Antenatal surveillance of fetal growth is an essential part of good maternity care, as lack of detection of fetal growth restriction is directly associated with stillbirth and perinatal morbidity. New algorithms and guidelines provide care pathways which rely on regular third trimester ultrasound biometry and plotting of estimated fetal weight in pregnancies considered to be at increased risk, and their implementation has increased pressures on ultrasound resources. Customised growth charts have improved the distinction between constitutional and pathological smallness and reduced unnecessary referrals. Their introduction, together with clinicians' training, e-learning and audit as the key elements of the growth assessment protocol, has resulted in increased antenatal detection of small for gestational age babies and a reduction in avoidable stillbirths. However, missed case audits highlight that further improvements are needed, and point to the need to address quality assurance and resource issues in ultrasound services.
The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa–initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI−/− mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX−/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI−/− mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa–mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.
The prevalence of opioid abuse in the United States has been steadily increasing over the last several years among many major demographics, including pregnant women. Rise in prenatal opioid abuse has resulted in subsequent escalation of neonatal abstinence syndrome incidence, prompting the US Congress to pass the Protecting Our Infants Act of 2015. This act specifically calls for a critical review of current treatment options for prenatal opioid abuse which may ultimately lead to the development of better therapies and a decreased incidence of neonatal abstinence syndrome. Currently, the American College of Obstetricians and Gynecologists recommends methadone, buprenorphine, or buprenorphine/naloxone in the treatment of prenatal opioid abuse. In this review, each maintenance therapy treatment option is discussed and compared revealing inconsistencies in postpartum retention rates, effects on fetal development, and availability to patients due to restrictions in health care coverage. Although each of these treatment options reduces opioid abuse and potential negative outcomes for the fetus, the shortcomings of these drugs highlight the overarching need for an improved standard of care. Drug developers and lawmakers should consider that affordability, coverage by health insurance, and success in retention rates substantially impacts the decision of the patient and healthcare provider regarding utilization of a particular opioid maintenance therapy.
Summary The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for “intercurrent” events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions (“does the drug delay recurrence if no patient had received subsequent therapy?” vs “does the drug delay recurrence with or without subsequent therapy?” vs “does the drug delay recurrence or start of subsequent therapy?”). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross‐industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.
The estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, for example, stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross‐industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference.
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