The impact of risk factors on aspirin's efficacy for the prevention of preterm birth.

BACKGROUND: The Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial was a landmark study that demonstrated a reduction in preterm birth and hypertensive disorders of pregnancy in nulliparous women who received low-dose aspirin. All women in the study had at least 1 moderate-risk factor for preeclampsia (nulliparity). Unlike current US Preventative Service Task Force guidelines, which recommend low-dose aspirin for ≥2 moderate-risk factors, women in this study were randomized to receive low-dose aspirin regardless of the presence or absence of an additional risk factor. OBJECTIVE: This study aimed to compare how low-dose aspirin differentially benefits nulliparous women with and without additional preeclampsia risk factors for the prevention of preterm birth and hypertensive disorders of pregnancy. STUDY DESIGN: This was a non-prespecified secondary analysis of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial that randomized nulliparous women with singleton pregnancies from 6 low-middle-income countries to receive low-dose aspirin or placebo. Our primary exposure was having an additional preeclampsia risk factor beyond nulliparity. Our primary outcome was preterm birth before 37 weeks of gestation, and our secondary outcomes included preterm birth before 34 weeks of gestation, preterm birth before 28 weeks of gestation, hypertensive disorders of pregnancy, and perinatal mortality. RESULTS: Among 11,558 nulliparous women who met the inclusion criteria, 66.8% had no additional risk factors. Low-dose aspirin similarly reduced the risk of preterm birth at <37 weeks of gestation in women with and without additional risk factors (relative risk: 0.75 vs 0.85; P=.35). Additionally for our secondary outcomes, low-dose aspirin similarly reduced the risk of preterm birth at <28 weeks of gestation, hypertensive disorders of pregnancy, and perinatal mortality in women with and without additional risk factors. The reduction of preterm birth at <34 weeks of gestation with low-dose aspirin was significantly greater in women without additional risk factors than those with an additional risk factor (relative risk: 0.69 vs 1.04; P=.04). CONCLUSION: Low-dose aspirin's ability to prevent preterm birth, hypertensive disorders of pregnancy, and perinatal mortality was similar in nulliparous women with and without additional risk factors. Professional societies should consider recommending low-dose aspirin to all nulliparous women.

Activity restriction and preterm birth prevention.

PURPOSE OF REVIEW: Since the 1900s, activity restriction (AR) has been widely prescribed as a strategy for preventing preterm birth (PTB). Over the past decade, the practice has been called into question as numerous studies have demonstrated that AR does not improve obstetrical and perinatal outcomes but does confer significant physical and psychological risks. The purpose of this review is to offer clinicians a summary of the latest data on the risks, benefits, and efficacy of AR for the prevention of PTB. RECENT FINDINGS: Both retrospective and prospective studies have demonstrated that AR does not significantly prolong pregnancy including those with multiple gestations, short cervices, ruptured membranes, and increased body mass indexes. Several studies have also shown that physical activity during pregnancy is associated with a higher incidence of vaginal delivery, a lower incidence of gestational diabetes mellitus, and a lower incidence of hypertensive disorders without increasing the risk of adverse neonatal outcomes. SUMMARY: The culmination of these data led to the Society for Maternal-Fetal Medicines' release of an updated committee recommendation in August of 2020; AR should not be routinely prescribed as a treatment to prevent PTB.

Childhood neurodevelopment after spontaneous versus indicated preterm birth.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. Individuals who survive preterm birth are at a higher risk for many long-term adverse effects, including neurodevelopmental deficits. There are many well-established risk factors for worse neurologic outcomes spanning the prenatal and postnatal periods; however, investigators have yet to assess whether the cause of preterm birth has an impact on neurodevelopment. OBJECTIVE: Our objective was to assess whether neurologic outcomes differ by children born via indicated versus spontaneous preterm birth. STUDY DESIGN: We performed secondary analysis of a multicenter trial assessing magnesium for neuroprotection in women at risk for preterm delivery from 24 to 31 weeks. We included women with live, nonanomalous, singleton gestations who delivered preterm; we excluded women whose children were missing 2-year follow-up information for reasons other than perinatal demise. The primary exposure was type of preterm birth: (1) spontaneous if the child's mother presented with preterm labor or ruptured membranes, or (2) indicated if the child was delivered preterm iatrogenically. The primary outcome was death (including stillbirths, neonatal intensive care unit deaths, and deaths after discharge) or an abnormal Bayley II score by 2 years of age, defined as a Mental Developmental Index score or Psychomotor Developmental Index score 2 standard deviations below the mean. Secondary outcomes included death or Mental Developmental Index and Psychomotor Developmental Index scores 1 standard deviation or less, and neonatal morbidities associated with prematurity. Bivariate analyses of baseline characteristics by exposure were conducted. A logistic regression model was fitted to adjust for confounders. RESULTS: Of 1678 subjects, 1631 (97.2%) underwent spontaneous preterm birth and 47 (2.8%) underwent indicated preterm birth. Baseline maternal demographics and gestational age at delivery were similar between groups (29.6 weeks ± 7.8 versus 28.8 weeks ± 2.5, P = .07). A Psychomotor Developmental Index score 2 standard deviations or less below the mean or death occurred in 340 (20.9%) spontaneous preterm birth subjects and 17 (36.2%) indicated preterm birth subjects (P = .01). When adjusting for confounders, there remained an increased probability of a Psychomotor Developmental Index scores 2 standard deviations or less or death in indicated preterm birth subjects (P = .02). Although not statistically significant, indicated preterm birth was also associated with higher odds of Mental Developmental Index scores 2 standard deviations or less or death, Psychomotor Developmental scores 1 standard deviation or less or death, and Mental Developmental Index scores 1 standard deviation or less or death (1.76, 1.59, and 1.45, respectively). Limiting the analysis to small for gestational age infants, there was no difference in neurologic outcomes. The same was true for when we excluded small for gestational age infants from our analysis. However, after adjusting for small for gestational age, the odds of a Psychomotor Developmental Index score 2 standard deviations or less or death remained significant higher in the indicated preterm birth group (adjusted odds ratio, 1.98; 95% confidence interval, 1.01-3.88). CONCLUSION: In this cohort of pregnant women who delivered preterm, indicated deliveries were associated with worse psychomotor development than were spontaneous deliveries. Other outcomes appeared to be poor, but our numbers were limited. This finding should be confirmed in a larger cohort of women undergoing medically indicated preterm deliveries.

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

UNLABELLED: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT: Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.