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Lancet (London, England) Jan 2023Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective,... (Meta-Analysis)
Meta-Analysis
Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.
BACKGROUND
Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy.
METHODS
For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371.
FINDINGS
We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92).
INTERPRETATION
We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted.
FUNDING
Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.
Topics: Female; Pregnancy; Humans; Antimalarials; Pregnancy Outcome; Quinine; Pregnancy Trimester, First; Abortion, Spontaneous; Stillbirth; Prospective Studies; Artemether; Artemether, Lumefantrine Drug Combination; Malaria, Falciparum; Malaria; Drug Combinations; Ethanolamines
PubMed: 36442488
DOI: 10.1016/S0140-6736(22)01881-5 -
Therapeutics and Clinical Risk... 2021Malaria is one of the infectious diseases with substantial risks for pregnant women, the fetus and the newborn child. Thus, prevention and treatment of malaria with safe... (Review)
Review
INTRODUCTION
Malaria is one of the infectious diseases with substantial risks for pregnant women, the fetus and the newborn child. Thus, prevention and treatment of malaria with safe and effective drugs is of paramount importance. Pregnant women are mostly excluded from clinical trials, and systematic approaches of pharmacovigilance in pregnancy are limited. This means the safety and efficacy of antimalarial agents during pregnancy are unclear.
PURPOSE
This study was designed to carry out a systematic review and aggregate data meta-analysis of literature published on efficacy and safety of artemisinin-based combination therapy (ACT) for uncomplicated malaria in pregnant women.
METHODS
A search of literature published between 1998 to 2020 on efficacy and safety of artemisinin-based combination therapy (ACT) in pregnant women was made using Cochrane Library, Medline and the Malaria in Pregnancy Consortium Library. Data were extracted independently by two reviewers, and any discrepancies were resolved by consensus. Meta-analysis was carried out using Open Meta-Analyst software. Random effects model was applied, and the heterogeneity of studies was evaluated using Higgins I.
RESULTS
Twenty-four studies that fulfilled the inclusion criteria were included in the final assessment. Overall, days 28 to 63 malaria treatment success rate was 96.1%. Overall days 28 to 63 cure rates for AL, AS+AQ, AS+MQ, DHA+PQ, AS+ATQ+PG and AS+SP were 95.1%, 92.2%, 97.0%,94.3%, 96.5% and 97.4%, respectively. Comparison of ACTs with non-ACTs revealed that the risk of treatment failure was substantially lower in patients treated with ACTs than with non-ACTs (risk ratio 0.20, 95% C.I. 0.09-0.43). The overall prevalences of miscarriage, stillbirth and congenital anomalies were 0.3%, 2.1% and 1.0%, respectively, and found to be comparable among various ACTs. There was comparable tolerability across ACTs during pregnancy.
CONCLUSION
ACTs demonstrated a high cure rate, safety and tolerability against infection in pregnant women. The higher treatment success and comparable tolerability could be used as an input for decision makers to support the continued usage of ACTs for treatment of uncomplicated falciparum malaria in pregnant women.
PubMed: 35221688
DOI: 10.2147/TCRM.S336771 -
Drug Safety Mar 2018Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of... (Review)
Review
INTRODUCTION
Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature.
METHODS
PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords. Studies designed to investigate the association were eligible for inclusion without restriction to any study design or language. The primary outcome was defined as suicidal conditions, while secondary outcomes included all other NEs.
RESULTS
Thirty-three studies were included for a narrative review. Four observational studies did not find a significant association, while ten pharmacovigilance studies using different global databases detected the signals. Notably, some studies suggest that the FDA warning issued in 2008 might have influenced the reporting rate of NEs as a result of increased awareness.
LIMITATIONS
The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association.
CONCLUSION
Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.
Topics: Animals; Humans; Leukotriene Antagonists; Leukotrienes; Mental Disorders; Neuropsychiatry; Observational Studies as Topic; Pharmacovigilance; United States; United States Food and Drug Administration
PubMed: 29076063
DOI: 10.1007/s40264-017-0607-1 -
Drug Safety Dec 2017β-lactam antibiotics are commonly prescribed antibiotic drugs. To describe the clinical characteristics, risk markers and outcomes of β-lactam antibiotic-induced... (Review)
Review
β-lactam antibiotics are commonly prescribed antibiotic drugs. To describe the clinical characteristics, risk markers and outcomes of β-lactam antibiotic-induced neurological adverse effects, we performed a general literature review to provide updated clinical data about the most used β-lactam antibiotics. For selected drugs in each class available in France (ticarcillin, piperacillin, temocillin, ceftazidime, cefepime, cefpirome, ceftaroline, ceftobiprole, ceftolozane, ertapenem and aztreonam), a systematic literature review was performed up to April 2016 via an electronic search on PubMed. Articles that reported original data, written in French, Spanish, Portuguese or English, with available individual data for patients with neurological symptoms (such as seizure, disturbed vigilance, confusional state, myoclonia, localising signs, and/or hallucinations) after the introduction of a β-lactam antibiotic were included. The neurological adverse effects of piperacillin and ertapenem are often described as seizures and hallucinations (>50 and 25% of cases, respectively). Antibiotic treatment is often adapted to renal function (>70%), and underlying brain abnormalities are seen in one in four to one in three cases. By contrast, the neurological adverse drug reactions of ceftazidime and cefepime often include abnormal movements but few hallucinations and seizures. These reactions are associated with renal insufficiency (>80%) and doses are rarely adapted to renal function. Otherwise, it appears that monobactams do not have serious neurological adverse drug reactions and that valproic acid and carbapenem combinations should be avoided. The onset of disturbed vigilance, myoclonus, and/or seizure in a patient taking β-lactam antibiotics, especially if associated with renal insufficiency or underlying brain abnormalities, should lead physicians to suspect adverse drug reactions and to consider changes in antibacterial therapy.
Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Nervous System Diseases; beta-Lactams
PubMed: 28755095
DOI: 10.1007/s40264-017-0578-2 -
Vector Borne and Zoonotic Diseases... Apr 2023Lyme borreliosis (LB) is the most common tick-borne disease in Europe, but the burden of disease is incompletely described. We conducted a systematic review across...
Lyme borreliosis (LB) is the most common tick-borne disease in Europe, but the burden of disease is incompletely described. We conducted a systematic review across PubMed, EMBASE, and CABI Direct (Global Health) databases, from January 1, 2005, to November 20, 2020, of epidemiological studies reporting incidence of LB in Europe (PROSPERO, CRD42021236906). The systematic review yielded 61 unique articles describing LB incidence (national or subnational) in 25 European countries. Substantial heterogeneity in study designs, populations sampled, and case definitions restricted data comparability. The European Union Concerted Action on Lyme Borreliosis (EUCALB)-published standardized LB case definitions were used by only 13 (21%) of the 61 articles. There were 33 studies that provided national-level LB incidence estimates for 20 countries. Subnational LB incidence was available from an additional four countries (Italy, Lithuania, Norway, and Spain). The highest LB incidences (>100 cases per 100,000 population per year [PPY]) were reported in Belgium, Finland, the Netherlands, and Switzerland. Incidences were 20-40/100,000 PPY in the Czech Republic, Germany, Poland, and Scotland and <20/100,000 PPY in Belarus, Croatia, Denmark, France, Ireland, Portugal, Russia, Slovakia, Sweden, and the United Kingdom (England, Northern Ireland, and Wales); markedly higher incidences were observed at the subnational level (up to 464/100,000 PPY in specific local areas). Although countries in Northern (Finland) and Western (Belgium, the Netherlands, and Switzerland) Europe reported the highest LB incidences, high incidences also were reported in some Eastern European countries. There was substantial subnational variation in incidence, including high incidences in some areas of countries with low overall incidence. This review, complemented by the incidence surveillance article, provides a comprehensive view into LB disease burden across Europe that may guide future preventive and therapeutic strategies-including new strategies on the horizon.
Topics: Animals; Incidence; Lyme Disease; Europe; Tick-Borne Diseases; Belgium
PubMed: 37071407
DOI: 10.1089/vbz.2022.0070 -
Expert Review of Vaccines Dec 2022Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV...
INTRODUCTION
Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination.
AREAS COVERED
We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints.
EXPERT OPINION
The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.
Topics: Male; Female; Humans; Papillomavirus Infections; Papillomavirus Vaccines; Papillomaviridae; Uterine Cervical Neoplasms; Vaccination
PubMed: 36178094
DOI: 10.1080/14760584.2022.2129615 -
Pharmacoepidemiology and Drug Safety Jun 2021Andrographis paniculata is one of the commonly used herbal medicines worldwide. Nevertheless, evidences on adverse events (AEs) associated with Andrographis paniculata... (Meta-Analysis)
Meta-Analysis
PURPOSE
Andrographis paniculata is one of the commonly used herbal medicines worldwide. Nevertheless, evidences on adverse events (AEs) associated with Andrographis paniculata are very limited. This systematic review and meta-analysis was conducted to estimate and to compare the AE incidence of oral monotherapy Andrographis paniculata with others among patients with upper respiratory tract infection, noninfective diarrhea, and autoimmune disease.
METHODS
Systematic search was performed through six databases from inception until August 2018. Randomized controlled trial (RCT), cohort, or intensive monitoring of AEs was eligible for review if AE incidence was examined. The incidence of AEs was, then, pooled across studies using meta-analysis.
RESULTS
Ten RCTs and 3 intensive monitoring studies were included. Incidence of serious AEs was very rare with the pooled incidence (95% CI) from RCTs of 0.02 per 1000 patients (0.0-0.5). However, the incidence of nonserious AEs was considered very common with the pooled incidence (95% CI) from RCTs of 102.6 per 1000 patients (10.7-256.1), and the pooled incidence (95% CI) from intensive monitoring of 34.2 per 1000 patients (0.0-229.6). The most common nonserious AEs were related to gastrointestinal disorder, and skin and subcutaneous disorder system.
CONCLUSIONS
Like other medicine, Andrographis paniculata can cause some AEs. However, it may be generally safe. Nevertheless, prospective patients who plan to use Andrographis paniculata should be thoroughly advised and closely monitored for common AEs. Due to the increasing use of Andrographis paniculata worldwide, larger studies with adequate methodological quality are warranted to monitor the safety of such product.
Topics: Andrographis; Cohort Studies; Humans
PubMed: 33372366
DOI: 10.1002/pds.5190 -
Vaccine Feb 2016New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children.
METHODS
We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted.
RESULTS
Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75-0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases.
CONCLUSIONS
Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01-adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted.
Topics: Adjuvants, Immunologic; Adolescent; Child; Child, Preschool; Clinical Trials as Topic; Drug Combinations; Humans; Infant; Likelihood Functions; Lipid A; Polysorbates; Risk; Saponins; Squalene; Vaccines; alpha-Tocopherol
PubMed: 26740250
DOI: 10.1016/j.vaccine.2015.12.024 -
Drug Safety Dec 2020Checkpoint inhibitor drugs including ipilimumab have been reported to induce intestinal injury. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Checkpoint inhibitor drugs including ipilimumab have been reported to induce intestinal injury.
OBJECTIVE
We aimed to evaluate the risk of chronic (> 6 weeks) enterocolitis following ipilimumab administration, and the likelihood that an enteritis vs colitis or enterocolitis is seen.
PATIENTS AND METHODS
We searched MEDLINE, EMBASE, CENTRAL, the World Health Organization International Clinical Trials Registry, and conference proceedings. We included: (1) randomized controlled trials comparing ipilimumab administration with placebo/standard care/other active chemotherapy regimens and (2) prospective observational studies. Separate meta-analyses were performed for randomized controlled trials and observational studies.
RESULTS
Of 4760 records, we included ten unique randomized controlled trials (n = 5814 subjects) and 34 unique prospective observational studies (n = 3699 subjects). In randomized controlled trials, the pooled relative risk of ≥ grade 3 enterocolitis or ≥ grade 3 diarrhea associated with ipilimumab was 13.31 (95% confidence interval 6.01-29.48, I = 0%, ten trials) and 6.72 (95% confidence interval 3.30-13.65, I = 63%, ten trials), respectively. In observational studies, the 3-monthly risk of developing grade 3 or higher enteritis, colitis, or enterocolitis was 4% (95% confidence interval 3-7, I = 77.40%, 25 studies). Randomized controlled trials and observational studies did not distinguish between acute and chronic enterocolitis. Of the included observational studies, the pooled risk of incurring small bowel involvement associated with ipilimumab was 1% (95% CI 0-4, I = 0%, four studies) per every 3-month time period.
CONCLUSIONS
Insufficient data exist to quantify or distinguish the risk of acute vs chronic enterocolitis following ipilmumab use. Because of the serious impact of chronic enterocolitis on quality of life and further cancer treatment, future trials evaluating the safety of immunotherapy should report gastrointestinal events in greater detail.
Topics: Enterocolitis; Humans; Immune Checkpoint Inhibitors; Ipilimumab; Pharmacovigilance; Randomized Controlled Trials as Topic
PubMed: 32749630
DOI: 10.1007/s40264-020-00979-4 -
Journal of Clinical Epidemiology Oct 2023The purpose of this study was to systematically review the statistical methods used in pharmacovigilance studies without a priori hypotheses. (Review)
Review
OBJECTIVES
The purpose of this study was to systematically review the statistical methods used in pharmacovigilance studies without a priori hypotheses.
STUDY DESIGN AND SETTING
A systematic review was performed on studies published in the MEDLINE database between 2012 and 2021. The included studies were analyzed for database name and type, statistical methods, anatomical therapeutic chemical class for the studied drug(s), and SOC MedDRA classification for the studied adverse drug reaction.
RESULTS
Ninety-two studies were included, with pharmacovigilance databases being the most used type. Disproportionality analysis using frequentist or Bayesian methods was the most common statistical method employed. The most studied drug classes were anti-infectives, nervous system drugs, and antineoplastics and immunomodulators. However, no common procedure was implemented to correct for multiple testing.
CONCLUSION
This review highlights the limited number of statistical methods employed for pharmacovigilance studies without a priori hypotheses, with no established consensus-based method and a lack of interest in multiple testing correction. The establishment of guidelines is recommended to improve the performance of such studies.
Topics: Humans; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Bayes Theorem; Databases, Factual; Drug-Related Side Effects and Adverse Reactions
PubMed: 37657615
DOI: 10.1016/j.jclinepi.2023.08.010