Non-Cochrane · aetiology · PM41907861
Cumulative evidence for the association between maternal hypertension and cleft lip and palate in offspring: a systematic review and meta-analysis.
Cui Xinping, Song Bin, Zhou Qian, et al. · Frontiers in oral health · 2026 · PubMed · doi:10.3389/froh.2026.1725513
Findings
Population Pregnant women and their offspring
57 findings
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring High quality studies (NOS/AHRQ) | OR 1.38 [1.21, 1.54] GRADE not reported 7 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Moderate quality, adjusted-results stratum | OR 1.36 [1.24, 1.48] GRADE not reported 3 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal BMI: Yes | OR 1.11 [1.05, 1.17] GRADE not reported 5 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal smoking: Yes | OR 1.33 [1.24, 1.42] GRADE not reported 2 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Banhidy 2014 | OR 1.74 [1.30, 2.32] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Bellizzi 2016 | OR 1.59 [1.324, 2.03] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring High quality, adjusted-results stratum | OR 1.42 [1.23, 1.60] GRADE not reported 5 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Moderate quality, unadjusted-results stratum | OR 1.17 [0.95, 1.39] GRADE not reported 2 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Case-control studies, adjusted-results stratum | OR 1.37 [1.25, 1.48] GRADE not reported 4 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Kishimba 2015 | OR 1.46 [1.18, 1.81] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Cohort studies, adjusted-results stratum | OR 1.41 [1.18, 1.63] GRADE not reported 3 studies |
| Maternal hypertension (any type) | No maternal hypertension | Cleft lip and/or palate (CLP) in offspring Sensitivity analysis: excluding Hang An 2022 | OR 1.62 [1.25, 2.11] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal age: No | OR 1.37 [1.21, 1.53] GRADE not reported 2 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for placental hemorrhage: No | OR 1.35 [1.25, 1.45] GRADE not reported 10 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for family history of CLP: Yes | OR 4.73 [2.71, 6.76] GRADE not reported 2 studies |
| Maternal hypertension (any type) | No maternal hypertension | Cleft lip and/or palate (CLP) in offspring Sensitivity analysis: excluding Luke 2025 | OR 1.66 GRADE not reported Studies not reported |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal abortion: No | OR 1.33 [1.23, 1.42] GRADE not reported 10 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Moderate quality studies (NOS/AHRQ) | OR 1.25 [1.08, 1.42] GRADE not reported 5 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal diabetes: No | OR 1.39 [1.23, 1.56] GRADE not reported 9 studies |
| Maternal hypertension (any type) | No maternal hypertension | Cleft lip and/or palate (CLP) in offspring Sensitivity analysis: excluding Luke 2025 (second listing) | OR 1.69 [1.28, 2.23] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Anthony H 2018 | OR 1.59 [1.24, 2.03] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Unadjusted estimates (Table 2) | OR 1.19 [1.01, 1.38] GRADE not reported 4 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal BMI: No | OR 1.19 [1.04, 1.34] GRADE not reported 7 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal age: Yes | OR 1.24 [1.03, 1.46] GRADE not reported 10 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal smoking: No | OR 1.94 [0.63, 3.25] GRADE not reported 10 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Trim-and-fill adjusted (0 missing studies) | OR 1.45 [1.27, 1.67] GRADE not reported 12 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for placental hemorrhage: Yes | OR 1.64 [1.16, 2.12] GRADE not reported 2 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sample size <10,000 | OR 1.47 [1.15, 1.78] GRADE not reported Studies not reported |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted estimates (Table 2) | OR 1.38 [1.27, 1.48] GRADE not reported 8 studies |
| Maternal hypertension (any type) | No maternal hypertension | Cleft lip and/or palate (CLP) in offspring Adjusted for family history of CLP: no | OR 1.33 [1.24, 1.42] GRADE not reported 10 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Case-control studies | OR 1.35 [1.24, 1.46] GRADE not reported 7 studies |
| Maternal hypertension (any type) | No maternal hypertension | Cleft lip and/or palate (CLP) in offspring Sensitivity analysis: excluding Wyszynski 2002 | OR 1.67 [1.25, 2.22] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal diabetes: Yes | OR 1.14 [1.09, 1.19] GRADE not reported 3 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Figueiredo 2015 | OR 1.49 [1.18, 1.88] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Adjusted for maternal abortion: Yes | OR 1.41 [1.03, 1.79] GRADE not reported 2 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Cohort studies | OR 1.29 [1.13, 1.45] GRADE not reported 4 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring | OR 1.44 [1.26, 1.64] GRADE not reported 12 studies · 4407254 participants |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring High quality, unadjusted-results stratum | OR 1.22 [0.87, 1.58] GRADE not reported 2 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Case-control studies, unadjusted-results stratum | OR 1.22 [0.87, 1.58] GRADE not reported 3 studies |
| Maternal hypertension (any type) | No maternal hypertension | Cleft lip and/or palate (CLP) in offspring Sensitivity analysis: excluding Wyszynski 2002 (second listing) | OR 1.61 [1.22, 2.13] GRADE not reported 11 studies |
| Any maternal hypertension (pre-pregnancy, gestational, preeclampsia, chronic) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sample size >10,000 | OR 1.42 [1.23, 1.60] GRADE not reported 8 studies |
| Maternal gestational hypertension (pregnancy-induced) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Anthony H 2018 | OR 1.38 [1.05, 1.82] GRADE not reported 4 studies |
| Maternal gestational hypertension (pregnancy-induced) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Barbara Luke 2025 | OR 1.54 [1.04, 2.30] GRADE not reported 4 studies |
| Maternal gestational hypertension (pregnancy-induced) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Hang An 2022 | OR 1.42 [1.03, 1.95] GRADE not reported 4 studies |
| Maternal gestational hypertension (pregnancy-induced) | No maternal hypertension | Cleft lip and palate (CLP) in offspring | OR 1.36 [1.06, 1.74] GRADE not reported 5 studies · 1334265 participants |
| Maternal gestational hypertension (pregnancy-induced) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Kishimba 2015 | OR 1.24 [1.06, 1.45] GRADE not reported 4 studies |
| Maternal gestational hypertension (pregnancy-induced) | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Wyszynski 2002 | OR 1.50 [0.98, 2.29] GRADE not reported 4 studies |
| Maternal preeclampsia | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Bellizzi 2016 | OR 1.69 [0.99, 2.89] GRADE not reported 3 studies |
| Maternal preeclampsia | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Banhidy 2014 | OR 2.68 [1.49, 4.83] GRADE not reported 3 studies |
| Maternal preeclampsia | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Hang An 2022 | OR 2.04 [0.86, 4.87] GRADE not reported 3 studies |
| Maternal preeclampsia | No maternal hypertension | Cleft lip and palate (CLP) in offspring | OR 2.10 [1.11, 3.96] GRADE not reported 4 studies · 578918 participants |
| Maternal preeclampsia | No maternal hypertension | Cleft lip and palate (CLP) in offspring Sensitivity: excluding Wyszynski 2002 | OR 2.32 [0.94, 5.76] GRADE not reported 3 studies |
| Maternal pre-pregnancy hypertension | No maternal hypertension | Cleft lip and palate (CLP) in offspring | OR 1.63 [0.72, 3.70] GRADE not reported 2 studies · 1126808 participants |
| Maternal antihypertensive medication use during pregnancy | No maternal antihypertensive medication use | Cleft lip and/or palate (CLP) in offspring All drug classes combined (beta-blocker and ACE inhibitor subgroups; 8 estimates from 5 studies) | OR 1.47 [1.01, 2.13] GRADE not reported 5 studies · 606025 participants |
| Maternal antihypertensive medication use in pregnancy | No antihypertensive medication | Cleft lip and palate (CLP) in offspring All antihypertensive medications | OR 2.37 [0.93, 6.04] GRADE not reported 5 studies · 606025 participants |
| Maternal antihypertensive medication use in pregnancy | No antihypertensive medication | Cleft lip and palate (CLP) in offspring Beta-blockers | OR 1.45 [0.98, 2.17] GRADE not reported 5 studies |
| Maternal antihypertensive medication use in pregnancy | No antihypertensive medication | Cleft lip and palate (CLP) in offspring ACE inhibitors | OR 1.69 [0.40, 7.07] GRADE not reported 3 studies |
Included primary studies 17
Open in Studies| Study | Year | Also included by | Outcomes it informs here | Trial data |
|---|---|---|---|---|
| An 2022 Association of gestational hypertension and preeclampsia with nonsyndromic orofacial clefts in China: a large prospective cohort study DOI:10.1097/hjh.0000000000003150 | 2022 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Banhidy 2011 Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring: a population-based study DOI:10.1038/hr.2010.227 | 2010 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Banhidy 2012 Association of pre-eclampsia with or without superimposed chronic hypertension in pregnant women with the risk of congenital abnormalities… DOI:10.1016/j.ejogrb.2012.03.015 | 2012 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Bateman 2014 Chronic hypertension in pregnancy and the risk of congenital malformations: a cohort study DOI:10.1016/j.ajog.2014.09.031 | 2015 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Bateman 2018 (beta-blocker) β-Blocker Use in Pregnancy and the Risk for Congenital Malformations: An International Cohort Study. PMID:30326014 | 2018 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Bellizzi 2016 Are hypertensive disorders in pregnancy associated with congenital malformations in offspring? Evidence from the WHO Multicountry cross… DOI:10.1186/s12884-016-0987-8 | 2016 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Bui 2018 Association Between Cleft Lip and/or Cleft Palate and Family History of Cancer DOI:10.1097/sap.0000000000001331 | 2018 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Figueiredo 2015 Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans DOI:10.1002/bdra.23417 | 2015 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Fisher 2018 Maternal antihypertensive medication use and selected birth defects in the National Birth Defects Prevention Study DOI:10.1002/bdr2.1372 | 2018 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Kishimba 2015 Factors associated with major structural birth defects among newborns delivered at Muhimbili National Hospital and Municipal Hospitals in… DOI:10.11604/pamj.2015.20.153.4492 | 2015 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Luke 2025 Maternal, reproductive and perinatal factors and the risks of birth defects: traditional and emerging factors DOI:10.1016/j.rbmo.2024.104781 | 2025 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Nakhai-Pour 2010 Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small‐for‐gestational‐age newborns DOI:10.1002/bdrb.20238 | 2010 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Puho 2007 Drug Treatment during Pregnancy and Isolated Orofacial Clefts in Hungary DOI:10.1597/05-208.1 | 2007 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Silva 2024 Risk of orofacial clefts in relation to maternal body mass index, diabetes and hypertension DOI:10.3233/npm-230118 | 2024 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Tabacova 2003 Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment DOI:10.1002/pds.796 | 2003 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Weber 2018 Occurrence of Selected Structural Birth Defects Among Women With Preeclampsia and Other Hypertensive Disorders DOI:10.1093/aje/kwx269 | 2017 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
| Wyszynski 2002 Prenatal and Perinatal Factors Associated with Isolated Oral Clefting DOI:10.1597/1545-1569_2002_039_0370_papfaw_2.0.co_2 | 2002 | this review only | Cleft lip and palate (CLP) in offspring | not extracted yet |
Review question
| Element | Planned (methods) | Found (results) |
|---|---|---|
| Population | Women with maternal hypertension (pre-pregnancy, gestational, preeclampsia or chronic hypertension) and their offspring | Pregnant women and offspring in 12 studies (4,407,254 participants) |
| Intervention | Maternal hypertension exposure (any type, gestational hypertension, preeclampsia, pre-pregnancy hypertension) | Maternal hypertension overall (n=12 studies), gestational hypertension (n=5), preeclampsia (n=4), pre-pregnancy hypertension (n=2), antihypertensive medication use (n=5 studies) |
| Comparison | Not specified | Not specified |
| Outcomes | Cleft lip and palate in offspring (non-syndromic; confirmed by clinical examination) | Cleft lip and palate in offspring |
| Study designs | Observational studies: cohort, case-control and cross-sectional designs | 12 studies: 4 cohort, 7 case-control, 1 cross-sectional (5 studies of antihypertensive medication use in a separate analysis) |
| Timing | Database inception to 30 July 2025 | Studies published 2002 to 2025 |