Centrally acting antiadrenergic (versus unexposed) updated on 03-11-2025

Small for gestational age (weight)

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S17152
R71936		 Al Khalaf - Methyldopa (Controls unexposed, disease free), 2022 Fetal growth restriction during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, disease free excluded Adjustment: No Indications Antihypertensive: Only chronic hypertension indication 1.86 [1.47;2.36] C
excluded (control group) 		71/1,952   34,584/1,739,944 34,655 1,952
ref
S17149
R71915		 Al Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fetal growth restriction during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: No Indications Antihypertensive: Only chronic hypertension indication 1.05 [0.81;1.38] C 71/1,952   270/7,809 341 1,952
ref
S13508
R52189		 Fitton - Centrally acting (Controls unexposed, disease free), 2020 Small for gestational age (birth weight below the 10th percentile) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified 1.23 [0.52;2.89]
excluded (control group) 		10/136   24,121/250,693 24,131 136
ref
S14423
R57255		 Fitton - Centrally acting (Controls unexposed, sick), 2020 Small for gestational age (birth weight below the 10th percentile) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified 0.52 [0.27;0.99] C 10/136   1,059/7,971 1,069 136
ref
S13880
R54299		 Kayser - Methyldopa, 2020 Small for gestational age (birth weight < 10th percentile for gestational age and sex- 2nd and/or 3rd trimester prospective cohort unexposed, disease free Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified 1.04 [0.57;1.89] C 15/147   58/587 73 147
ref
S13928
R54512		 Fisher b - Centrally acting (Controls unexposed, disease free), 2018 Small for gestational age (birthweight < 10th percentile for a given gestational age in weeks, sex, race/ethnicity, and parity) during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified 1.72 [0.77;3.85]
excluded (control group) 		8/67   923/10,050 931 67
ref
S13929
R54513		 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Small for gestational age (birthweight < 10th percentile for a given gestational age in weeks, sex, race/ethnicity, and parity) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified 0.99 [0.46;2.13] C 8/67   101/839 109 67
ref
S13479
R51996		 Orbach - Methyldopa, 2013 Small for gestational age 3rd trimester retrospective cohort (claims database) unexposed, disease free Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified 1.36 [0.67;2.75] 8/340   1,704/97,820 1,712 340
ref
S13450
R51815		 Su - Centrally acting (Controls unexposed, disease free), 2013 Small for gestational age (<10th percentile for gestational age and gender) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free excluded Adjustment: No Indications Antihypertensive: Only chronic hypertension indication 2.30 [1.66;3.18] C
excluded (control group) 		53/181   1,250/8,181 1,303 181
ref
S13444
R51797		 Su - Centrally acting (Controls unexposed, sick), 2013 Small for gestational age (<10th percentile for gestational age and gender) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, sick Adjustment: Yes Indications Antihypertensive: Only chronic hypertension indication 1.88 [1.31;2.70] 53/181   184/1,006 237 181
ref
S13475
R51974		 Nakhai-Pour - Centrally acting, 2010 Small for gestational age (a birth weight less than the 10th percentile for that gestational age and gender) 2nd and/or 3rd trimester nested case control unexposed (general population or NOS) Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified 2.61 [1.64;4.15] C 25/88   7,420/56,246 7,445 88
ref
S13386
R52201		 Mabie - Methyldopa, 1986 Intra-uterine growth retardation (birthweight < 10th percentile according to Lubchenco curve) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No Indications Antihypertensive: Only chronic hypertension indication 5.57 [1.69;18.35] C 12/54   4/82 16 54
ref
S14191
R55609		 Welt - Methyldopa, 1981 Small for gestational age 2nd and/or 3rd trimester randomized controlled trial unexposed, sick Adjustment: Randomisation Indications Antihypertensive: Only chronic hypertension indication 3.67 [0.12;113.74] C 1/6   0/6 1 6
ref
Total 9 studies 1.39 [0.95;2.03] 11,003 2,971
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Al Khalaf - Methyldopa (Controls unexposed, sick), 2022Al Khalaf - Methyldopa, 2022 1 1.05[0.81; 1.38]3411,95217%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Fitton - Centrally acting (Controls unexposed, sick), 2020Fitton - Centrally acting, 2020 2 0.52[0.27; 0.99]1,06913612%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: moderateROB mesure: moderateROB reporting: moderate Kayser - Methyldopa, 2020Kayser - Methyldopa, 2020 1.04[0.57; 1.89]7314712%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Fisher b - Centrally acting (Controls unexposed, sick), 2018Fisher b - Centrally acting, 2018 3 0.99[0.46; 2.13]1096710%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Orbach - Methyldopa, 2013Orbach - Methyldopa, 2013 1.36[0.67; 2.75]1,71234011%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Su - Centrally acting (Controls unexposed, sick), 2013Su - Centrally acting, 2013 4 1.88[1.31; 2.70]23718116%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Nakhai-Pour - Centrally acting, 2010Nakhai-Pour - Centrally acting, 2010 2.61[1.64; 4.15]7,4458814%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Mabie - Methyldopa, 1986Mabie - Methyldopa, 1986 5.57[1.69; 18.35]16546%ROB confusion: criticalROB selection: moderateROB classification: unclearROB missing: unclearROB mesure: moderateROB reporting: moderate Welt - Methyldopa, 1981Welt - Methyldopa, 1981 3.67[0.12; 113.74]161%ROB confusion: lowROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (9 studies) I2 = 73% 1.39[0.95; 2.03]11,0032,9710.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick; 3: Controls unexposed, sick; 4: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.23[0.84; 1.80]3,5572,87770%NAAl Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fitton - Centrally acting (Controls unexposed, sick), 2020 Kayser - Methyldopa, 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Orbach - Methyldopa, 2013 Su - Centrally acting (Controls unexposed, sick), 2013 Mabie - Methyldopa, 1986 7 case control studiescase control studies 2.61[1.64; 4.15]7,44588 -NANakhai-Pour - Centrally acting, 2010 1 RCTRCT 3.67[0.12; 113.74]16 -NAWelt - Methyldopa, 1981 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.59[0.88; 2.89]9,23057568%NAKayser - Methyldopa, 2020 Orbach - Methyldopa, 2013 Nakhai-Pour - Centrally acting, 2010 3 unexposed, sickunexposed, sick 1.29[0.78; 2.15]1,7732,39675%NAAl Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fitton - Centrally acting (Controls unexposed, sick), 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Su - Centrally acting (Controls unexposed, sick), 2013 Mabie - Methyldopa, 1986 Welt - Methyldopa, 1981 6 Tags Adjustment   - No  - No 1.30[0.84; 2.04]10,7652,78476%NAAl Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fitton - Centrally acting (Controls unexposed, sick), 2020 Kayser - Methyldopa, 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Orbach - Methyldopa, 2013 Nakhai-Pour - Centrally acting, 2010 Mabie - Methyldopa, 1986 7   - Randomisation  - Randomisation 3.67[0.12; 113.74]16 -NAWelt - Methyldopa, 1981 1   - Yes  - Yes 1.88[1.31; 2.70]237181 -NASu - Centrally acting (Controls unexposed, sick), 2013 1 Indications Antihypertensive   - All hypertensions, any indications ...  - All hypertensions, any indications or not specified 1.16[0.65; 2.08]10,40877877%NAFitton - Centrally acting (Controls unexposed, sick), 2020 Kayser - Methyldopa, 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Orbach - Methyldopa, 2013 Nakhai-Pour - Centrally acting, 2010 5   - Only chronic hypertension indication  - Only chronic hypertension indication 1.81[0.98; 3.34]5952,19376%NAAl Khalaf - Methyldopa (Controls unexposed, sick), 2022 Su - Centrally acting (Controls unexposed, sick), 2013 Mabie - Methyldopa, 1986 Welt - Methyldopa, 1981 4 All studiesAll studies 1.39[0.95; 2.03]11,0032,97173%NAAl Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fitton - Centrally acting (Controls unexposed, sick), 2020 Kayser - Methyldopa, 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Orbach - Methyldopa, 2013 Su - Centrally acting (Controls unexposed, sick), 2013 Nakhai-Pour - Centrally acting, 2010 Mabie - Methyldopa, 1986 Welt - Methyldopa, 1981 90.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.14.52.1030.000Al Khalaf - Methyldopa (Controls unexposed, sick), 2022Fitton - Centrally acting (Controls unexposed, sick), 2020Kayser - Methyldopa, 2020Fisher b - Centrally acting (Controls unexposed, sick), 2018Orbach - Methyldopa, 2013Su - Centrally acting (Controls unexposed, sick), 2013Nakhai-Pour - Centrally acting, 2010Mabie - Methyldopa, 1986Welt - Methyldopa, 1981

Asymetry test p-value = 0.6463 (by Egger's regression)

slope=0.1419 (0.3548); intercept=0.6674 (1.3921); t=0.4794; p=0.6463

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 13450, 13928, 13508, 17152

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.83[1.47; 2.29]70,2502,91133%NAAl Khalaf - Methyldopa (Controls unexposed, disease free), 2022 Fitton - Centrally acting (Controls unexposed, disease free), 2020 Kayser - Methyldopa, 2020 Fisher b - Centrally acting (Controls unexposed, disease free), 2018 Orbach - Methyldopa, 2013 Su - Centrally acting (Controls unexposed, disease free), 2013 Nakhai-Pour - Centrally acting, 2010 7 unexposed, sick controlsunexposed, sick controls 1.29[0.78; 2.15]1,7732,39675%NAAl Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fitton - Centrally acting (Controls unexposed, sick), 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Su - Centrally acting (Controls unexposed, sick), 2013 Mabie - Methyldopa, 1986 Welt - Methyldopa, 1981 60.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Al Khalaf (centrally acting antiadrenergic) ( ...Al Khalaf (centrally acting antiadrenergic) (Small for gestational age (adjusted studies)) 1.62[1.09; 2.42]32%-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT2 Al Khalaf (centrally acting antiadrenergic) ( ...Al Khalaf (centrally acting antiadrenergic) (Small for gestational age (adjusted studies)) 1.01[1.00; 1.02]NA-U,DFunexposed, disease freeAnyduring pregnancy (anytime or not specified)studies TTT1 Al Khalaf (centrally acting antiadrenergic) ( ...Al Khalaf (centrally acting antiadrenergic) (Small for gestational age (crude OR studies)) 1.36[0.67; 2.76]NA-U,DFunexposed, disease freeAnyduring pregnancy (anytime or not specified)studies TTT1 Al Khalaf (centrally acting antiadrenergic) ( ...Al Khalaf (centrally acting antiadrenergic) (Small for gestational age (crude OR studies)) 1.95[1.12; 3.40]56%-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT3 Bellos - Methyldopa (Small for gestational ag ...Bellos - Methyldopa (Small for gestational age (Randomized controlled trial and Cohort studies)) 1.62[0.97; 2.71]NA-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT-9 Bone - Methyldopa - GESTATIONAL HYPERTENSION ...Bone - Methyldopa - GESTATIONAL HYPERTENSION (Small for gestational age infants) 0.81[0.40; 1.77]29%-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT-9 Bone - Methyldopa - GESTATIONAL HYPERTENSION ...Bone - Methyldopa - GESTATIONAL HYPERTENSION (Small for gestational age infants (versus beta-blockers)) 0.86[0.16; 4.17]32%-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT-9 Bellos - Methyldopa (Small-for-gestational ag ...Bellos - Methyldopa (Small-for-gestational age (Randomized controlled trial only)) 1.11[0.69; 1.80]NA-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT-9 Abalos (Small-for-gestational age (RCT versus ...Abalos (Small-for-gestational age (RCT versus no antihypertensive drugs/placebo)) 0.96[0.02; 47.65]72%-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT2 metaPregmetaPreg 1.39[0.95; 2.03]73%2,971----Al Khalaf - Methyldopa (Controls unexposed, sick), 2022 Fitton - Centrally acting (Controls unexposed, sick), 2020 Kayser - Methyldopa, 2020 Fisher b - Centrally acting (Controls unexposed, sick), 2018 Orbach - Methyldopa, 2013 Su - Centrally acting (Controls unexposed, sick), 2013 Nakhai-Pour - Centrally acting, 2010 Mabie - Methyldopa, 1986 Welt - Methyldopa, 1981 90.510.01.0