Contraceptive efficacy of a depot progestin and androgen combination in men

WHO studies provided proof of concept for hormonal male contraception using a prototype androgen-alone regimen. Combined testosterone plus progestin regimens offer more practical promise, but no contraceptive efficacy studies have been completed. The objective of this study was to establish the proof of principle for depot hormonal androgen/progestin combination as a male contraceptive. We performed a contraceptive efficacy study of 55 healthy men in stable fertile relationships seeking a change in contraceptive method. Testosterone (four 200-mg implants, every 4 or 6 months) and 300 mg depot medroxyprogesterone acetate, im, every 3 months were administered. Once sperm output was suppressed (<1 million/ml for 2 consecutive months), men entered a 12-month contraceptive efficacy period, ceasing other contraception. The main outcome measure was contraceptive failure (pregnancy) rate. No pregnancies occurred in 426 person-months (35.5 person-years; 95% confidence limits for contraceptive failure rate, 0-8%/annum), superior to the first year failure rate of condoms, the only reversible male method. Sperm density fell rapidly, so 94% of men entered the efficacy phase by 3 months, with only 2 of 55 (3.6%) men not sufficiently suppressed to enter efficacy. A few men treated with testosterone implants at 6-month intervals demonstrated androgen deficiency symptoms and/or escape of gonadotropin and spermatogenic suppression between months 5 and 6; after a protocol amendment, all men receiving testosterone implants at 4-month intervals avoided androgen deficiency or loss of gonadotropin and sperm output suppression. Recovery was complete (median, 3.6 months to sperm reappearance and 5.0 months to 20 million sperm/ml) in all but one man with an incidental testicular disorder. Discontinuations were for protocol-related reasons (n = 15) or altered personal circumstances (n = 12), but there were no serious adverse effects related to drug exposure. The first male contraceptive efficacy study using a prototype depot androgen/progestin combination demonstrates high contraceptive efficacy with satisfactory short-term safety and recovery of spermatogenesis. Further studies of purpose-developed products are required to extend the overall safety and efficacy experience with depot androgen/progestin combinations, the most promising approach to hormonal male contraception.     

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions—phenotypically and genetically—although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.The set of conditions diagnosed as autism spectrum disorders (ASDs) vary enormously in their presentation (1). The most severely impaired individuals—often those with intellectual disabilities, limited speech, and severe behavioral problems—can require lifelong care. At the other end of the functional spectrum, people diagnosed with ASDs can be verbally fluent and academically gifted and can achieve independence in adulthood (2, 3). The broad range of cognitive and behavioral profiles seen in diagnosed ASDs has been long viewed as a challenge by the research community (4). Although it is well established that (i) the cognitive/behavioral profile of people diagnosed with ASDs varies widely and (ii) the set of genetic factors related to ASDs varies widely (5, 6), the degree to which phenotype can be used to predict patterns in disease architecture remains unclear.Recent insights into the genetic influences on ASDs offer an opportunity to investigate this question through the lens of de novo vs. familial effects. On average, ASDs run in families. The siblings of children with ASDs are 10–20 times more likely to receive a diagnosis of ASD themselves (7, 8); the parents of children with ASDs are more likely to manifest autistic features, as well as a variety of other neuropsychiatric conditions, such as schizophrenia and bipolar disorder (9, 10). These epidemiologic observations are consistent with analyses suggesting that ASDs are influenced by thousands of common genetic variants transmitted between generations. It has been estimated that common, genotyped SNPs account for 20–60% of variation in ASD risk, although the effect of any individual SNP is likely very small (11–13). Many of these influences are shared with other psychiatric disorders (12, 14), which at least in part explains the familial clustering of different types of behavior problems.However, statistics about ASD heritability reflect an average. For example, there are likely many affected families for whom sibling recurrence risk is less than 10–20%. The strongest evidence toward this claim comes from studies of rare, severely deleterious genetic events that are associated with ASDs (15–20). Events of this type, for example copy number variants and loss of function (LOF) mutations, are often de novo (not seen in an affected individual’s parents). Although cases of ASDs involving a de novo mutation could reflect a concert of spontaneous and inherited genetic events, de novo events of large effect may reduce the likelihood of seeing psychiatric problems in an affected individual’s family members.     

Seroprevalence of Seven Zoonotic Pathogens in Pregnant Women from the Caribbean

Studies examining the prevalence of zoonotic agents in the Caribbean are very limited. The objective of this study was to examine the seroprevalence of seven zoonotic agents among individuals residing on 10 English-speaking Caribbean countries. Sera from healthy, pregnant women were collected from Antigua-Barbuda, Belize, Bermuda, Dominica, Grenada, Jamaica, Montserrat, St. Kitts-Nevis, St. Lucia, and St. Vincent-Grenadines and tested for the presence of IgG antibodies to dengue virus, hepatitis E virus, hantaviruses, leptospiral agents, spotted fever group rickettsiae (SFGR), typhus group rickettsiae (TGR), and Coxiella burnetii (Q fever). The highest seroprevalence values were observed for dengue virus, SFGR, and leptospirosis, although the lowest seroprevalence values were observed for hepatitis E virus, C. burnetii, and TGR. Antibodies to hantaviruses were not detected in any individuals.     

The impact of interpregnancy weight change on perinatal outcomes in women and their children: A systematic review and meta‐analysis

Prepregnancy overweight and obesity are associated with higher risk of perinatal complications. However, the effect of weight change prior to pregnancy on perinatal outcome is largely unknown. Therefore, it is aimed to examine the impact on perinatal outcomes of interpregnancy BMI change in women of different BMI categories. The MEDLINE, EMBASE, LILACS, and CINAHL databases were searched (1990‐August 2019). Observational studies on interpregnancy BMI change were selected. Outcomes evaluated were gestational diabetes mellitus (GDM), preeclampsia, gestational hypertension (GH), cesarean section, preterm birth, and newborns being large (LGA) or small (SGA) for gestational age. Meta‐analyses and meta‐regression analyses were executed. Thirty studies were included (n > 1 million). Interpregnancy BMI gain was associated with a higher risk of GDM (for BMI gain ≥3 kg/m²: OR 2.21; [95%CI 1.53‐3.19]), preeclampsia (1.77 [1.53‐2.04]), GH (1.78 [1.61‐1.97]), cesarean section (1.32 [1.24‐1.39]), and LGA (1.54 [1.28‐1.86]). The effects of BMI gain were most pronounced in women with BMI <25 kg/m² before the first pregnancy regarding GDM, GH, and cesarean section. Except for LGA, interpregnancy BMI loss did not result in a decreased risk of perinatal complications. In this study, women of normal weight who gain weight before pregnancy were identified as a high‐risk population for perinatal complications. This emphasizes that weight management is important for women of all BMI categories and a pregnancy wish.