Bifurcation and sensitivity analysis reveal key drivers of multistability in a model of macrophage polarization.

In this paper, we present and analyze a mathematical model for polarization of a single macrophage which, despite its simplicity, exhibits complex dynamics in terms of multistability. In particular, we demonstrate that an asymmetry in the regulatory mechanisms and parameter values is important for observing multiple phenotypes. Bifurcation and sensitivity analyses show that external signaling cues are necessary for macrophage commitment and emergence to a phenotype, but that the intrinsic macrophage pathways are equally important. Based on our numerical results, we formulate hypotheses that could be further investigated by laboratory experiments to deepen our understanding of macrophage polarization.

Thyroid hormone replacement therapy in pregnancy and motor function, communication skills, and behavior of preschool children: The Norwegian Mother, Father, and Child Cohort Study.

PURPOSE: Limited research has focused on the association between prenatal thyroid hormone replacement therapy (THRT) and motor function, communication skills, and behavior in preschool children. Here, we estimated the association between THRT during pregnancy and the first trimester and these developmental outcomes. METHODS: This study was based on the Norwegian Mother, Father, and Child Cohort Study (MoBa) and other national registries. We included mother-child pairs exposed to THRT during pregnancy (n = 663), after delivery (n = 728), or unexposed (n = 28 040). Exposure to THRT was defined according to filled prescriptions. Child outcomes, presented as T-score differences, were parent-reported using the Ages and Stages Questionnaire, Strengths and Difficulties Questionnaire, and Child Behavior Checklist. RESULTS: Of 29 431 mother-child pairs, 2.3% were prenatally exposed to THRT. We found no difference between prenatally exposed and unexposed children in regards to gross motor function (ß: 0.17, 95% CI -1.19, 1.54), fine motor function (ß: -0.17, 95% CI -1.14, 0.80), communication (ß: -0.31, 95% CI -1.58, 0.96), externalizing (ß: -0.03, 95% CI -1.07, 1.01), internalizing (ß: 0.89, 95% CI -0.20, 1.97), or social behaviors (ß: -0.04, 95% CI -0.92, 0.84). Somatic complaints were higher in THRT-exposed children (ß: 0.98, 95% CI 0.08, 1.87), and children whose mothers were exposed after delivery had more sleep problems than unexposed children (ß: 0.99, 95% CI 0.24, 1.74). CONCLUSIONS: Children prenatally exposed to THRT have developmental outcomes as positive as unexposed children on motor function, communication, and behavior. The association with somatic complaints and sleep were not clinically relevant.

Risk factors for discontinuation of thyroid hormone replacement therapy in early pregnancy: a study from the Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway.

INTRODUCTION: Approximately 3-5% of pregnant women have hypothyroidism. Despite the potential impact of untreated hypothyroidism on infant neurodevelopment, few studies have investigated the risk factors associated with discontinuation of thyroid hormone replacement therapy (THRT) in pregnancy. We aimed to identify such factors in a population of women using THRT prior to pregnancy. MATERIAL AND METHODS: Data from the Norwegian Mother and Child Cohort Study were linked to records in the Medical Birth Registry of Norway. Pregnant women with hypothyroidism prior to pregnancy were categorized as discontinuers or continuers of THRT in pregnancy. The main analysis used generalized estimating equations based on multiply imputed data. RESULTS: Of 86 848 enrolled pregnant women, 2720 (3.2%) had a medically confirmed thyroid disorder and/or reported use of thyroid therapy. More than half (n = 1587; 57.8%) used THRT prior to pregnancy; of these, 207 (13.0%) discontinued and 1380 (86.9%) continued THRT during early pregnancy. Having a non-medicated mental disorder [odds ratio (OR) 1.64, 95% CI 1.03-2.63] and non-compliance with recommended nutritional supplementation (OR 2.51, 95% CI 1.82-3.47) increased the odds of discontinuing THRT. Women medicated for somatic comorbidities (OR 0.56, 95% CI 0.33-0.98) had a 44% decreased odds of discontinuing THRT. CONCLUSIONS: In Norway, around 13% of women with hypothyroidism discontinue THRT in early pregnancy. For discontinuers, non-medicated mental comorbidity and non-compliance with nutritional supplements presented increased risk, whereas having a medicated somatic disorder was protective. Health professionals advising women with hypothyroidism should be aware of risk factors associated with THRT discontinuation.

Maternal Thyroid Hormone Replacement Therapy Exposure and Language and Communication Skills of Offspring at 8 Years of Age.

Importance: Hypothyroidism during pregnancy is associated with neurodevelopmental delays in the offspring. However, it remains unknown whether prenatal thyroid hormone replacement therapy (THRT) has benefits regarding children's language and communication skills. Objective: To quantify associations between prenatal THRT exposure and risk of language impairment diagnosis and parent-reported symptoms of language and communication skill deficits in offspring at 8 years of age. Design, Setting, and Participants: The Norwegian Mother, Father and Child Cohort Study (MoBa), a nationwide population-based cohort study, recruited pregnant women from throughout Norway between June 1999 and December 2008. MoBa was linked to several nationwide registries: the Norwegian Medical Birth Registry, Norwegian Prescription Database, and Norwegian Patient Registry. For this study, the analyzed cohort was restricted to singleton pregnancies resulting in a live-born infant, enrolled in the MoBa between 2005 and 2008. Statistical analysis was performed from January 2 to May 7, 2019. Exposures: In both study samples, mother-child pairs were categorized into 3 mutually exclusive groups: THRT exposure during pregnancy, based on dispensed prescription records; unexposed to THRT during pregnancy (population comparison); and mothers initiating THRT after delivery (THRT after delivery), comprising incident postpartum THRT users. Main Outcomes and Measures: Two defined study samples were analyzed with different outcome measures. In the Norwegian Patient Registry sample, outcome was defined by a diagnosis of language and speech impairment. In the MoBa sample, children were followed up until age 8 years via parental self-completed questionnaires. Hazard ratios were calculated for language impairment diagnosis, estimated by Cox proportional hazards regression. Standardized mean score (ß) was calculated for parent-reported symptoms of language and communication deficits, estimated using generalized linear models. Results: The Norwegian Patient Registry sample included 53 862 mother-child pairs (mean [SD] age, 30.4 [4.6] years; offspring, 26 145 girls and 27 717 boys; 1204 pairs exposed to THRT [2.2%]) and the MoBa sample included 23 686 mother-child pairs (mean [SD] age, 30.8 [4.4] years; offspring, 11 536 girls and 12 150 boys; 532 pairs exposed to THRT [2.2%]). Language and speech impairment diagnosis was not significantly associated with prenatal THRT exposure compared with the unexposed group (adjusted hazard ratio, 0.75; 95% CI, 0.38-1.43) or the THRT after delivery group (adjusted hazard ratio, 0.63; 95% CI, 0.26-1.53). Language outcomes also did not significantly differ between these groups. Conclusions and Relevance: There was no significant difference in child outcomes between children exposed to THRT in the prenatal period compared with children in the population comparison group. These results support current guidelines recommending hypothyroidism treatment during pregnancy. Future research should further examine the use of THRT after delivery or a proper disease comparison group.

Maternal use of thyroid hormone replacement therapy before, during, and after pregnancy: agreement between self-report and prescription records and group-based trajectory modeling of prescription patterns.

PURPOSE: A reliable definition of exposure and knowledge about long-term medication patterns is important for drug safety studies during pregnancy. Few studies have investigated these measures for thyroid hormone replacement therapy (THRT). The purpose of this study was to 1) calculate the agreement between self-report and dispensed prescriptions of THRT and 2) classify women with similar adherence patterns to THRT into disjoint longitudinal trajectories. METHODS: Our analysis used data from the Norwegian Mother and Child Cohort Study (MoBa), a prospective population-based cohort study. MoBa was linked to prescription records from the Norwegian Prescription Database (NorPD). We estimated Cohen's kappa coefficients (k) and approximate 95% CIs for agreement between self-report and prescription records for the 6-month period prior to pregnancy and for each pregnancy trimester. Using group-based trajectory models (GBTMs), we estimated adherence trajectories among women who self-reported and had a THRT prescription. RESULTS: There were 56,148 women in MoBa, who had both a record in NorPD and available prescription history up to 1 year prior to pregnancy. Of these, 1,171 (2.1%) self-reported and received a prescription for THRT. Agreement was "perfect" in the 6-month period prior to pregnancy (k=0.86; CI 0.85-0.88), in the first (k=0.83; CI 0.82-0.85) and in the second trimesters (k=0.89; CI 0.87-0.90), while this was moderate (k=0.57; CI 0.54-0.59) in the third trimester. Among the subset of the 1,171 women, we identified four disjoint GBTM adherence groups: Constant-High (50.2%), Constant-Medium (32.9%), Increasing-Medium (11.0%), and Decreasing-Low (5.8%). CONCLUSION: Agreement between self-report and prescription records was high for THRT in the early pregnancy period. Based on our GBTM results, about one in two women with hypothyroidism had adequate adherence to prescribed THRT throughout pregnancy. Given the potential consequences, evidence of low adherence in 5.8% of pregnant women with hypothyroidism is of concern.