First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study.

BACKGROUND: Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage. METHODS: We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995-2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications. RESULTS: ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20). CONCLUSION: We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.

Childhood Adversity and Incident Psychotic Experiences in Early Adulthood: Cognitive and Psychopathological Mediators.

BACKGROUND AND HYPOTHESIS: Childhood adversity is often described as a potential cause of incident psychotic experiences, but the underlying mechanisms are not well understood. We aimed to examine the mediating role of cognitive and psychopathological factors in the relation between childhood adversity and incident psychotic experiences in early adulthood. STUDY DESIGN: We analyzed data from the Avon Longitudinal Study of Parents and Children, a large population-based cohort study. Childhood adversity was measured prospectively from birth to age 11 years, mediators (anxiety, depression, external locus of control [LoC], negative symptoms) were assessed at approximately 16 years of age, and incident psychotic experiences were assessed at ages 18 and 24 years. Mediation was examined via the counterfactual g-computation formula. STUDY RESULTS: In total, 7% of participants had incident suspected or definite psychotic experiences in early adulthood. Childhood adversity was related to more incident psychotic experiences (ORadjusted = 1.34, 95% CI = 1.21; 1.49), and this association was partially mediated via all mediators examined (proportion mediated: 19.9%). In separate analyses for each mediator, anxiety, depression, external LoC, and negative symptoms were all found to mediate the link between adversity and incident psychotic experiences. Accounting for potential confounders did not modify our results. CONCLUSIONS: Our study shows that cognitive biases as well as mood symptomatology may be on the causal pathway between early-life adversity and the development of psychotic experiences. Future studies should determine which mediating factors are most easily modifiable and most likely to reduce the risk of developing psychotic experiences.

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study.

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics.

Bias amplification of unobserved confounding in pharmacoepidemiological studies using indication-based sampling.

PURPOSE: Estimating causal effects in observational pharmacoepidemiology is a challenging task, as it is often plagued by confounding by indication. Restricting the sample to those with an indication for drug use is a commonly performed procedure; indication-based sampling ensures that the exposed and unexposed are exchangeable on the indication-limiting the potential for confounding by indication. However, indication-based sampling has received little scrutiny, despite the hazards of exposure-related covariate control. METHODS: Using simulations of varying levels of confounding and applied examples we describe bias amplification under indication-based sampling. RESULTS: We demonstrate that indication-based sampling in the presence of unobserved confounding can give rise to bias amplification, a self-inflicted phenomenon where one inflates pre-existing bias through inappropriate covariate control. Additionally, we show that indication-based sampling generally leads to a greater net bias than alternative approaches, such as regression adjustment. Finally, we expand on how bias amplification should be reasoned about when distinct clinically relevant effects on the outcome among those with an indication exist (effect-heterogeneity). CONCLUSION: We conclude that studies using indication-based sampling should have robust justification - and that it should by no means be considered unbiased to adopt such approaches. As such, we suggest that future observational studies stay wary of bias amplification when considering drug indications.

Childhood Trauma As a Mediator of the Association Between Autistic Traits and Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children Cohort.

BACKGROUND: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. STUDY DESIGN: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. STUDY RESULTS: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. CONCLUSIONS: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study.

BACKGROUND: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. METHODS: We used data from a UK-based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising 7689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age-adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder-adjusted regression models. Multiple imputation was used to account for missing data, and restricted cubic splines were used to investigate nonlinear associations. Mendelian randomization was used to strengthen causal inference. RESULTS: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR = 0.98, 95% CI = 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR = 0.99, 95% CI = 0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR = 1.08, 95% CI = 0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. LIMITATIONS: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. CONCLUSIONS: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

Mode of delivery and maternal sexual wellbeing: A longitudinal study.

OBJECTIVES: To investigate the association between mode of delivery and subsequent maternal sexual wellbeing. DESIGN: Prospective birth cohort study. SETTING: Avon (in Bristol area), UK. POPULATION: Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: Mode of delivery was abstracted from obstetric records and sexual wellbeing measures were collected via a self-report questionnaire. Missing data were imputed using multiple imputation, and ordinal logistic regression models for ordered categorical outcomes were adjusted for the covariates maternal age at delivery, pre-pregnancy body mass index, diabetes during pregnancy, socio-economic position, parity, depression and anxiety. MAIN OUTCOME MEASURES: Sexual enjoyment and frequency at four time points postpartum (between 33 months and 18 years) and two types of sex-related pain (pain in the vagina during sex and elsewhere after sex) at 11 years postpartum. RESULTS: We found no association between mode of delivery and sexual enjoyment (e.g. adjusted odds ratio [OR] 1.11, 95% confidence interval [95% CI] 0.97-1.27 at 33 months) or sexual frequency (OR 0.99, 95% CI 0.88-1.12 at 33 months). Caesarean section was associated with an increased odds of pain in the vagina during sex at 11 years postpartum as compared with vaginal delivery in the adjusted model (OR 1.74, 95% CI 1.46-2.08). CONCLUSIONS: These findings provide no evidence supporting associations between caesarean section and sexual enjoyment or frequency. However, mode of delivery was shown to be associated with dyspareunia, which may not be limited to abdominal scarring.

Maternal smoking and smokeless tobacco use during pregnancy and offspring development: sibling analysis in an intergenerational Swedish cohort.

BACKGROUND: The association between maternal smoking in pregnancy and offspring intellectual disability (ID) is less well understood than that of smoking and fetal growth restriction. As fetal growth and cognitive development may share similar confounding structures, comparison of the two associations may improve understanding of the causal nature of the association with ID. Furthermore, comparisons of smoking with smokeless tobacco use may aid identification of mechanisms of action. METHODS: This was a cohort study of all Swedish births between 1999 and 2012 (n = 1 070 013), with prospectively recorded data. We assessed the association between maternal smoking during pregnancy and offspring outcomes ID and born small for gestational age (SGA). Analyses were repeated for snus use in pregnancy. Using a sibling design, we estimated within-family effects that control for shared sibling characteristics. RESULTS: Those exposed to maternal smoking in pregnancy had increased odds of ID [odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.16-1.33] and SGA (OR = 2.19, 95% CI: 2.11-2.27) after confounder adjustment. Within-family effects were found for SGA (OR = 1.44, 95% CI: 1.27-1.63) but not ID (OR = 0.92, 95% CI: 0.74-1.14). For snus use, the results for ID were similar to smoking. We found increased odds of offspring SGA among mothers who used snus in pregnancy in sensitivity analyses but not in primary analyses. CONCLUSIONS: Our findings are consistent with a causal effect of maternal smoking in pregnancy on risk of offspring born SGA but not on risk of ID. We found no evidence for a causal effect of snus use in pregnancy on ID and inconclusive evidence for SGA.

Intellectual disability in the children of the Avon Longitudinal Study of Parents and Children (ALSPAC).

Background: Intellectual disability (ID) describes a neurodevelopmental condition involving impaired cognitive and functional ability. Here, we describe a multisource variable of ID using data from the Avon Longitudinal Study of Parents and Children (ALSPAC).  Methods: The multisource indicator variable for ID was derived from i) IQ scores less than 70 measured at age 8 and at age 15, ii) free text fields from parent reported questionnaires, iii) school reported provision of educational services for individuals with a statement of special educational needs for cognitive impairments, iv) from relevant READ codes contained in GP records, iv) international classification of disease diagnoses contained in electronic hospital records and hospital episode statistics and v) recorded interactions with mental health services for ID contained within the mental health services data set. A case of ID was identified if two or more sources indicated ID. A second indicator, labelled as "probable ID", was created by relaxing the cut off in IQ scores to be less than 85. An indicator variable for known causes of ID was also created to aid in aetiological studies where ID with a known cause may need to be excluded.  Results: 158 of 14,370 participants (1.10%) were indicated as having ID by two or more sources and 449 (3.12%) were indicated as having probable ID when the criteria for IQ scores was relaxed to less than 85. There were 476 participants (3.31%) with 1 or fewer sources of available information on ID; these participants had their multisource variable set to missing. The number of cases of ID with known cause was 31 (0.22% of the cohort, 19.6% of those with ID).   Conclusions: The multisource variable of ID can be used in future analyses on ID in ALSPAC children.

Maternal smoking during pregnancy and offspring intellectual disability: sibling analysis in an intergenerational Danish cohort.

BACKGROUND: Maternal smoking has known adverse effects on fetal development. However, research on the association between maternal smoking during pregnancy and offspring intellectual disability (ID) is limited, and whether any associations are due to a causal effect or residual confounding is unknown. METHOD: Cohort study of all Danish births between 1995 and 2012 (1 066 989 persons from 658 335 families after exclusions), with prospectively recorded data for cohort members, parents and siblings. We assessed the association between maternal smoking during pregnancy (18.6% exposed, collected during prenatal visits) and offspring ID (8051 cases, measured using ICD-10 diagnosis codes F70-F79) using logistic generalised estimating equation regression models. Models were adjusted for confounders including measures of socio-economic status and parental psychiatric diagnoses and were adjusted for family averaged exposure between full siblings. Adjustment for a family averaged exposure allows calculation of the within-family effect of smoking on child outcomes which is robust against confounders that are shared between siblings. RESULTS: We found increased odds of ID among those exposed to maternal smoking in pregnancy after confounder adjustment (OR 1.35, 95% CI 1.28-1.42) which attenuated to a null effect following adjustment for family averaged exposure (OR 0.91, 95% CI 0.78-1.06). CONCLUSIONS: Our findings are inconsistent with a causal effect of maternal smoking during pregnancy on offspring ID risk. By estimating a within-family effect, our results suggest that prior associations were the result of unmeasured genetic or environmental characteristics of families in which the mother smokes during pregnancy.

Caesarean section and its relationship to offspring general cognitive ability: a registry-based cohort study of half a million young male adults.

BACKGROUND: A relationship between caesarean section and offspring cognitive ability has been described, but data are limited, and a large-scale study is needed. OBJECTIVE: To determine the relationship between mode of delivery and general cognitive ability. METHODS: A cohort of 579 244 singleton males, born between 1973 and 1987 who conscripted before 2006, were identified using the Swedish population-based registries. Their mode of delivery was obtained from the Swedish Medical Birth registry. The outcome measure was a normalised general cognitive test battery (mean 100, SD 15) performed at military conscription at around age 18. FINDINGS: Males born by caesarean section performed poorer compared with those born vaginally (mean score 99.3 vs 100.1; adjusted mean difference -0.84; 95% CI -0.97 to -0.72; p<0.001). Both those born by elective (99.3 vs 100.2; -0.92; 95% CI -1.24 to -0.60; p<0.001) and non-elective caesarean section (99.2 vs 100.2; -1.03; 95% CI -1.34 to -0.72; p=0.001), performed poorer than those born vaginally. In sibling analyses, the association was attenuated to the null (100.9 vs 100.8; 0.07; 95% CI -0.31 to 0.45; p=0.712). Similarly, neither elective nor non-elective caesarean section were associated with general cognitive ability in sibling analyses. CONCLUSION: Birth by caesarean section is weakly associated with a lower general cognitive ability in young adult males. However, the magnitude of this association is not clinically relevant and seems to be largely explained by familial factors shared between siblings. CLINICAL IMPLICATION: Clinicians and gravidas ought not to be concerned that the choice of mode of delivery will impact offspring cognitive ability.

Association of maternal pre-pregnancy BMI and breastfeeding with NAFLD in young adults: a parental negative control study.

BACKGROUND: The importance of the maternal-infant dyad in the genesis of nonalcoholic fatty liver disease (NAFLD) is of increasing interest. The Avon Longitudinal Study of Parents and Children (ALSPAC) showed that at age 24, 1 in 5 had NAFLD measured by transient elastography and controlled attenuation parameter (CAP). Our aim was to investigate the association between breastfeeding duration and maternal pre-pregnancy BMI on offspring NAFLD in young adulthood. METHODS: 4021 participants attended clinic for FibroScan and CAP measurement using Echosens 502 Touch®. 440 participants with Alcohol Use Disorders were excluded. Offspring of 100 non-singleton pregnancies were excluded. 2961 valid CAP measurements for NAFLD were analysed. Exposures of interest were breastfeeding of any duration, ≥6months exclusive breastfeeding, and maternal pre-pregnancy BMI. Multivariable regression models estimated the odds of NAFLD at 24 years. We performed a paternal negative control test to explore residual confounding in the analyses of pre-pregnancy BMI. FINDINGS: There was a modest inverse association of exclusive and non-exclusive breastfeeding ≥6 months having a protective effect on NAFLD in offspring (OR 0·92 [95%CI 0·66-1·27] and OR 0·90 [0·67-1·21] respectively).The odds of offspring NAFLD in overweight pre-pregnancy maternal BMI and paternal BMI was OR 2·09 [1·62-2·68] and OR 1·33 [95%CI 1·07-1·65] respectively, with the ratio of effect sizes OR 1·57 [1·11-2·22]. Similarly, odds of offspring NAFLD with obese pre-pregnancy maternal BMI and paternal BMI was OR 2·66 [1·71-4·14] and OR 1·35 [0·91-2·00] respectively, with the ratio of effect sizes OR 1·98 [1·05-3·74]. INTERPRETATION: Higher maternal pre-pregnancy BMI was associated with offspring NAFLD, having accounted for shared parental confounding. We did not replicate previous work that found a strong association between breastfeeding and NAFLD. FUNDING: Medical Research Council UK, Alcohol Research UK, David Telling Charitable Trust.

Childhood trauma and cognitive biases associated with psychosis: A systematic review and meta-analysis.

Childhood trauma is associated with an increased risk of psychosis, but the mechanisms that mediate this relationship are unknown. Exposure to trauma has been hypothesised to lead to cognitive biases that might have causal effects on psychotic symptoms. The literature on whether childhood trauma is associated with psychosis-related cognitive biases has not been comprehensively reviewed. A systematic review and meta-analysis or narrative synthesis of studies examining the association between childhood trauma and the following biases: external locus of control (LOC), external attribution, probabilistic reasoning, source monitoring, top-down processing, and bias against disconfirmatory evidence. Studies were assessed for quality, and sources of heterogeneity were explored. We included 25 studies from 3,465 studies identified. Individuals exposed to childhood trauma reported a more external LOC (14 studies: SMD Median = 0.40, Interquartile range 0.07 to 0.52), consistent with a narrative synthesis of 11 other studies of LOC. There was substantial heterogeneity in the meta-analysis (I2 = 93%) not explained by study characteristics examined. Narrative syntheses for other biases showed weaker, or no evidence of association with trauma. The quality of included studies was generally low. Our review provides some evidence of an association between childhood trauma and a more external LOC, but not with the other biases examined. The low quality and paucity of studies for most of the cognitive biases examined highlights the need for more rigorous studies to determine which biases occur after trauma, and whether they mediate an effect of childhood trauma on psychosis.

Familial confounding of the association between maternal smoking in pregnancy and autism spectrum disorder in offspring.

Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991-2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism - no ADHD, 2,205 autism + ID, and 11,342 autism - no ID. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13-1.22]) but attenuated in the maternal cluster (0.98 [0.88-1.09]) and sibling (0.86 [0.64-1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2020, 13: 134-144. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Smoking during pregnancy has many harmful impacts, which may include harming the baby's developing brain. However, in a study of thousands of families in Denmark, it does not appear that smoking in pregnancy leads to autism or autism in combination with intellectual problems or attention deficits, once you account for the way smoking patterns and developmental disabilities run in families.

Simulations and directed acyclic graphs explained why assortative mating biases the prenatal negative control design.

OBJECTIVE: The negative control design can be used to provide evidence for whether a prenatal exposure-outcome association occurs by in utero mechanisms. Assortative mating has been suggested to influence results from negative control designs, although how and why has not yet been adequately explained. We aimed to explain why mutual adjustment of maternal and paternal exposure in regression models can account for assortative mating. STUDY DESIGN AND SETTING: We used directed acyclic graphs to show how bias can occur when modeling maternal and paternal effects separately. We empirically tested our claims using a simulation study. We investigated how increasing assortative mating influences the bias of effect estimates obtained from models that do and do not use a mutual adjustment strategy. RESULTS: In models without mutual adjustment, increasing assortative mating led to increased bias in effect estimates. The maternal and paternal effect estimates were biased by each other, making the difference between them smaller than the true difference. Mutually adjusted models did not suffer from such bias. CONCLUSIONS: Mutual adjustment for maternal and paternal exposure prevents bias from assortative mating influencing the conclusions of a negative control design. We further discuss issues that mutual adjustment may not be able to resolve.

The proportion of missing data should not be used to guide decisions on multiple imputation.

OBJECTIVES: Researchers are concerned whether multiple imputation (MI) or complete case analysis should be used when a large proportion of data are missing. We aimed to provide guidance for drawing conclusions from data with a large proportion of missingness. STUDY DESIGN AND SETTING: Via simulations, we investigated how the proportion of missing data, the fraction of missing information (FMI), and availability of auxiliary variables affected MI performance. Outcome data were missing completely at random or missing at random (MAR). RESULTS: Provided sufficient auxiliary information was available; MI was beneficial in terms of bias and never detrimental in terms of efficiency. Models with similar FMI values, but differing proportions of missing data, also had similar precision for effect estimates. In the absence of bias, the FMI was a better guide to the efficiency gains using MI than the proportion of missing data. CONCLUSION: We provide evidence that for MAR data, valid MI reduces bias even when the proportion of missingness is large. We advise researchers to use FMI to guide choice of auxiliary variables for efficiency gain in imputation analyses, and that sensitivity analyses including different imputation models may be needed if the number of complete cases is small.