a possible moderate decrease in nausea and vomiting, with low certainty of evidence. CONCLUSIONS: Several scientific knowledge gaps were identified. Studies on treatments for hyperemesis gravidarum are few, and the certainty of evidence for different treatments is either low or very low. To establish more robust evidence, it is essential to use validated scoring systems, the recently established diagnostic criteria, clear descriptions and measurements of core outcomes and to perform larger studies.

Pregnancy-related maternal physiological adaptations and fetal chemical exposure.

Prenatal life represents a susceptible window of development during which chemical exposures can permanently alter fetal development, leading to an increased likelihood of disease later in life. Therefore, it is essential to assess exposure in the fetus. However, direct assessment in human fetuses is challenging, so most research measures maternal exposure. Pregnancy induces a range of significant physiological changes in women that may affect chemical metabolism and responses. Moreover, placental function, fetal sex, and pregnancy complications may further modify these exposures. The purpose of this narrative review is to give an overview of major pregnancy-related physiological changes, including placental function and impacts of pregnancy complications, to summarize existing studies assessing chemical exposure in human fetal organs, and to discuss possible interactions between physiological changes and exposures. Our review reveals major knowledge gaps in factors affecting fetal chemical exposure, highlighting the need to develop more sophisticated tools for chemical health risk assessment in fetuses.

Mixtures of persistent organic pollutants are found in vital organs of late gestation human fetuses.

Persistent organic pollutants (POPs) are industrial chemicals with long half-lives. Early life exposure to POPs has been associated with adverse effects. Fetal exposure is typically estimated based on concentrations in maternal serum or placenta and little is known on the actual fetal exposure. We measured the concentrations of nine organochlorine pesticides (OCPs), ten polychlorinated biphenyl (PCB) congeners, and polybrominated diphenyl ether (PBDE) congeners by gas chromatography - tandem mass spectrometry in maternal serum, placenta, and fetal tissues (adipose tissue, liver, heart, lung and brain) in 20 pregnancies that ended in stillbirth (gestational weeks 36-41). The data were combined with our earlier data on perfluoroalkyl substances (PFASs) in the same cohort (Mamsen et al. 2019). HCB, p,p'-DDE, PCB 138 and PCB 153 were quantified in all samples of maternal serum, placenta and fetal tissues. All 22 POPs were detected in all fetal adipose tissue samples, even in cases where they could not be detected in maternal serum or placenta. Tissue:serum ratios were significantly higher in later gestations, male fetuses, and pregnancies with normal placental function. OCPs showed the highest tissue:serum ratios and PFAS the lowest. The highest chemical burden was found in adipose tissue and lowest in the brain. Overall, all studied human fetuses were intrinsically exposed to mixtures of POPs. Tissue:serum ratios were significantly modified by gestational age, fetal sex and placental function. Importantly, more chemicals were detected in fetal tissues compared to maternal serum and placenta, implying that these proxy samples may provide a misleading picture of actual fetal exposures.

Polyunsaturated Fatty Acids and Their Metabolites in Hyperemesis Gravidarum.

Polyunsaturated fatty acids (PUFAs) have been studied in relation to pregnancy. However, there is limited knowledge on PUFAs and their metabolites in relation to hyperemesis gravidarum (HG), a pregnancy complication associated with nutritional deficiencies and excessive vomiting. In order to survey the field, a systematic review of the literature was performed, which also included nausea and vomiting of pregnancy (NVP) due to its close relationship with HG. In the very few published studies found, the main subjects of the research concerned free fatty acids (four records), lipid profiles (three records), and bioactive lipids (one article about prostaglandin E2 and one about endocannabinoids). The authors of these studies concluded that, although no cause-and-effect relationship can be established, HG is linked to increased sympathetic responsiveness, thermogenic activity and metabolic rate. In addition, NVP is linked to a metabolic perturbance (which lasts throughout pregnancy). The low number of retrieved records underlines the need for more research in the area of PUFAs and HG, especially with regard to the underlying mechanism for the detected effects, potentially involving growth differentiation factor 15 (GDF15) since evidence for GDF15 regulation of lipid metabolism and the role for GDF15 and its receptor in nausea and vomiting is emerging.

Enhanced local and systemic inflammatory cytokine mRNA expression in women with endometriosis evokes compensatory adaptive regulatory mRNA response that mediates immune suppression and impairs cytotoxicity.

PROBLEM: Endometriosis is a disease characterized by ectopic implantation of endometrium and impaired immune responses. To explore its pathogenic mechanisms, we studied the local and systemic cytokine mRNA profiles and their role in the immunity of patients with endometriosis and healthy controls. METHOD OF STUDY: mRNA for eleven cytokines defining cytotoxic Th1, humoral Th2, regulatory Tr1/Th3, and inflammatory cytokine profiles was characterized locally in endometriotic tissue and endometrium, and systemically in PBMCs from women with endometriosis and healthy controls, using real-time qRT-PCR. In addition, immunohistochemical stainings with monoclonal antibodies were performed looking for T regulatory cells in endometriotic lesions. RESULTS: We found a downregulation of mRNA for cytokines mediating cytotoxicity and antibody response and an upregulation of inflammatory and T-regulatory cytokines in the endometriotic tissues and endometrium from the patients with endometriosis, suggesting enhanced local inflammation and priming of an adaptive regulatory response. Consistent with those findings, there was an abundancy of T regulatory cells in the endometriotic lesions. CONCLUSIONS: The ectopic implantation seen in endometriosis could be possible as a consequence of increased inflammation and priming of adaptive T regulatory cells, resulting in impaired cytotoxicity and enhanced immune suppression.

Concentrations of perfluoroalkyl substances (PFASs) in human embryonic and fetal organs from first, second, and third trimester pregnancies.

BACKGROUND: The persistent environmental contaminants perfluoroalkyl substances (PFASs) have gained attention due to their potential adverse health effects, in particular following early life exposure. Information on human fetal exposure to PFASs is currently limited to one report on first trimester samples. There is no data available on PFAS concentrations in fetal organs throughout all three trimesters of pregnancy. METHODS: We measured the concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnA), and perfluorohexane sulfonic acid (PFHxS) in human embryos and fetuses with corresponding placentas and maternal serum samples derived from elective pregnancy terminations and cases of intrauterine fetal death. A total of 78 embryos and fetuses aged 7-42 gestational weeks were included and a total of 225 fetal organs covering liver, lung, heart, central nervous system (CNS), and adipose tissue were analyzed, together with 71 placentas and 63 maternal serum samples. PFAS concentrations were assayed by liquid chromatography/triple quadrupole mass spectrometry. RESULTS: All evaluated PFASs were detected and quantified in maternal sera, placentas and embryos/fetuses. In maternal serum samples, PFOS was detected in highest concentrations, followed by PFOA > PFNA > PFDA = PFUnA = PFHxS. Similarly, PFOS was detected in highest concentrations in embryo/fetal tissues, followed by PFOA > PFNA = PFDA = PFUnA. PFHxS was detected in very few fetuses. In general, PFAS concentrations in embryo/fetal tissue (ng/g) were lower than maternal serum (ng/ml) but similar to placenta concentrations. The total PFAS burden (i.e. the sum of all PFASs) was highest in lung tissue in first trimester samples and in liver in second and third trimester samples. The burden was lowest in CNS samples irrespective of fetal age. The placenta:maternal serum ratios of PFOS, PFOA and PFNA increased across gestation suggesting bioaccumulation in the placenta. Further, we observed that the ratios were higher in pregnancies with male fetuses compared to female fetuses. CONCLUSIONS: Human fetuses were intrinsically exposed to a mixture of PFASs throughout gestation. The compounds were detected in all analyzed tissues, suggesting that PFASs reach and may affect many types of organs. Collectively, our results demonstrate that PFASs pass the placenta and deposit to embryo and fetal tissues, calling for risk assessment of gestational exposures.

Enhanced Th1 and inflammatory mRNA responses upregulate NK cell cytotoxicity and NKG2D ligand expression in human pre-eclamptic placenta and target it for NK cell attack.

PROBLEM: Pre-eclampsia (PE), a severe human pregnancy disorder, is associated with exaggerated systemic inflammation, enhanced cytokine production, and increased shedding of microvesicles leading to endothelial dysfunction, coagulopathy, and extensive placenta destruction. The cause of PE is still unclear. Evidence suggests that its origin lies in the placenta and that the maternal immune system is involved. A shift in cytokine production in PE pregnancy promotes NK cell activation, suggested to be important in PE pathogenesis. In line with this suggestion, we studied NK cell cytotoxicity in peripheral blood of PE patients and controls and the mRNA expression of cytokines and of the NKG2D receptor and its ligands MICA/B and ULBP1-3 in PE- and normal placenta. METHOD OF STUDY: The cytotoxic capacity of peripheral blood NK cells was analyzed using K562 target cells. The cytokine mRNA profiles and the mRNA expression of the NKG2D receptor and its ligands MICA/B and ULBP 1-3 in PE placenta were assessed and compared to those in normal placenta using real-time quantitative RT-PCR. RESULTS: The cytotoxicity of peripheral blood NK cells was upregulated in PE cases. Further, we found an enhanced inflammatory cytokine mRNA response combined with a dysregulated regulatory response and a significant mRNA overexpression of NKG2D receptor and its ligands MICA/B and ULBP in PE placenta. CONCLUSION: The destruction of chorionic villi observed in PE placenta might be conveyed by an enhanced local cytotoxic response through the NKG2D receptor-ligand pathway, which in turn might be promoted by an intense inflammatory response not counteracted by regulatory cytokine responses.

Antenatal corticosteroid treatment and placental pathology, with a focus on villous maturation.

INTRODUCTION: Mothers at risk of preterm birth are treated with antenatal corticosteroids, which have advantageous effects for prematurely born infants. Accelerated villous maturation in the placenta is also associated with improved perinatal outcome. The primary aim of this study was to examine the association between antenatal corticosteroids and accelerated villous maturation. The secondary aim was to study associations with other placental pathologies. MATERIAL AND METHODS: A retrospective cohort study including 105 women who had (n = 75) or had not (n = 30) been treated with antenatal corticosteroids. The women gave birth between 22+0 and 26+6  weeks of gestation in Stockholm County between 1 April 2004 and 31 March 2007. A pathologist blinded to all clinical data except gestational age examined the placental slides to identify pathology parameters. The outcomes were correlated with antenatal corticosteroid treatment, and confounding factors were adjusted using logistic regression. RESULTS: Accelerated villous maturation was significantly higher in the group treated with corticosteroids (odds ratio 16, 95% CI 2.4-690, p = 0.0005). After adjustment for gestational age and preeclampsia, the difference remained significant (odds ratio 8.9, 95% CI 1.2-389, p = 0.021). No significant associations were found regarding the secondary outcome variables, after adjusting for possible confounders. CONCLUSIONS: Antenatal corticosteroid treatment before preterm birth is associated with accelerated villous maturation. This could be one of the pathways by which corticosteroids are beneficial for preterm infants.

Placental pathology in smoking and non-smoking preeclamptic women.

OBJECTIVE: To ascertain whether the protective effect of smoking during preeclampsia (PE) can be visualized in the placenta. METHODS: The study cohort consisted of placentas (n = 523) from pregnancies complicated by PE, delivered at Karolinska University Hospital in Stockholm during the period 2000-2009. Of the women included in the study, 488 were non-smokers and 35 were smokers at first visit to maternity care. Outcome variables were placental infarctions and decidual arteriopathy. RESULTS: Infarctions (affecting ≥5% of the placental tissue) were found in 15.6% of the placentas from non-smokers and in 25.7% of the placentas from smokers (OR 1.88: CI 0.84-4.16, p = 0.12). Decidual arteriopathy was found in 27.5% of the placentas from non-smokers and in 40.0% of the placentas from smokers (1.76: CI 0.87-3.56, p = 0.12). When diagnosed histopathologically, placental abruption was found in 15.4% among non-smokers and in 17.1% among smokers (1.14: CI 0.46-2.84, p = 0.98). Those differences did not show any statistical significance. CONCLUSION: No significant differences concerning placental infarctions, decidual arteriopathy or abruption were found between preeclamptic placentas from non-smokers compared to smokers.

Association between cerebral palsy and microscopically verified placental infarction in extremely preterm infants.

INTRODUCTION: Previously, cerebral palsy has been associated with placental infarctions diagnosed macroscopically by midwifes. However, the risk of misclassification of infarctionsis is high without a histological verification. Therefore, the objective of this study was to study placental histopathology in relation to developmental outcome at 2.5 years corrected age in a population born extremely preterm. MATERIAL AND METHODS: A prospective cohort study was carried out at Karolinska University Hospital, Stockholm, Sweden on a population of 139 live born infants delivered <27 gestational weeks during 2004-2007. A senior perinatal pathologist, who was blinded to outcome data, evaluated all placental slides microscopically. Neuromotor and sensory functions of the children were evaluated. Bayley Scales of Infant and Toddler Development-III (Bayley-III) were used to assess development at corrected age 2.5 years. The outcome data were evaluated without reference to obstetrical and pathology data. The primary outcome measure was neurological and developmental status at 2.5 years of corrected age. This was measured as diagnosis of cerebral palsy, visual impairment, hearing impairment as well as performance on Bayley-III scales evaluating cognitive, language and motor functions. RESULTS: Two out of seven children with placental infarction were diagnosed with cerebral palsy compared with one child of 51 without placental infarction (p = 0.036). For developmental outcome according to Bayley-III at 2.5 years no statistically significant associations with placental pathology were found. CONCLUSION: A possible association between placental infarction, verified by microscopic examination, and cerebral palsy has been identified in this extremely preterm population.

Placental pathology in relation to stillbirth and neonatal outcome in an extremely preterm population: a prospective cohort study.

OBJECTIVE: To study associations between placental histopathology and stillbirth as well as neonatal outcome in a population born extremely preterm. DESIGN: Prospective cohort study. SETTING: Stockholm, Sweden. POPULATION: 167 infants born <27 gestational weeks during 2004-2007. METHODS: One senior perinatal pathologist, blinded to outcome data, evaluated all placental slides. MAIN OUTCOME MEASURES: Intrauterine fetal death, small-for-gestational age, major neonatal morbidity (intraventricular hemorrhage ≥grade 3, retinopathy of prematurity ≥grade 3, necrotizing enterocolitis, cystic periventricular leukomalacia or severe bronchopulmonary dysplasia) and neonatal mortality. Additional outcome variables were Apgar score at 5 min, sepsis, and treated patent ductus arteriosus. RESULTS: Accelerated villous maturation was associated with a decreased risk for Apgar score <7 at 5 min (p = 0.041). Fetal thrombosis and low placental weight were associated with an increased risk for both intrauterine fetal death (p < 0.001 and p = 0.011, respectively) and small-for-gestational age (p < 0.001 and p < 0.001, respectively). CONCLUSION: Placental histology may have prognostic value as it appears to be associated with intrauterine fetal death, as well as with being small-for-gestational age and assignment of a low Apgar score at birth.

Association between placental pathology and neonatal outcome in preeclampsia: a large cohort study.

OBJECTIVE: To study associations between placental histopathology and neonatal outcome in preeclampsia (PE). STUDY DESIGN: The cohort consisted of 544 singleton pregnancies complicated by PE and managed at Karolinska University Hospital, Stockholm, Sweden during 2000-2009. Evaluation of placental histopathology was made by one senior perinatal pathologist, blinded to outcome. Clinical outcome was obtained from prospectively collected medical registry data and medical records. Main outcome measures were intrauterine fetal death, smallness for gestational age, admission to neonatal unit, major neonatal morbidity (defined as presence of intraventricular hemorrhage ≥ grade 3, retinopathy of prematurity ≥ grade 3, necrotizing enterocolitis, cystic periventricular leucomalacia and/or severe bronchopulmonary dysplasia) and neonatal mortality. Logistic regression analyses including gestational age were performed. RESULTS: Abnormal placental weight, both low (adjusted odds ratio (OR) [95% confidence interval] 5.2 [1.1-24], p = 0.03) and high (adjusted OR 1048 [21-51 663], p < 0.001) for gestational age, was associated with major neonatal morbidity in preterm infants. Accelerated villous maturation was less prevalent in intrauterine fetal death pregnancies (adjusted OR 0.18 [0.04-0.77], p = 0.02). Decidual arteriopathy increased the odds for admission to neonatal care (adjusted OR 2.7 [1.1-6.5], p = 0.03). Infarction involving ≥5% of the placenta was associated with intrauterine fetal death and small for gestational age infants (adjusted OR's 75 [5.5-1011], p = 0.001 and 3.2 [1.7-5.9], p < 0.001; respectively). No relations between histological variables and neonatal mortality could be found. CONCLUSION: Placental pathology in PE reflects adverse perinatal events and deviant placental weight predicts adverse neonatal outcome in preeclamptic women delivering preterm. Placental investigation without delay can contribute to neonatal risk assessment.

The severity of clinical manifestations in preeclampsia correlates with the amount of placental infarction.

OBJECTIVE: To correlate placental histopathology, in particular ischemic changes, with the clinical severity of preeclampsia. DESIGN: A blinded retrospective study. SETTING: One Swedish hospital. SAMPLE: One hundred and fifty-seven women with severe (n= 116) or mild (n= 41) preeclampsia and 157 normotensive women matched according to gestational-age. METHODS: One senior pathologist, blinded to clinical data and group, examined all histological slides. In the statistical analyses, adjustment for gestational week was done when appropriate. MAIN OUTCOME MEASURES: Placental histopathological findings. RESULTS: Amount of infarction increased with the severity of preeclampsia (p < 0.001). Infarction involving ≥5% of the placental tissue was seen in 39.7% of severe preeclampsia, 17.1% of mild preeclampsia and 5.1% of non-preeclampsia. When comparing placentas in severe preeclampsia, mild preeclampsia and non-preeclampsia, there was an increase in the presence of any infarction (80.2%, 61.0%, vs. 20.4%). Also, there was a difference in the presence of decidual arteriopathy (35.3%, 22.0%, vs. 3.8%) and accelerated villous maturation (71.6%, 53.3%, vs. 12.6%). We found no difference in intervillous thrombosis, abruption placenta or placental weight in relation to gestational week. CONCLUSIONS: In pregnancies with mild or severe preeclampsia, a large proportion of the placentas had histological signs of pathology, in particular signs of ischemia. The pathology was similar, but more pronounced in severe compared to mild preeclampsia, suggesting mild and severe preeclampsia to have similar underlying etiology.

The number of CD68(+) (Hofbauer) cells is decreased in placentas with chorioamnionitis and with advancing gestational age.

Hofbauer cells are placental macrophages found in chorionic villous stroma; they express classic monocyte/macrophage markers, such as CD68. Little is known about their participation in placental disease and immunologic interactions at the placental interface. The aim of this study was to quantify the amount of Hofbauer cells in placentas complicated, or not, by chorioamnionitis and in placentas from different gestational ages. Fifty-eight 2nd- and 3rd-trimester placentas with the histologic diagnosis of acute chorioamnionitis were compared with 42 control placentas matched according to gestational age. Immunohistochemistry evaluation was performed with a monoclonal anti-CD68 antibody. Five areas of each placenta were photographed and 5 investigators, with the help of a computerized image analysis program, independently evaluated the number of CD68(+) cells. Our results showed that there are significantly fewer CD68(+) cells per villous area in placentas diagnosed with chorioamnionitis than in those of controls (P < 0.001). Moreover, there was a significant overall decrease in the number of these cells in 3rd as compared with 2nd trimester placentas (P  =  0.02), as well as in placentas from term as compared to preterm pregnancies (P  =  0.004). Our data indicate that CD68(+) Hofbauer cells may be involved in placental infection and possibly associated with the developmental maturation of the fetoplacental unit.

Severe preeclampsia with and without HELLP differ with regard to placental pathology.

The aim of the present study was to evaluate the histopathology in placentas from patients with severe preeclampsia with and without hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. An additional aim was to compare the prevalence of infants born small for gestational age in the 2 groups. The study is retrospective and includes 178 women who have been diagnosed at the Karolinska University Hospital Huddinge or at the Free University Medical Center between 2000 and 2005 with severe preeclampsia. A total of 96 women had severe preeclampsia without signs of HELLP (preeclampsia group), whereas 82 fulfilled the criteria for having HELLP syndrome (HELLP group). Infarction (P=0.014), intervillous thrombosis (P<0.001), and abruption (P=0.002) were more common in the preeclampsia group than in the HELLP group. There was no statistically significant difference in the frequency of accelerated villous maturation (P=0.61), decidual arteriopathy (P=0.27), or chorioamnionitis (P=0.61). Furthermore, there was a higher mean placental weight, adjusted for gestational age, in the Swedish HELLP material than in the preeclampsia group (P<0.001). Finally, mothers in the preeclampsia group gave birth significantly more often to small for gestational age babies than mothers suffering from HELLP syndrome (P<0.001). The histopathologic profile and the range of placental lesions were partly different in the preeclampsia and HELLP patients. Considering the central role that placenta seems to have in preeclampsia, the present result might suggest that different underlying pathogenetic mechanisms and courses can be in play in patients with preeclampsia and HELLP syndrome.