Maternal obesity in pregnancy and children's cardiac function and structure: A systematic review and meta-analysis of evidence from human studies.

The prevalence of obesity is increasing worldwide. Experimental animal studies demonstrate that maternal obesity during pregnancy directly affects cardiac structure and function in their offspring, which could contribute to their increased cardiovascular disease (CVD) risk. Currently, a systematic overview of the available evidence regarding maternal obesity and alterations in cardiac structure and function in human offspring is lacking. We systematically searched the electronic databases Embase, MEDLINE and NARCIS from inception to June 29, 2022 including human studies comparing cardiac structure and function from fetal life onwards in offspring of women with and without obesity. The review protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (identifier: CRD42019125071). Risk of bias was assessed using a modified Newcastle-Ottawa scale. Results were expressed using standardized mean differences (SMD). The search yielded 1589 unique publications, of which thirteen articles were included. Compared to offspring of women without obesity, fetuses of women with obesity had lower left ventricular strain, indicative of reduced systolic function, that persisted in infancy (SMD -2.4, 95% confidence interval (CI) -4.4 standard deviation (SD) to -0.4 SD during fetal life and SMD -1.0, 95% CI -1.6 SD to -0.3 SD in infancy). Furthermore, infants born to women with obesity had a thicker interventricular septum (SMD 0.6 SD, 95% CI 0.0 to 1.2 SD) than children born to women without obesity. In conclusion, cardiac structure and function differs between fetuses and children of women with and without obesity. Some of these differences were present in fetal life, persisted in childhood and are consistent with increased CVD risk. Long-term follow-up research is warranted, as studies in offspring of older age are lacking.

Limited data to evaluate real-world effectiveness of enzyme replacement therapy for mucopolysaccharidosis type I.

Orphan medicinal products (OMPs) are often authorized based on pivotal phase II and III trials that do not always meet high quality criteria. Laronidase is an example of an OMP used for treatment of mucopolysaccharidosis I (MPS I). One randomized controlled trial demonstrated efficacy on several somatic symptoms. However, effectiveness in the real-world setting remains to be determined. We performed a systematic review to evaluate the effectiveness of enzyme replacement therapy (ERT) on clinically relevant outcomes in MPS I. A search in OVID MEDLINE and OVID EMBASE was performed. Postmarketing studies including MPS I patients treated with ERT and reporting data on any of 19 predefined clinical outcome measures obtained before the start of ERT and at follow-up were eligible. Three scenarios were used to define effectiveness of ERT. The first scenario (A) assumes that improvement is essential, while the second scenario (B) also includes stabilization of signs and symptoms. The third scenario (C) defines failure of therapy. Twenty case series were included. The criteria indicating effectiveness (A), were met for four of 19 outcome measures while the criteria, indicating unclear effectiveness (B) were met for five of 19. For one of 19 nonverifiable data were reported and for nine of 19 no overall conclusions could be drawn (ambiguous results). Real-world effectiveness of laronidase is extremely difficult to assess, 15 years after marketing authorization. This is partially due to insufficient natural history data. We recommend the conduct of rigorous and independent postmarketing studies including core outcome sets for OMPs, enforced by marketing and/or reimbursing authorities aiming to demonstrate real-world effectiveness within a reasonable time frame.