Women with bipolar disorder (BIP) have a higher risk of developing polyendocrine metabolic ovarian syndrome (PMOS). Shared genetic architecture may underlie this comorbidity. Valproate, a mood-stabilizer commonly used to treat BIP, increases the risk of PMOS. Still, the mechanism underlying PMOS in BIP remains unknown. Here, we aimed to identify genetic variants shared between BIP and PMOS, as well as their interaction with valproate. We used the results of large-scale genome-wide association studies of BIP (41,510 cases and 354,340 controls), and PMOS (3609 cases and 229,788 controls). Using conditional false discovery rate, we discovered genetic variants jointly associated with BIP and PMOS. Gene mapping of identified variants was performed using the Open Targets platforms. We analyzed the tissue-specific expression, interaction with valproate, and involvement in biological pathways of the mapped genes. We identified two loci shared between BIP and PMOS. Among the 10 genes mapped to the locus on chromosome 8:11,444,837-11,463,015, GATA4, NEIL2, and FDFT1 showed expression profiles suggesting their role in the observed comorbidity. Mapped to the locus on chromosome 12:2499,849-2514,270, CACNA1C, FKBP4, DCP1B, and ITFG2 are expressed in both the ovaries and the brain. Valproate interacts with CACNA1C, and CACNA1C is part of biological pathways that also include other genes interacting with valproate. We identified shared genetic underpinnings of BIP and PMOS and highlighted genes that may potentially contribute to the biological mechanisms underlying their comorbidity and to a hypothesized role of valproate in these mechanisms.

Women with bipolar disorder (BIP) have a higher risk of developing polycystic ovary syndrome (PCOS). Shared genetic architecture may underlie this comorbidity. Valproate, a mood-stabilizer commonly used to treat BIP, increases the risk of PCOS. Still, the mechanism underlying PCOS in BIP remains unknown. Here, we aimed to identify genetic variants shared between BIP and PCOS, as well as their interaction with valproate. We used the results of large-scale genome-wide association studies of BIP (41,510 cases and 354,340 controls), and PCOS (3,609 cases and 229,788 controls). Using conditional false discovery rate, we discovered genetic variants jointly associated with BIP and PCOS. Gene mapping of identified variants was performed using the Open Targets platforms. We analyzed the tissue-specific expression, interaction with valproate, and involvement in biological pathways of the mapped genes. We identified two loci shared between BIP and PCOS. Among the 10 genes mapped to the locus on chromosome 8:11455262, GATA4, NEIL2, and FDFT1 showed expression profiles suggesting their role in the observed comorbidity. Mapped to the locus on chromosome 12:2499849, CACNA1C, FKBP4, DCP1B, and ITFG2 are expressed in both the ovaries and the brain. CACNA1C expression is affected by valproate, and CACNA1C plays a role in biological pathways involving other valproate-affected genes. We identified shared genetic underpinnings of BIP and PCOS, and implicated genes which may explain the biological mechanisms of the comorbidity between these disorders and a potential mechanism for the role of valproate.

Background:Postpartum depression (PPD) affects 18% of postpartum women globally. PPD is a heterogeneous condition with diverse presentations, which may differ in underlying etiology, potential outcomes, and optimal treatment. This study aimed to identify and validate PPD subtypes using comprehensive phenotypic and genetic data from a large, nationwide cohort. Methods:In this population-based cohort study, we used data from the Norwegian Mother, Father, and Child Cohort Study and Medical Birth Registry of Norway (MoBa), and applied unsupervised clustering (Uniform Manifold Approximation and Projection [UMAP] + Density-Based Spatial Clustering of Applications with Noise [DBSCAN]) to identify PPD subtypes among 7859 women with PPD (training set n = 5239). All pregnant women in Norway were eligible to enroll in MoBa between Jun 1, 1999 and Dec 31, 2008. Among women with their first recorded pregnancies in MoBa, they were considered to have clinically significant PPD if they scored ≥8 on the 6-item version of the Edinburgh Postnatal Depression Scale (EPDS) (equivalent to ≥11 on the full EPDS) administered at six months after birth. Input variables included psychiatric symptom severity, psychiatric history, trauma history, pain, and substance use. We then characterized clusters and tested associations with perinatal-relevant auxiliary variables and polygenic scores (PGS) for eight psychiatric and neurodevelopmental conditions. Findings were validated in a reserved test set (n = 2620). Findings:Nine clusters were identified in the training set (n = 5239), with seven replicating in the independent test set (n = 2620). Clusters were differentiated by symptom severity, onset timing, trauma history, and pain during pregnancy. In the training set, the cluster with the most severe symptoms was characterized by depression + trauma and comprised 28% [1483/5239] of training sample. This cluster showed marked socioeconomic adversity and elevated genetic risk for psychiatric conditions compared to other clusters (ADHD PGS OR 1.19, 95% CI 1.12-1.28; major depression PGS OR 1.15, 95% CI 1.07-1.23; PTSD PGS OR 1.09, 95% CI 1.02-1.17). In the test set, this cluster also comprised 28% [729/2620] and showed consistent associations with ADHD (OR 1.23, 95% CI 1.12-1.35), major depression (OR 1.09, 95% CI 0.99-1.20), and PTSD (OR 1.17, 95% CI 1.06-1.29). Conversely, the mild PPD cluster (10% [498/5239] of training sample) showed a protective profile (ADHD PGS OR 0.81, 95% CI 0.73-0.90; major depression PGS OR 0.85, 95% CI 0.77-0.94). In the test set, it represented 10% (263/2620), with consistent protective associations for ADHD (OR 0.84, 95% CI 0.72-0.96) and major depression (OR 0.77, 95% CI 0.67-0.89). Two early-onset clusters demonstrated distinct profiles despite similar symptom severity. The cluster characterized as early-onset PPD + pain (6% of training set [310/5239] and 7% of test set [178/2620]) had the highest prevalence of somatic conditions, including migraines (19% [58/310] training; 15% [26/178] test), nausea (47% [144/310] training; 53% [94/178] test), prenatal hospitalization (41% [128/310] training; 35% [62/178] test), and birth by caesarean section (10% [31/310] training; 8% [14/178] test), whereas the cluster characterized as early-onset PPD + anger (6% [307/5239] of training sample; 6% [158/2620] of test sample) showed many fewer physical health burdens. The clusters in the training and testing set had moderate to high concordance (ARI = 0.76 [95% CI 0.74, 0.77], FMI = 0.79 [95% CI 0.77, 0.81]). Interpretation:This study identifies clinically relevant PPD subtypes with distinct genetic and obstetric profiles, highlighting the importance of trauma-informed care, pain management, and holistic obstetric approaches in PPD prevention and treatment. Limitations of this study include reliance on self-reported data, lack of diversity in the genetically homogeneous Norwegian sample, and genetic analyses subject to power constraints, which may limit generalizability and reduce precision of results. Despite these limitations, identification of reproducible subtypes with different risk factors and outcomes provides a framework for developing targeted interventions and advancing precision psychiatry in maternal mental health. Funding:National Institute of Mental Health; National Institute of Child Health and Human Development; MRC Integrative Epidemiology Unit, University of Bristol; European Research Council; Marie Skłodowska-Curie Actions; South-Eastern Norway Regional Health Authority; Research Council of Norway; NordForsk; European Union Horizon 2020; Novo Nordisk Foundation.

OBJECTIVE:Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the pathogenesis of perinatal mood disorders. Further, HPA axis response is known to be blunted during breastfeeding. We hypothesized that 1) postpartum depression/anxiety symptoms would be associated with HPA axis dysregulation, indexed by loss of expected adrenocorticotropic hormone (ACTH)-cortisol coupling, and 2) this association would vary by method of infant feeding. METHODS:Participants (N=222) intending to breastfeed were recruited in their 3rd trimester of pregnancy. During a lab visit at 2 months postpartum, depression and anxiety symptoms were assessed (Beck Depression Inventory score ≥14 and/or Speilberger State-Trait Anxiety Inventory score ≥40). Participants then breast or bottle-fed their infants as they would at home. After a 10-minute rest, participants completed the Trier Social Stress Test (TSST), a standardized stressor involving speech and math tasks. Blood ACTH and cortisol were measured 10 minutes after feeding, during each task, and at 10, 20, and 30 minutes of recovery. Multilevel models evaluated whether coupling of ACTH at time j with cortisol at time j+1 differed between those with and without depression/anxiety symptoms, and whether differences varied by feeding method. RESULTS:Of 205 participants who completed the TSST, 44 had depression/anxiety symptoms at 2-months postpartum. Depression/anxiety symptoms were associated with reduced ACTH-cortisol coupling (adjusted beta: -0.03; p-value: 0.03). Among those who breastfed, those with depression/anxiety showed greater blunting of ACTH-cortisol coupling than those without (adjusted beta: -0.04; p-value: 0.02), while those who bottle-fed had similar coupling patterns regardless of depression/anxiety symptoms (adjusted beta: -0.01; p-value: 0.87). CONCLUSION:HPA axis response was blunted in those with postpartum depression/anxiety symptoms, and blunting varied by method of infant feeding. Findings support HPA axis dysregulation in perinatal mood and anxiety disorders. Future research should explore how method of infant feeding influences the relationship between perinatal mood disorders and HPA axis dysregulation. Elucidating the mechanistic pathways underlying perinatal mood disorders can aid in the development of better diagnostic and treatment strategies.

Objective Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. Study Design We conducted a nested case–control study within the Norwegian Mother, Father and Child Birth Cohort (1999–2008) of 2,596 mother–child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. Results Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01). Conclusion Evidence for gene–smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene–environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures. Key Points

BACKGROUND:The COVID-19 pandemic has created an epidemic of distress-related mental disorders such as depression, while simultaneously necessitating a shift to virtual domains of mental health care; yet, the evidence to support the use of virtual interventions is unclear.OBJECTIVE:The purpose of this study was to evaluate the efficacy of virtual interventions for depressive disorders by addressing three key questions: (1) Does virtual intervention provide better outcomes than no treatment or other control conditions (ie, waitlist, treatment as usual [TAU], or attention control)? (2) Does in-person intervention provide better outcomes than virtual intervention? (3) Does one type of virtual intervention provide better outcomes than another?METHODS:We searched the PubMed, EMBASE, and PsycINFO databases for trials published from January 1, 2010, to October 30, 2021. We included randomized controlled trials of adults with depressive disorders that tested a virtual intervention and used a validated depression measure. Primary outcomes were defined as remission (ie, no longer meeting the clinical cutoff for depression), response (ie, a clinically significant reduction in depressive symptoms), and depression severity at posttreatment. Two researchers independently selected studies and extracted data using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Risk of bias was evaluated based on Agency for Healthcare and Research Quality guidelines. We calculated odds ratios (ORs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes.RESULTS:We identified 3797 references, 24 of which were eligible. Compared with waitlist, virtual intervention had higher odds of remission (OR 10.30, 95% CI 5.70-18.60; N=619 patients) and lower posttreatment symptom severity (SMD 0.81, 95% CI 0.52-1.10; N=1071). Compared with TAU and virtual attention control conditions, virtual intervention had higher odds of remission (OR 2.27, 95% CI 1.10-3.35; N=512) and lower posttreatment symptom severity (SMD 0.25, 95% CI 0.09-0.42; N=573). In-person intervention outcomes were not significantly different from virtual intervention outcomes (eg, remission OR 0.84, CI 0.51-1.37; N=789). No eligible studies directly compared one active virtual intervention to another.CONCLUSIONS:Virtual interventions were efficacious compared with control conditions, including waitlist control, TAU, and attention control. Although the number of studies was relatively small, the strength of evidence was moderate that in-person interventions did not yield significantly better outcomes than virtual interventions for depressive disorders.

The COVID-19 pandemic has been particularly difficult for mothers. Women with a history of peripartum depression (PPD) may be vulnerable to relapse. We sought to understand changes in depressive and anxious symptoms throughout the pandemic and which stressors increased symptoms in women with a history of PPD. In June 2020, all US participants with a history of PPD ( n = 12,007) in the global MomGenes Fight PPD study were invited to the COVID-19 follow-up study. Respondents ( n = 2163, 18%) were sent biweekly and then monthly surveys until January 31, 2022. We employed time-varying effects models to evaluate trajectories of depressive (patient health questionnaire, PHQ-9) and anxious (generalized anxiety disorder, GAD-7) symptoms and to estimate longitudinal associations between perceived stress, fears, COVID-19 case rates, and symptoms. Peaks of PHQ-9, GAD-7, PSS, and perceived COVID-19 risk scores corresponded with timing of national COVID-19 case surges. High perceived stress was the strongest predictor of PHQ-9 (beta = 7.27; P = 1.48e − 38) and GAD-7 (beta = 7.73; P = 6.19e − 70). Feeling lack of control and unlikely to survive increased PHQ-9 and GAD-7 scores by 2 points. COVID-19 case rates, pandemic restrictions, and region were not independently associated with symptoms. This study suggests that the collective trauma of the pandemic has significantly affected mothers with a history of PPD, exemplified by high levels of perceived stress and the strong association with depressive and anxious symptoms. The next pandemic phase is uncertain, but will continue to influence mental health collectively and dynamically. Interventions must be flexible and responsive and should address fear, trauma, and feelings of control, particularly for mothers with a history of PPD.

Preeclampsia is a heterogeneous disease characterized by new onset of hypertension along with signs of organ damage, affects 2% to 8% of pregnancies, and can result in serious complications to the mother and her child. There is little empirical evidence on the clinical importance of differences in blood pressure trajectories over the course of pregnancy, particularly in pregnancies affected by preeclampsia. We undertook an investigation of longitudinal changes in gestational blood pressure in a nested case-control study of preeclampsia in MoBa (Norwegian Mother, Father and Child Cohort Study). We included 1906 validated preeclampsia cases and 1413 validated controls. We derived blood pressure trajectory clusters using longitudinal k-means clustering and examined demographic and early-pregnancy predictors and birth outcomes, in relation to clusters. Maternal age, prepregnancy body mass index, and parity were substantially different across blood pressure clusters of cases. Pregnancy outcomes, including preterm birth, small for gestational age, and birthweight Z score, were meaningfully worse for individuals with a more rapid increase in blood pressure, as well as for individuals with a high starting blood pressure. For example, risk of preterm birth was 11-fold to 35-fold higher for steep and high trajectory clusters, and risk of small for gestational age was 2-fold higher compared with the reference cluster. Future studies may leverage these trajectories to differentiate preeclampsia cases in relation to circulating biomarkers, which may help in the development of preeclampsia prediction tools.

This review article highlights the current state of perinatal depression (PND) research including established standards of care and innovative research in progress. PND can have a significant adverse impact on mother, child, and family; however, to date, wide‐scale identification, prevention, and treatment have been limited. PND is heterogenous in presentation with likely multifactorial etiologies for each woman. Challenges in PND research are discussed including a need for universal tools, standardized measures, benchmarks, and best practices. Current examples are reviewed that highlight approaches to novel treatment paradigms and interventions. This includes reviewing epidemiologic studies in PND research, examining the biological underpinnings of PND, and discussing examples from this field and other fields currently developing translational research that spans from bench to bedside. Current and future challenges and opportunities in developing best practices for the treatment of PND are outlined. We also discuss the use of the NIMH Research Domain Criteria approach for PND research and provide recommendations for future directions in PND research collaboration. In conclusion, greater precision in perinatal psychiatry can be possible in the future with the development of guidelines and best practices that build on current work and apply innovative and collaborative approaches of scientists, providers, patients, community members, and government officials.

HPA axis dysregulation has been implicated in the pathogenesis of perinatal mood and anxiety disorders. We hypothesized that perinatal depression and anxiety would be associated with HPA axis dysregulation, indexed by loss of expected associations in adrenocorticotropic (ACTH)-cortisol (CRT) coupling. Women intending to breastfeed were recruited in the 3rd trimester of pregnancy. Past or current depression or anxiety disorders were assessed by Structured Clinical Interview at enrollment. Dyads attended a lab visit at 2 months postpartum, where depression (Beck Depression Inventory ≥14) and anxiety (Speilberger State-Trait Anxiety Inventory ≥40) were assessed. Following peripheral IV placement, women chose to breast or bottle-feed their infants, as they would at home. After a 10-minute post-feed rest, women participated in the Trier Social Stress Test (TSST), a standardized social stressor that includes a speech and a math task. Blood samples for ACTH and CRT were collected 10 minutes after feeding, during each task, and at 10, 20, and 30 minutes of recovery. Multilevel models were used to evaluate whether coupled ACTH at time j with CRT at time j+1 differed between women with depression or anxiety and without. A total of 222 women were enrolled; 205 completed the TSST and had measured ACTH and CRT. Of these, 79 had active prenatal depression or anxiety, 60 had a lifetime history, and 66 had no evidence of mood disorder. Prenatal psychopathology (active/history/none) was associated with ACTH-CRT coupling response (p= < 0.01); ACTH-CRT coupling slope was reduced in both active prenatal mood disorder and lifetime history of mood disorder compared with women with no evidence of mood disorders (figure). ACTH-CRT coupling did not differ by either depression symptoms (p=0.09) or anxiety symptoms (p=0.17) at 2 months. HPA axis response was blunted among women with prenatal active or lifetime history of depression or anxiety. These findings support HPA axis dysregulation in perinatal mood disorders, but future research should further examine timing and type of symptoms.

Both oxytocin and depression have been shown to blunt the HPA axis response to stressors. We aimed to determine whether postpartum depression symptoms, infant feeding, and their interaction are associated with HPA axis dysregulation, indexed by loss of expected associations in adrenocorticotropic (ACTH)-cortisol (CRT) coupling. Women intending to breastfeed were recruited in the 3rd trimester of pregnancy, oversampling for past or current anxiety/depression. At 2 months postpartum, dyads attended a lab visit. Following peripheral IV placement, women chose to breast or bottle-feed their infants, as they would at home. After a 10-minute post-feed rest, women participated in the Trier Social Stress Test (TSST), a standardized social stressor that includes a speech and a math task. Blood samples for ACTH and CRT were collected 10 minutes after feeding, during each task, and at 10, 20, and 30 minutes of recovery. Multilevel models were used to evaluate whether associations between ACTH at time j and CRT at time j+1 differed between women with or without current depression symptoms (Beck Depression Inventory ≥14 vs. < 14) and infant feeding type (breast vs. bottle). A total of 222 women were enrolled; 205 completed the 2 month visit, and 165 breastfed before the TSST (80.5%). Breastfeeding women had lower ACTH (p=0.01) and CRT (p=0.02) than bottle-feeding women, but no differences in ACTH-CRT coupling (p=0.15). ACTH (p=0.37), CRT (p=0.93), and ACTH-CRT coupling (p=0.09) were similar in women with and without depression symptoms. There was a significant interaction (p=0.03) between depression symptoms and infant feeding on ACTH-CRT coupling. Symptomatic women who breastfed had lower ACTH-CRT coupling responses compared with those who bottle-fed, but there were no differences by feeding in asymptomatic women (figure). We found that breastfeeding blunted HPA axis response only among women with depression symptoms but not among women without. The influence of breastfeeding and oxytocin on HPA axis reactivity may play a role in the pathophysiology of perinatal mood disorders.

Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 ( n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery ( n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02–1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81–1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19–1.74) and without (OR, 1.88; 95% CI: 1.26–2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.

This study aimed to quantify the relationship between postpartum depression and anxiety, oxytocin, and breastfeeding. We conducted a longitudinal prospective study of mother-infant dyads from the third trimester of pregnancy to 12 months postpartum. A sample of 222 women were recruited to complete the Beck Depression Inventory II and Spielberger State-Trait Anxiety Inventory-state subscale, participate in observed infant feeding sessions at 2 and 6 months postpartum, and provide venous blood samples during feeding. Maternal venous oxytocin levels in EDTA-treated plasma and saliva were determined by enzyme immunoassay with extraction and a composite measure of area under the curve (AUC) was used to define oxytocin across a breastfeeding session. Linear regression was used to estimate associations between postpartum depression and anxiety as predictors and oxytocin AUC during breastfeeding as the outcome at both 2 and 6 months postpartum. Mixed models accounting for correlations between repeated oxytocin measures were used to quantify the association between current depression and/or anxiety symptoms and oxytocin profiles during breastfeeding. We found no significant differences in oxytocin AUC across a feed between depressed or anxious women and asymptomatic women at either 2 or 6 months postpartum. Repeated measures analyses demonstrated no differences in oxytocin trajectories during breastfeeding by symptom group but possible differences by antidepressant use. Our study suggests that external factors may influence the relationship between oxytocin, maternal mood symptoms, and infant feeding.

OBJECTIVE:To estimate the proportion of women for whom use of hormonal contraception was associated with reporting a decreased breast milk supply. STUDY DESIGN:The Lactational Effects of Contraceptive Hormones: an Evaluation ("LECHE") Study was an anonymous, internet-based, exploratory, cross-sectional survey of postpartum women using approximately 70 questions. Women were eligible to participate in the survey if they were 18 years or older, had a singleton infant between 3 and 9 months of age, had breastfed this infant for any amount of time and could read English. The survey included questions about breastfeeding, reproductive health, demographic characteristics and the timing of postpartum events. RESULTS:A total of 3971 participants clicked on the survey. Our final study population included 2922 participants. Overall, 1201 (41%) reported having had milk supply concerns at some point in the first 12 weeks postpartum. The median time from birth until milk supply concerns was 3 weeks (IQR 1-7). Eight hundred fifty-two women (29%) started hormonal contraception in the first 12 weeks postpartum. Fifteen percent (127/852) of women reported new or additional milk supply concerns after starting hormonal contraception. Reported milk supply concerns were higher for women who used hormonal contraception than those who did not (44% vs. 40%; p=.05) Adjusted hazard ratios (HRs) assessing the association between contraceptive use and time to milk supply concerns were not statistically significant (HR 1.18, 95% confidence interval 0.94-1.47 for any type of hormonal contraception). CONCLUSIONS:This study found a slightly increased proportion of reported milk supply concerns among women who started hormonal contraception. IMPLICATIONS:It is important for caregivers in the postpartum period to recognize the potential for multiple factors, including initiation of hormonal contraception, to affect breastfeeding. Patient-centered counseling can help elicit women's values and preferences regarding breastfeeding and pregnancy prevention.

As researchers and consultants, we have spent the last few years helping a dozen major public and private organizations understand what went wrong with their strategic planning. We discovered that executives have a hard time with strategy because they are at a loss when the time comes to engage in strategic dialogue. Either their teams debate the organization’s values and goals when such issues should be settled, or they waste time on the details of specific projects that have yet to receive the green light. But whether the conversation is too broad or too narrow, strategy stays out of view. Drawing on recent developments in strategy-as-practice and decision-making literature, we propose a model that executives can follow to take control of strategy meetings and keep their teams on track. We ask them to focus on the right decision purpose, adjust the meeting’s communication style, and cast the right leader for the job. When these three simple rules are followed, the pillars of successful dialogue are aligned, and executives can finally talk about what matters most to them: strategy.

OBJECTIVE:To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia. DESIGN:One and two sample mendelian randomisation analyses. SETTING:Two European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study). PARTICIPANTS:7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis. EXPOSURES:Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables. MAIN OUTCOME MEASURES:Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy. RESULTS:In the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia: odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L. CONCLUSIONS:No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.

BACKGROUNDPreeclampsia is thought to originate during placentation, with incomplete remodelling and perfusion of the spiral arteries leading to reduced placental vascular capacity. Nitric oxide (NO) and carbon monoxide (CO) are powerful vasodilators that play a role in the placental vascular system. Although family clustering of preeclampsia has been observed, the existing genetic literature is limited by a failure to consider both mother and child.METHODSWe conducted a nested case-control study within the Norwegian Mother and Child Birth Cohort of 1545 case-pairs and 995 control-pairs from 2540 validated dyads (2011 complete pairs, 529 missing mother or child genotype). We selected 1518 single-nucleotide polymorphisms (SNPs) with minor allele frequency >5% in NO and CO signalling pathways. We used log-linear Poisson regression models and likelihood ratio tests to assess maternal and child effects.RESULTSOne SNP met criteria for a false discovery rate Q-value <0.05. The child variant, rs12547243 in adenylate cyclase 8 (ADCY8), was associated with an increased risk (relative risk [RR] 1.42, 95% confidence interval [CI] 1.20, 1.69 for AG vs. GG, RR 2.14, 95% CI 1.47, 3.11 for AA vs. GG, Q = 0.03). The maternal variant, rs30593 in PDE1C was associated with a decreased risk for the subtype of preeclampsia accompanied by early delivery (RR 0.45, 95% CI 0.27, 0.75 for TC vs. CC; Q = 0.02). None of the associations were replicated after correction for multiple testing.CONCLUSIONSThis study uses a novel approach to disentangle maternal and child genotypic effects of NO and CO signalling genes on preeclampsia.

•DAGs are a tool to reduce bias, improve transparency, and increase precision.•An example from addiction research illustrates the benefits of a DAG approach.•DAGs allow researchers to communicate assumptions regarding causal concepts.