Dataset Information

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

ABSTRACT:

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.

SUBMITTER: Saito M

PROVIDER: S-EPMC9874756 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

Saito Makoto M McGready Rose R Tinto Halidou H Rouamba Toussaint T Mosha Dominic D Rulisa Stephen S Kariuki Simon S Desai Meghna M Manyando Christine C Njunju Eric M EM Sevene Esperanca E Vala Anifa A Augusto Orvalho O Clerk Christine C Were Edwin E Mrema Sigilbert S Kisinza William W Byamugisha Josaphat J Kagawa Mike M Singlovic Jan J Yore Mackensie M van Eijk Anna Maria AM Mehta Ushma U Stergachis Andy A Hill Jenny J Stepniewska Kasia K Gomes Melba M Guérin Philippe J PJ Nosten Francois F Ter Kuile Feiko O FO Dellicour Stephanie S

Lancet (London, England) 20221125 10371

<h4>Background</h4>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-AB ...[more]

PMID: 36442488

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Project description:BackgroundAnimal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment.Methods and findingsElectronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns.ConclusionsCompared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens.Review registrationPROSPERO CRD42015032371.

Project description:Microelements involved in the oxidative balance have a significant impact on human health, but their role in pregnancy are poorly studied. We examined the relationships between first trimester levels of selenium (Se), iron (Fe), zinc (Zn), and copper (Cu), as well as maternal characteristics and pregnancy results. The data came from a Polish prospective cohort of women in a single pregnancy without chronic diseases. A group of 563 women who had a complete set of data, including serum microelements in the 10-14th week was examined, and the following were found: 47 deliveries <37th week; 48 cases of birth weight <10th and 64 newborns >90th percentile; 13 intrauterine growth restriction (IUGR) cases; 105 gestational hypertension (GH) and 15 preeclampsia (PE) cases; and 110 gestational diabetes mellitus (GDM) cases. The microelements were quantified using mass spectrometry. The average concentrations (and ranges) of the elements were as follows: Se: 60.75 µg/L (40.91-125.54); Zn: 618.50 µg/L (394.04-3238.90); Cu: 1735.91 µg/L (883.61-3956.76); and Fe: 1018.33 µg/L (217.55-2806.24). In the multivariate logistic regression, we found that an increase in Se of 1 µg/L reduces the risk of GH by 6% (AOR = 0.94; p = 0.004), the risk of IUGR by 11% (AOR = 0.89; p = 0.013), and the risk of birth <34th week by 7% (but close to the significance) (AOR = 0.93; p = 0.061). An increase in Fe of 100 µg/L reduces the risk of PE by 27% (AOR = 0.73; p = 0.009). In the multivariable linear regression, we found negative strong associations between prepregnancy BMI, Se (β = -0.130; p = 0.002), and Fe (β = -0.164; p < 0.0001), but positive associations with Cu (β = 0.320; p < 0.000001). The relationships between Se and maternal age (β = 0.167; p < 0.0001), Se and smoking (β = -0.106; p = 0.011) and Cu, and gestational age from the 10-14th week (β = 0.142; p < 0.001) were also found. Secondary education was associated with Zn (β = 0.132; p = 0.004) and higher education was associated with Cu (β = -0.102; p = 0.023). A higher financial status was associated with Fe (β = 0.195; p = 0.005). Other relationships were statistically insignificant. Further research is needed to clarify relationships between first trimester microelements and pregnancy complications. In addition, attention should be paid to lifestyle-related and socioeconomic factors that affect microelement levels.

Project description:ObjectiveTo document the terminology patients hear during the treatment course for a nonviable pregnancy and to ask patients their perceived clarity and preference of terminology to identify a patient-centered lexicon.MethodsWe performed a preplanned substudy survey of English-speaking participants in New York, Pennsylvania, and California at the time of enrollment in a randomized multisite trial of medical management of first-trimester early pregnancy loss. The six-item survey, administered on paper or an electronic tablet, was developed and piloted for internal and external validity. We used a visual analog scale and quantified tests of associations between participant characteristics and survey responses using risk ratios.ResultsWe approached 155 English-speaking participants in the parent study, of whom 145 (93.5%) participated. In the process of receiving their diagnosis from a clinician, participants reported hearing the terms "miscarriage" (n=109 [75.2%]) and "early pregnancy loss" (n=73 [50.3%]) more than "early pregnancy failure" (n=31 [21.3%]) and "spontaneous abortion" (n=21 [14.4%]). The majority selected "miscarriage" (n=79 [54.5%]) followed by "early pregnancy loss" (n=49 [33.8%]) as their preferred term. In multivariable models controlling for study site, ethnicity, race, history of induced abortion, and whether the current pregnancy was planned, women indicated that "spontaneous abortion" and "early pregnancy failure" were significantly less clear than "early pregnancy loss" (53/145, adjusted risk ratio 0.12, 95% CI 0.07-0.19 and 92/145, adjusted risk ratio 0.38, 95% CI 0.24-0.61, respectively, as compared with 118/145 for "early pregnancy loss"). "Miscarriage" scored similarly to "early pregnancy loss" in clarity (119/145, adjusted risk ratio 1.05, 95% CI 0.62-1.77).ConclusionThe terminology used to communicate "nonviable pregnancy in the first trimester" is highly variable. In this cohort of women, most preferred the term "miscarriage" and classified both "miscarriage" and "early pregnancy loss" as clear labels for a nonviable pregnancy. Health care providers can use these terms to enhance patient-clinician communication.Clinical trial registrationClinicalTrials.gov, NCT02012491.

Project description:BackgroundSARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes, including fetal death and preterm birth. It is not known whether that risk occurs only during the time of acute infection or whether the risk persists later in pregnancy.ObjectiveThis study aimed to evaluate whether the risk of SARS-CoV-2 infection during pregnancy persists after an acute maternal illness.Study designA retrospective cohort study of pregnant patients with and without SARS-CoV-2 infection delivering at 17 hospitals in the United States between March 2020 and December 2020. Patients experiencing a SARS-CoV-2-positive test at or before 28 weeks of gestation with a subsequent delivery hospitalization were compared with those without a positive SAR-CoV-2 test at the same hospitals with randomly selected delivery days during the same period. Deliveries occurring at <20 weeks of gestation in both groups were excluded. The study outcomes included fetal or neonatal death, preterm birth at <37 weeks of gestation and <34 weeks of gestation, hypertensive disorders of pregnancy (HDP), any major congenital malformation, and size for gestational age of <5th or <10th percentiles at birth based on published standards. HDP that were collected included HDP and preeclampsia with severe features, both overall and with delivery at <37 weeks of gestation.ResultsOf 2326 patients who tested positive for SARS-CoV-2 during pregnancy and were at least 20 weeks of gestation at delivery from March 2020 to December 2020, 402 patients (delivering 414 fetuses or neonates) were SARS-CoV-2 positive before 28 weeks of gestation and before their admission for delivery; they were compared with 11,705 patients without a positive SARS-CoV-2 test. In adjusted analyses, those with SARS-CoV-2 before 28 weeks of gestation had a subsequent increased risk of fetal or neonatal death (2.9% vs 1.5%; adjusted relative risk, 1.97; 95% confidence interval, 1.01-3.85), preterm birth at <37 weeks of gestation (19.6% vs 13.8%; adjusted relative risk, 1.29; 95% confidence interval, 1.02-1.63), and HDP with delivery at <37 weeks of gestation (7.2% vs 4.1%; adjusted relative risk, 1.74; 95% confidence interval, 1.19-2.55). There was no difference in the rates of preterm birth at <34 weeks of gestation, any major congenital malformation, and size for gestational age of <5th or <10th percentiles. In addition, there was no significant difference in the rate of gestational hypertension overall or preeclampsia with severe features.ConclusionThere was a modest increase in the risk of adverse pregnancy outcomes after SARS-CoV-2 infection.

Project description:BackgroundThrombocytopenia is a common manifestation of antiphospholipid syndrome (APS), and is a main concern for bleeding on the standard treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) in obstetric APS (OAPS).ObjectiveThis study assesses the possible relationship between thrombocytopenia during the first trimester and adverse pregnancy outcomes (APOs) in OAPS patients.MethodsA case-control study was conducted at Peking University People's Hospital, Beijing, China. The clinical, immunologic, and pregnancy outcomes of the OAPS patients were collected. Univariate and multivariate logistic regression analyses were applied to assess the relationship between APOs and thrombocytopenia in the first trimester.ResultsA total of 115 participants were included in the analysis. There were no difference on antepartum and postpartum hemorrhage between the two groups. The gestational age in the thrombocytopenia group was less than that in the control group (34.12 ± 8.44 vs. 37.44 ± 3.81 weeks, p = 0.002). Hypocomplementemia, double aPL positive, and high titers of anti-β2 glycoprotein I were more frequent in APS patients with thrombocytopenia (p < 0.05). Compared to the control group, thrombocytopenia in the first trimester was correlated with SGA (12.12% vs. 31.25%, p = 0.043), premature birth <37 weeks (16.16% vs 43.75%, p = 0.010) and intrauterine fetal death (2.02% vs 12.50%, p = 0.033). Thrombocytopenia in first-trimester independently increased the risk of preterm birth <37 weeks (OR = 5.40, 95% CI: 1.35-21.53, p = 0.02) after adjusting for demographic and laboratory factors. After adding medication adjustments, these factors above become insignificant (p > 0.05). Of note, the number of platelets increased after delivery in 14 thrombocytopenia patients with live fetuses (p = 0.03).ConclusionThis study demonstrates that thrombocytopenia in the first trimester increases the risks of preterm birth in women with APS. The effective OAPS treatments may improve pregnancy outcomes and not increase the risk of antepartum and postpartum hemorrhage.

Project description:BackgroundTo investigate the association of crown-rump length (CRL) during the first trimester of pregnancy with neonatal outcomes.MethodsA total of 15,524 women with a reliable first day of the last menstrual period and a regular menstrual cycle (28 ± 4 days) were included from January 2015 to November 2016. CRL was measured by ultrasound from 7+0 to 13+6 weeks during pregnancy and transformed to a standard deviation score (SDS) adjusted for gestational age. Linear regression was used to explore risk factors for CRL. A generalised linear model was used to evaluate the association between CRL and neonatal outcomes.ResultsIn the multivariate analysis, maternal age (0.25 mm, 95% CI = [0.22-0.28], P < 0.001; 0.04 SDS, 95% CI = [0.03-0.04], P < 0.001), multipara (0.30 mm, 95% CI = [0.08-0.52], P = 0.007; 0.04 SDS, 95% CI = [0.00-0.07], P = 0.031) and folic acid supplement use (0.78 mm, 95% CI = [0.49-1.08], P < 0.001; 0.05 SDS, 95% CI = [0.01-0.10], P < 0.019) were positively associated with CRL, while pre-pregnancy BMI (-0.17 mm, 95% CI = [-0.21 to -0.13], P < 0.001; -0.02 SDS, 95% CI = [-0.03 to -0.02], P < 0.001) was negatively related to CRL. For neonatal outcomes, CRL was negatively associated with small for gestational age (SGA) ([risk ratio] (RR) = 0.733, 95% [CI] = 0.673-0.8004, Padjusted < 0.001) and neonatal intensive care unit (NICU) admission ([RR] = 0.928, 95% [CI] = 0.883-0.976, Padjusted = 0.003), and preterm birth ([RR] = 1.082, 95% [CI] = 1.008-1.162, Padjusted = 0.029), but positively related to large for gestational age (LGA) ([RR] = 1.241, 95% [CI] = 1.184-1.301, Padjusted = 0.012). When stratified by pre-pregnancy BMI, the risk of SGA and LGA remained significant in all groups, while the increased risk of preterm birth was only observed in the lean group (BMI < 18.5 kg/m2) and decreased risk of NICU admission rate in the normal group (BMI 18.5-24 kg/m2).ConclusionsMaternal characteristics were independently associated with CRL in the first trimester, which was negatively related to foetal size, SGA, preterm birth, and admission rate to the NICU, but positively related to LGA.

Dataset Information

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

Background

Methods

Findings

Interpretation

Funding

Publications

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

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