Does Presymptomatic Treatment of Spinal Muscular Atrophy Improve Outcomes?  

BACKGROUND AND PURPOSE: 

  • Biallelic SMN1 deletions and three SMN2 copies usually leads to the development of spinal muscular atrophy (SMA) type 2 in childhood 
  • Onasemnogene abeparvovec is gene replacement therapy  
    • Delivers SMN cDNA using an adeno-associated virus-9 (AAV9) vector 
    • Single IV infusion  
  • Strauss et al. (Nature Medicine, 2022) investigated the efficacy and safety of onasemnogene abeparvovec treatment for pre-symptomatic children with SMA type 2 

METHODS: 

  • Open-label, single-arm, Phase III study  
    • 16 sites in 6 countries 
  • Participants 
    • Infants identified with SMA through newborn screening  
    • Normal neuromuscular function who were able to swallow and breathe normally 
  • Intervention 
    • Onasemnogene abeparvovec 
  • Study design 
    • Single infusion over 60 minutes  
    • Multiple outpatient assessment visits through 24 months of age  
  • Primary outcome 
    • Independent standing, for at least 3 seconds at any visit up to 24 months of age 
  • Secondary outcome 
    • Walking independently, for at least five steps at any visit up to 24 months of age 

RESULTS: 

  • 15 children | 9 female  
    • Median gestational age at birth: 39 weeks 
    • Median weight: 3.4 kg  
    • Median age at time of molecular confirmation: 8 days  
  • At screening, all children had normal neuromuscular function 
  • Standing independently at 24 months (P<0.0001) 
    • Treatment group: 100% (14 occurred within normal developmental window) 
    • Natural history population: 24% 
  • Walking independently at 24 months (P<0.0001)  
    • Treatment group: 93% 
    • Natural history population: 21% 
  • All children survived without permanent ventilation at 14 months 
  • Maintained body weight (≥3rd WHO percentile) without feeding support through 24 months: 67% 
  • No children required nutritional or respiratory support 
  • There were no serious adverse events that were treatment-related 

CONCLUSION: 

  • For asymptomatic infants with SMA type 2, onasemnogene abeparvovec was effective and safe 
  • Most treated children were able to sit and walk independently at 24 months of age 
  • The authors state 

Given the durability of benefit observed in the follow-up study of the Phase I START trial, and the fact that motor neurons are non-dividing cells, we are optimistic that one-time treatment with onasemnogene abeparvovec will add years of independent mobility, intact bulbar function, and good health-related quality of life for children in the three-copy cohort 

Learn More – Primary Sources: 

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial

Meta-Analysis: Idiopathic Polyhydramnios and Adverse Pregnancy Outcomes

BACKGROUND AND PURPOSE:

  • Pagan et al. (Ultrasound in Obstetrics & Gynecology, 2022) analyzed pregnancy outcomes in singleton pregnancies with idiopathic polyhydramnios

METHODS:

  • Systematic review and meta-analysis
  • Study Inclusion criteria
    • Prospective and retrospective studies
    • Presence of a control group (normal amniotic fluid volume)
    • Singleton pregnancies
    • Idiopathic polyhydramnios: Identified using sonographic amniotic fluid volume assessment
  • Study design
    • Polyhydramnios definition: Four-quadrant AFI with polyhydramnios ≥24 cm or single deepest pocket (SDP) ≥8 cm | AFI >25 cm also included (commonly used definition)
    • Idiopathic polyhydramnios: No etiology identified on ultrasound
    • Effect estimates expressed as odds ratio (OR) and its corresponding 95% CI
    • Data pooled using random effects model
  • Primary outcome
    • Intrauterine fetal demise
  • Secondary outcomes
    • NICU admission
    • Macrosomia: ≥4000 g birthweight
    • 5 minute APGAR score <7
    • Neonatal death
    • Low birthweight
    • Malpresentation
    • Cesarean delivery

RESULTS:

  • 12 studies
    • Idiopathic polyhydramnios patients: 2392 | Controls: 160,135
  • Pregnancies complicated by idiopathic polyhydramnios had higher odds of
    • Neonatal death: OR 8.68 (95% CI, 2.91 to 25.87)
    • Intrauterine fetal demise: OR 7.64 (95% CI, 2.50 to 23.38)
    • NICU admission: OR 1.94 (95% CI, 1.45 to 2.59)
    • 5-minute APGAR score <7: OR 2.21 (95% CI, 1.34 to 3.62)
    • Macrosomia: OR 2.93 (95% CI, 2.39 to 3.59)
    • Malpresentation: OR 2.73 (95% CI, 2.06 to 3.61)
    • Cesarean delivery: OR 2.31 (95% CI, 1.79 to 2.99)

CONCLUSION:

  • Pregnancies with idiopathic polyhydramnios are associated with increased odds of adverse pregnancy outcomes, particularly neonatal death and intrauterine fetal demise
  • Antenatal fetal surveillance may be a consideration for pregnancies with idiopathic polyhydramnios
  • The authors state

Currently, there is insufficient data on the threshold of the AFV (mild, moderate or severe) at which antenatal testing should be initiated

Future investigations are needed to determine an AFV threshold above which antenatal testing would be helpful

Learn More – Primary Sources:

Idiopathic polyhydramnios and pregnancy outcomes: systematic review and meta-analysis

RCT Results: Does Relugolix Combined with Estradiol and Progestin Improve Endometriosis Pain While Preserving Bone Mineral Density?

BACKGROUND AND PURPOSE:

  • Relugolix is an oral gonadotropin-releasing hormone receptor antagonist
    • Combined with estradiol and a progestin to limit hot flashes and maintain bone mineral density
  • Giudice et al. (The Lancet, 2022) evaluated the efficacy and safety of relugolix combined with estradiol and a progestin for the treatment of endometriosis-related pain

METHODS:

  • Two phase 3, multicenter, randomized, double-blind, placebo-controlled trials
  • Participants
    • Women 18 to 50 years
    • Multicenter: Africa | Australasia | Europe | North America | South America
    • Women had either
      • Surgically or directly visualized endometriosis with or without histological confirmation
      • Endometriosis with histological diagnosis alone
    • Eligible women had
      • Moderate to severe endometriosis-associated pain during the 35-day run-in period
      • Dysmenorrhea Numerical Rating Scale (NRS) score of ≥4.0 on two or more days
      • Mean non-menstrual pelvic pain NRS score of ≥2.5 or a mean score of ≥1.25 that included a score of ≥5 on ≥4 days
  • Interventions
    • Once-daily relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg) for 24 weeks
    • Delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks)
    • Placebo
  • Study design
    • Randomization 1:1:1
    • Efficacy and safety were analyzed in the modified intent-to-treat population
    • Post-treatment follow-up for safety, specifically for bone mineral density and menses recovery, is ongoing at the time of publication
  • Primary outcomes
    • Responder rates at week 24 for dysmenorrhea and non-menstrual pelvic pain

RESULTS:

  • SPIRIT 1: 638 patients | SPIRIT 2: 623 patients
  • Dysmenorrhea responder criteria was significantly improved with combination therapy
    • SPIRIT 1
      • Relugolix combination therapy: 75%
      • Placebo: 27%
      • Treatment difference 47.6% (95% CI, 39.3 to 56.0); p<0.0001
    • SPIRIT 2
      • Relugolix combination therapy: 75%
      • Placebo: 30%
      • Treatment difference 44.9% (95% CI, 36.2 to 53.5); p<0.0001
  • Non-menstrual pain was significantly improved with combination therapy
    • SPIRIT 1
      • Relugolix combination therapy: 58%
      • Placebo: 40%
      • Treatment difference 18.9% (95% CI, 9.5 to 28.2); p<0.0001
    • SPIRIT 2
      • Relugolix combination therapy: 66%
      • Placebo: 43%
      • Treatment difference 23.4% (95% CI, 13.9 to 32.8); p<0.0001
  • Delayed relugolix combination was also associated with pain improvement (p<0.0001 for treatment difference vs placebo)    
    • Dysmenorrhea
      • SPIRIT 1: 72%
      • SPIRIT 3: 73%
    • Non-menstrual pelvic pain
      • SPIRIT 1: 58%
      • SPIRIT 2: 53%
  • Most common adverse events
    • Headache
    • Nasopharyngitis
    • Hot flushes
  • There were nine reports of suicidal ideation across both studies
    • Placebo run-in: 2 reports
    • Placebo: 2
    • Relugolix combination therapy: 2
    • Delayed relugolix combination therapy: 3
  • There were no deaths
  • Bone mineral density loss in the relugolix combination therapy groups was higher than in placebo, but was less than 1% in both studies
    • SPIRIT 1
      • Relugolix combination therapy: –0.70%
      • Delayed relugolix combination: –2.0%
      • Placebo: 0.21%
    • SPIRIT 2
      • Relugolix combination therapy: –0.78%
      • Delayed relugolix combination: –1.9%
      • Placebo: 0.02%
  • Decreases in opioid use were seen in treated patients as compared with placebo

CONCLUSION:

  • Endometriosis-associated pain was significantly improved with relugolix combination therapy
    • The combination therapy was well tolerated, with minimal bone mineral density losses, and mostly minor adverse side effects
  • Combination therapy may allow for long-term treatment that does not rely on opioid use or repeat surgical intervention
  • The authors state

The combination of relugolix, estradiol, and norethisterone acetate might provide the therapeutic benefits of GnRH receptor antagonism to suppress endogenous oestradiol concentrations and improve symptoms of endometriosis while minimising the risk of hypoestrogenic-related bone loss and vasomotor symptoms, potentially enabling long-term use

Learn More – Primary Sources:

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2)

Does Genetic Testing for Familial Hypercholesterolemia Improve Disease Detection vs Clinical Features Alone?

BACKGROUND AND PURPOSE:

  • Heterozygous familial hypercholesterolemia (FH) is a common, heritable disorder that causes premature cardiovascular disease
  • Despite the genetic basis of FH, there is no national screening program in the US to identify individuals with pathogenic or likely pathogenic variants
  • Bellows et al. (Journal of the American Heart Association) sought to determine if using genetic testing would enhance screening methods based on clinical factors only

METHODS:

  • Population
    • UK Biobank participants
  • Exposures
    • Clinical characteristics
    • FH variant status
  • Study design
    • A regression model to predict the probability of having any FH variants was developed using participant exposure statuses
    • The regression model and modified Dutch Lipid Clinic Network criteria were applied to adult participants in the National Health and Nutrition Examination Survey (NHANES) to estimate the yield of FH screening programs using
      • Dutch Lipid Clinic Network clinical criteria alone (no genetic variant status)
      • Genetic testing alone
      • Combining clinical criteria with genetic testing
  • Primary outcomes
    • Accuracy of regression model
    • Yield of potential FH screening programs

RESULTS:

  • 49,738 UK Biobank participants used for regression model generation | 39,790 participants in NHANES used to estimate yield of screening
  • The regression model accurately predicted FH variant status in UK Biobank participants
    • Observed prevalence: 0.27%
    • Predicted prevalence: 0.26%
    • Area under the receiver-operator characteristic (ROC) curve: 0.88
  • In NHANES, estimated yield per 1000 individuals screened
    • With Dutch Lipid Clinic Network clinical criteria alone
      • 3.7 cases (95% CI, 3.0 to 4.6)
    • With genetic testing alone
      • 3.8 cases (95% CI, 2.7 to 5.1)
    • With combination of clinical criteria with genetic testing
      • 6.6 cases (95% CI, 5.3 to 8.0)
  • In young adults 20 to 39 years
    • Clinical criteria alone: Estimated to yield 1.3 FH cases per 1000 people screened (95% CI, 0.6 to 2.5)
    • Addition of genetic testing: Estimated to increase to 4.2 FH cases (95% CI, 2.6 to 6.4)

CONCLUSION:

  • Combining genetic screening with clinical criteria may improve detection of FH, increasing opportunities for early treatment
  • The authors state

Targeted screening strategies, such as offering genetic testing to adults with an LDL‐C ≥160 mg/dL or adults aged 20 to 39 years, may increase screening yield, and could allow for earlier identification and treatment of FH

Learn More – Primary Sources:

Estimated Yield of Screening for Heterozygous Familial Hypercholesterolemia With and Without Genetic Testing in US Adults

RCT Results: Is the Mediterranean Diet or a Low-Fat Diet Better for Secondary Prevention of Cardiovascular Disease?

BACKGROUND AND PURPOSE:

  • Mediterranean and low-fat diets are both protective against cardiovascular disease (CVD)
    • Whether these diets are also effective at secondary prevention of CVD, and whether one diet is better than the other, is understudied
  • Delgado-Lista et al. (The Lancet, 2022) performed a long-term randomized trial to compare the effects of these two diets in secondary prevention of CVD

METHODS:

  • Single-center, randomized clinical trial
    • The CORDIOPREV study
  • Participants
    • Patients with established coronary heart disease
    • 20 to 75 years
  • Interventions
    • Mediterranean diet
    • Low-fat diet
  • Study design
    • Follow-up: 7 years
    • Clinical investigators were masked to treatment assignment, but participants were not
    • Analysis was by intention to treat
  • Primary outcome
    • Composite of major cardiovascular events
      • Myocardial infarction | Revascularization | Ischemic stroke | Peripheral artery disease | Cardiovascular death

RESULTS:

  • Low-fat diet: 500 participants | Mediterranean: 502 participants
    • Mean age: 59.5 years | 82.5% men
  • There was a higher incidence of the primary outcome in the participants assigned to the low-fat diet
    • Mediterranean: 28.1 per 1000 person-years (95% CI, 27.9 to 28.3)
    • Low-fat: 37.7 per 1000 person-years (95% CI, 37.5 to 37.9)
    • Log-rank p=0.039
  • Adjusted hazard ratios (HRs) of the different models favored the Mediterranean diet
    • Range: 0.719 (95% CI, 0.541 to 0.957) to 0.753 (95% CI, 0.568 to 0.998)
  • These effects were more pronounced in men
    • Mediterranean: 16.2% experienced primary outcome
    • Low-fat: 22.8% experienced primary outcome
    • Multi-adjusted HR 0.669 (95% CI, 0.489 to 0.915); log-rank p=0.013
  • In women, no difference was found between groups

CONCLUSION:

  • For the secondary prevention of CVD, a Mediterranean diet was more effective than a low-fat diet
  • Inability to find a difference among women may be due to study being underpowered in the female group or there is a sex factor difference in dietary response
  • The authors state

In summary, the CORDIOPREV study reports that a Mediterranean diet is superior to a low-fat diet in preventing major cardiovascular events in secondary prevention of cardiovascular disease

Learn More – Primary Sources:

Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial

RCT Results: Does Tirzepatide Improve Weight Reduction in the Setting of Obesity?

BACKGROUND AND PURPOSE:

  • Tirzepatide is a once-weekly subcutaneous injectable peptide that may improve weight reduction in people with obesity
    • Tirzepatide targets two nutrient-stimulated hormone receptors that regulate energy homeostasis in the body
  • Jastreboff et al. (NEJM, 2022) evaluated the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes

METHODS:

  • Phase 3 double-blind, randomized, controlled trial
  • Participants
    • Adults with either
      • BMI ≥30
      • BMI ≥27 and at least one weight-related complication, excluding diabetes
  • Interventions
    • Once-weekly, subcutaneous tirzepatide for 72 weeks at
      • 5 mg
      • 10 mg
      • 15 mg
    • Placebo
  • Study design
    • Randomization: 1:1:1:1
    • There was a 20-week dose-escalation period
    • Intention-to-treat population: Effects assessed regardless of treatment discontinuation
  • Primary outcomes
    • Percentage change in weight from baseline
    • Weight reduction ≥5%

RESULTS:

  • 2539 participants
    • Mean body weight at baseline: 104.8 kg
    • Mean BMI at baseline: 38.0
    • BMI ≥30: 94.5%
  • Compared to placebo, the mean percentage change in weight at week 72 was greater with all dosages (P<0.001)
    • 5-mg doses: −15.0% (95% CI, −15.9 to −14.2)
    • 10-mg doses: −19.5% (95% CI, −20.4 to −18.5)
    • 15-mg doses: –20.9% (95% CI, −21.8 to −19.9)
    • Placebo: −3.1% (95% CI, −4.3 to −1.9)
  • Percentage of participants who had weight reduction of ≥5% (P<0.001 for all comparisons with placebo)
    • 5-mg doses: 85% (95% CI, 82 to 89)
    • 10-mg doses: 89% (95% CI, 86 to 92)
    • 15-mg doses: 91% (95% CI, 88 to 94)
    • Placebo: 35% (95% CI, 30 to 39)
  • Percentage of participants with a reduction in body weight of ≥20% (P<0.001 for all comparisons with placebo)
    • 10-mg doses: 50% (95% CI, 46 to 54)
    • 15-mg doses: 57% (95% CI, 53 to 61)
    • Placebo: 3% (95% CI, 1 to 5)
  • Tirzepatide led to improvements in all prespecified cardiometabolic measures
  • Most common adverse events were gastrointestinal
    • Most were mild to moderate in severity
  • Adverse events causing treatment discontinuation
    • 5-mg doses: 4.3%
    • 10-mg doses: 7.1%
    • 15-mg doses: 6.2%
    • Placebo: 2.6%

CONCLUSION:

  • For patients with obesity, tirzepatide, at doses of 5-mg, 10-mg and 15-mg, improved body weight reduction vs placebo
  • The authors state

This is an unusually substantial degree of weight reduction in response to an antiobesity medication as compared with findings reported in other phase 3 clinical trials

Given that tirzepatide is both a GIP receptor and GLP-1 receptor agonist, we speculate that there may be additive benefit in targeting multiple endogenous nutrient-stimulated hormone pathways that have been implicated in energy homeostasis

Learn More – Primary Sources:

Tirzepatide Once Weekly for the Treatment of Obesity

RCT Results: Would Double Dosing Emergency Oral Contraceptives Improve Outcomes in Those with Obesity?

BACKGROUND AND PURPOSE:

  • Obesity is a risk factor for emergency contraception failure
  • Edelman et al. (Obstetrics & Gynecology, 2022) assessed whether doubling the dose of emergency levonorgestrel (LNG)-containing oral contraception improves pharmacodynamic outcomes in individuals with obesity

METHODS:

  • Randomized controlled trial
  • Participants
    • 18 to 35 years
    • Regular menstrual cycles (21 to 35 days)
    • BMI >30
    • Weight ≥176 lbs
  • Interventions
    • Single dose: 1.5 mg LNG
    • Double dose: 3 mg LNG
  • Study design
    • Ovulation was confirmed in all participants (luteal progesterone level >3 ng/mL)
    • Participants were monitored with transvaginal ultrasonography and blood sampling for progesterone, LH, and estradiol every other day
    • Intervention provided at the point when a dominant follicle ≥15 mm was identified
    • Daily monitoring for up to 7 days
  • Power analysis
    • 80% power to detect a 30% difference in the proportion of cycles with at least a 5 day delay in follicle rupture (50% decrease)
    • 5% significance level
    • Sample size calculation: 70 participants (taking into account potential drop out)
  • Primary outcome
    • Difference in the proportion of participants with no follicle rupture 5 days postdosing between groups

RESULTS:

  • 70 total participants
    • Mean age 28 years | Mean BMI 38
  • No difference seen in the proportion of participants without follicle rupture more than 5 days post–LNG dosing between the groups
    • LNG 1.5 mg: 51.4%
    • LNG 3.0 mg: 68.6%
    • P=0.14
  • Among participants with follicle rupture before 5 days, the time to rupture did not differ between groups
  • The day at which there was a 75% probability of no rupture is day 2 for both groups

CONCLUSION:

  • Doubling the dose of LNG-based emergency oral contraceptive did not improve rate of ovulation inhibition in participants with obesity, suggesting that double dosing would not improve outcomes in this population
  • Limitations of this study include ovulation inhibition being used as a proxy for ovulation | Actual outcome of interest would be pregnancy rate
  • The authors state

Our results do not support a recommendation of double dosing of LNG for emergency contraception in individuals with obesity

Clinical studies suggest that emergency contraception with LNG does not work in women who weigh more than 70 kg, but that ulipristal acetate appears effective

Learn More – Primary Sources:

Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial

Meta-Analysis: Azithromycin vs Erythromycin for PPROM

BACKGROUND AND PURPOSE:

  • Seaman et al. (AJOG, 2022) estimated the effect of erythromycin vs azithromycin on the latency and the rate of clinical chorioamnionitis in women with PPROM

METHODS:

  • Systematic review and meta-analysis
  • Study inclusion criteria
    • Studies comparing duration of latency and the rate of clinical chorioamnionitis in the setting of PPROM
    • Patients treated with erythromycin and azithromycin
  • Study design
    • Mean differences and odds ratios (OR) with 95% confidence intervals were estimated for outcomes
    • Results pooled using random effects model
    • Chorioamnionitis diagnosis: ≥2 of the following signs and symptoms
      • Temperature ≥38°C | Uterine tenderness | Maternal tachycardia | Fetal tachycardia | Leukocytosis
  • Primary outcomes
    • Mean length of latency
    • Rate of clinical chorioamnionitis

RESULTS:

  • 5 studies | 1289 women
  • Mean length of latency in women with PPROM was similar between individuals treated with erythromycin and azithromycin
    • Erythromycin: 6.6 days
    • Azithromycin: 6.7 days
    • Mean difference 0.07 days (95% CI, −0.45 to 0.60)
  • Median point prevalence rates of clinical chorioamnionitis
    • Erythromycin: 25% (95% CI, 12 to 32)
    • Azithromycin: 14% (95% CI, 9 to 24)
  • The overall clinical chorioamnionitis rate in women treated with azithromycin was lower than women treated with erythromycin
    • Pooled OR: 0.53 (95% CI, 0.39 to 0.71)
  • Neonatal outcomes were similar between groups for the following
    • Neonatal sepsis | RDS | Perinatal death

CONCLUSION:

  • Treating PPROM with azithromycin and erythromycin results in similar latency period
  • There was a lower rate of chorioamnionitis with azithromycin treatment
  • Limitations of the study include lack of any trials that randomized patients to one macrolide antibiotic vs the other
  • The authors state

Organizations involved in national guideline development weighing the harms and benefits in the context of the current strength of evidence available may consider revising the existing recommendation for the use of the macrolide erythromycin with PPROM to allow alternative macrolide regimens

However, until the result of prospective RCTs currently ongoing are available, contemporary guidelines recommend using erythromycin concurrently with a beta-lactam antibiotic unless erythromycin is unavailable, or the patient does not tolerate its administration 

Learn More – Primary Sources:

Erythromycin vs azithromycin for treatment of preterm prelabor rupture of membranes: a systematic review and meta-analysis

More Evidence: Is Prenatal Antiseizure Medication Exposure Linked to Childhood Neurodevelopmental Impairment?

BACKGROUND AND PURPOSE:

  • Bjørk et al. (JAMA Neurol, 2022) assessed whether prenatal antiseizure medication (ASM) is associated with increased risk for neurodevelopmental disorders

METHODS:

  • Population-based cohort study
    • Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED)
  • Population
    • Mother-child pairs in Denmark, Finland, Iceland, Norway, and Sweden
    • From 1996 to 2017
  • Exposure
    • Prenatal exposure to ASM: Derived from maternal prescription fills
  • Study design
    • Cox proportional hazards regression was used to generate hazard ratios (HR), with adjustment for potential confounders
  • Primary outcome
    • Cumulative incidence of neurodevelopmental disorders at age 8 years in exposed and unexposed children
      • Autism spectrum disorder (ASD)
      • Intellectual disability (ID)
      • Any neurodevelopmental disorder (ASD and/or ID)

RESULTS:

  • 4,494,926 mother-child pairs
    • 50.3% male, median (IQR) age at end of follow-up: 8 (4.0 to 12.1) years
  • Neurodevelopmental disorders were more likely in children whose mothers had epilepsy and were taking ASM, compared to children whose mothers had epilepsy but were not taking ASM
    • No exposure
      • ASD diagnosis: 1.5%
      • ID diagnosis: 0.8%
    • Topiramate monotherapy
      • ASD: 4.3%
        • aHR 2.8 (95% CI, 1.4 to 5.7)
      • ID: 3.1%
        • aHR 3.5 (95% CI, 1.4 to 8.6)
    • Valproate monotherapy
      • ASD: 2.7%
        • aHR 2.4 (95% CI, 1.7 to 3.3)
      • ID: 2.4%
        • aHR 2.5 (95% CI, 1.7 to 3.7)
  • Some duotherapies were also associated with increased risks of neurodevelopmental disorders in children of women with epilepsy
    • Levetiracetam with carbamazepine
      • 8-year cumulative incidence: 5.7%
      • aHR 3.5 (95% CI, 1.5 to 8.2)
    • Lamotrigine with topiramate
      • 8-year cumulative incidence: 7.5%
      • aHR 2.4 (95% CI, 1.1 to 4.9)
  • Evetiracetam with lamotrigine was not associated with an increased risk of neurodevelopmental disorders
    • 8-year cumulative incidence: 1.6%
    • aHR 0.9 (95% CI, 0.3 to 2.5)

CONCLUSION:

  • This study demonstrates significant associations between certain prenatal antiseizure medications and neurodevelopmental disorders in offspring
    • Associations persisted after adjusting for confounding factors
  • The authors state

…prenatal exposure to topiramate and valproate was associated with a risk of ASD and ID, which increased with higher doses

ASM duotherapies, except lamotrigine with levetiracetam, were similarly associated with neurodevelopmental disorders 

Learn More – Primary Sources:

Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability

Meta-analysis: Estrogen-Containing Contraceptives and VTE Recurrence

BACKGROUND AND PURPOSE:

  • Wiegers et al. (Journal of Thrombosis and Haemostasis, 2022) determined the rate of recurrent VTE after discontinuation of anticoagulant treatment in women with a first episode of VTE related to estrogen-containing contraceptives

METHODS:

  • Systematic review and meta-analysis
  • Study inclusion criteria
    • Prospective and retrospective studies
    • Studies that reported on recurrence after a first VTE (DVT or PE) related to estrogen-containing contraceptives | Mean age <50 years
    • Focus on combined oral estrogen-containing contraceptives and estrogen-containing vaginal patches or rings
    • Patients completed ≥3 months of anticoagulant treatment
  • Study design
    • Recurrence rates per 100 patient-years
    • Data pooled using random-effects model
    • Incidence rates were reported separately based on
      • Study follow-up duration (≤1 year, 1 to 5 years, and >5 years)
      • Subgroup analyses
  • Primary Outcome
    • VTE Recurrence rates

RESULTS:

  • 14 studies
  • Pooled recurrence rate
    • 1.57 per 100 patient-years (95% CI, 1.10 to 2.23)
  • Recurrence rate by follow-up duration
    • ≤1 year follow-up
      • 2.73 per 100 patient-years (95% CI, 0.00 to 3643)
    • 1 to 5 years of follow-up
      • 1.35 per 100 patient-years (95% CI, 0.68 to 2.68)
    • >5 years of follow-up
      • 1.42 per 100 patient-years (95% CI, 0.84 to 2.42)

CONCLUSION:

  • Risk of VTE recurrence after a primary VTE incident related to estrogen-containing contraception appears to be low
    • The authors suggest that short-term anticoagulation is the favorable treatment option
  • Limitations of this study include insufficient data to determine the impact of different formulations and types of estrogen-containing contraceptives | Large prospective studies are needed
  • The authors state

The risk of VTE recurrence in women with estrogen-containing contraceptives appears to be low, which supports short-term anticoagulation for 3–6 months after VTE related to estrogen-containing contraceptives

However, data and contributing risk factors for this specific patient population are limited and strong recommendations about duration of anticoagulants cannot be made

Learn More – Primary Sources:

Risk of recurrence in women with venous thromboembolism related to estrogen-containing contraceptives: Systematic review and meta-analysis

What is the Live Birth Rate After Oocyte Cryopreservation?

BACKGROUND AND PURPOSE:

  • Data are limited regarding live birth rate following oocyte cryopreservation
  • Cascante et al. (Fertility and Sterility, 2022) reviewed outcomes of patients who underwent autologous oocyte thaw after planned oocyte cryopreservation

METHODS:

  • Retrospective cohort study
  • Population
    • All patients who underwent ≥1 autologous oocyte thaw before December 2020
  • Primary outcome
    • Final live birth rate (FLBR) per patient
  • Inclusion: Patients who had a live birth or consumed all remaining oocytes or embryos
  • Secondary outcomes
    • Laboratory outcomes
    • Live birth rates per transfer

RESULTS:

  • 543 patients | 800 ooctye cryopreservations | 605 thaws | 436 transfers
    • Median age at first cryopreservation: 38.3 years
    • Median time between first cryopreservation and thaw: 4.2 years
    • The median numbers of thawed
      • Oocytes: 14 per patient
      • Metaphase II oocytes (M2s): 12 per patient
    • Overall survival of all thawed oocytes: 79%
    • Patients who underwent ≥1 transfer: 61%
    • Usable embryos derived from
      • Thawed M2s: 25%
  • Live birth rates
    • For euploid transfers (n=262): 55%
    • For nonbiopsied transfers (n=158): 31%
  • FLBR per patient: 39%
  • Age at cryopreservation and the number of M2s thawed were predictive of live birth
    • The FLBR per patient was >50% for patients aged <38 years at cryopreservation or who thawed ≥20 M2s

CONCLUSION:

  • For patients who underwent transfer of autologous thawed oocytes, the final live birth rate was 39%
    • Comparable to the final live birth rate with age-matched IVF
  • Limitation of this study includes small sample size | Analyses in larger cohorts are necessary
  • The authors state

This study is the largest US report of thaw outcomes from OC performed for age-related fertility decline and provides important insight into OC outcomes

Our results provide realistic expectations for those considering OC and demonstrate that OC empowers women with reproductive autonomy

Learn More – Primary Sources:

Fifteen years of autologous oocyte thaw outcomes from a large university-based fertility center