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Chronic hypertension in pregnancy and
the risk of congenital malformations:
a cohort study
dr. Iman Ruansa
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Chronic hypertension is a common medicalcondition in pregnancy, and its prevalence is
rising because a larger number of parturients
are obese and of advanced maternal age
Little is known about the role of chronic
hypertension alone in conferring risk of
congenital malformation
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O!"C#I$"
% #he purpose of the study was to e&aminethe association between maternal chronic
hypertension and the risk of congenital
malformations in the offspring.
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'#()* )"'I+
% -e defined a cohort of /,012 completedpregnancies linked to infant medicalrecords using the 3edicaid 4nalytic"&tract.
% #he risk of congenital malformations wascompared between normotensive controlsand those with treated and untreatedchronic hypertension. Confounding was
addressed using propensity scorematching.
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34#"RI4L 4) 3"#5O)'
% Cohort
)erived from the 3edicaid 4nalytic e6tract73468
#he cohort is restricted to women who wereeligible for 3edicaid continuously from 9months prior to the estimated L3 monththrough 0 month postpartum.
Restricted to women with 1 days or more of
enrollment each month and without restrictedbenefits, private insurance, or certain state;specific managed care programs 7thatunderreport claims to 3468.
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Exclusion
-omen who were e&posed to known teratogenic
medications including lithium, antineoplastic
agents, retinoids, or thalidomide from the
"stimated L3 through the date of deliverybased on claims for dispensed medications
or who had an infant with an inpatient or
outpatient diagnosis code indicating the
presence of a chromosomal abnormality.
-omen who were e&posed to antihypertensive
3edications during the first trimester but who
lacked diagnosis codes indicating chronic
5ypertension because of a significant risk
of misclassifying the presence or absence
of hypertension in these patients 7becausethe women may have received the medications
for other indications
The final analytic cohort
included 878,126 pregnancies
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% Exposure
-omen without chronic hypertension
who did not receive antihypertensive medicationsin first trimester
3 Groups
-omen with chronic hypertension
who were treated with an antihypertensive medications
during first trimester
-omen with chronic hypertension
who were not treated with an antihypertensive medication
during first trimester
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4ntihypertensive e&posure during the firsttrimester was defined by a filled
prescription whose days< supply
overlapped the period from the L3 to =>
days after the L3.
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% Outcoes #he primary outcome was defined as the presence of ama?or congenital malformation in the offspring.
3a?or congenital malformations were defined based onhaving codes on 1 or more separate days in the infant
inpatient or outpatient records during the first 9 monthsof life indicating an organ;specific class of malformationsincluding central nervous system malformations@ eye,ear, neck, and face malformations@ cardiacmalformations@ respiratory malformations@ cleft palate orlip@ gastrointestinal malformations@ genitourinary
malformations@ musculoskeletal malformations@ or othermalformations.
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% Co!ariates
" groups of
potential confounders
measures ofhealth care utiliAation
maternal medications
obstetric characteristicsB
conditions
comorbid
medical conditions
maternal
demographic characteristics
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% 'tatistical 4nalyses
aseline
Characteristics
-omen -I#5O(# chronic
hypertension who did notreceive antihypertensive
medications in the first
trimester
-omen with C5ROIC5*"R#"'IO who were
e&posed to an antihypertensive
medication during the first
trimester
-omen with C5ROIC
5*"R#"'IO who were not
treated with an ntihypertensive
during the first trimester
Controls
(ntreated
chronic
hypertension
#reated
chronic
hypertension
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% 'ensitivity and e&ploratory analyses
Controls vs sub?ectstreated for chronic
hypertension
Controls vs untreatedchronic hypertension
freuency and unad?usted
odds ratio 7OR8 and =DE
confidence intervals 7CIs8
Logistic regression model
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% #ensiti!ity and exploratory analysesecause diabetes is such a strong risk factor
for congenital and the possibility e&ists thatthere may be residual confounding, evenad?usting for the presence of diabetes e&cluding patients with any codes ormedications indicating the presence of diabetes,=9/ patients e&cluded
'econd sensitivity analysis e&cluding patientswith preterm delivery =,>F= patientse&cluded
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R"'(L#
% 4fter matching, compared with normotensivecontrols,pregnancies complicated by treated chronichypertension were at increased risk of congenitalmalformations 7odds ratio GORH, 0.9@ =DE confidenceinterval GCIH, 0.1e0.D8, as were pregnancies withuntreated chronic hypertension 7OR 0.1@ =DE CI,0.0e0.98.
% In our analysis of organ;specific malformations, bothtreated and untreated chronic hypertension wasassociated with a significant increase in the risk of
cardiac malformations 7OR, 0.2@ =DE CI, 0.Fe0.=and OR, 0.D@ =DE CI, 0.9e0./, respectively8.% #hese associations persisted across a range of
sensitivity analyses.
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% Ta$le 1 %aseline characteristics of study patients&ithout chronic hypertension Treated chronic
hypertensi!es'nreated chronichypertensi!es
#otal D,99/ 9>/ 00,F1
4ge group, y
0= 1D2,=/9 71=.=8 F>1 7F.8 1>29 708 1>;1F 9>,0F> 79D.=8 0D9= 70.D8 9F9D 71=.=
1D;1= 0/9,1=0 71>.18 19=2 71.8 1=D 71D.8
9>;9F /,/10 7=.18 11>0 712.D8 0/=F 70D.28
9D;9= 99,=/ 7F8 0920 702.F8 =F= 7.98
JF> /11D 7>.8 F> 7F.=8 19 71.D8
RaceBethnicity
-hite, non;5ispanic 9F=,92= 7F>./8 12F 791.98 F909 79/.28
lack, non;5ispanic 1=,2/ 799.8 F99/ 7D1.18 D0/= 7FD.08
5ispanic 090,>D/ 70D.98 2= 7.98 000> 7=./8
4sian 1=,20 79.D8 0D 71.18 1D/ 71.18
Other F0,>9= 7F.8 1F 798 F>1 79.D8
(nknown 0/,91F 71.>8 02F 71.>8 110 70.=8
atients characteristics
ree&isting )3 99,2=F 79.=8 0== 719.=8 022= 70F.D8
+estational )3 2/,>0 7/.8 1011 71D.D8 1102 70=.98
Chronic renal disease =921 70.08 F>F 7F.=8 D0/ 7F.D8
#obacco use /0,102 7.98 220 7.>8 0>>/ 7.8
3edication e&posure
Insulin 0D,2F 70.8 09F9 702.18 0>>D 7.8
Oral diabetes medications 02,21 70.=8 1>F1 71F.28 0>0> 7.8
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% Ta$le 2 %aseline characteristics of study patients after propensity score atching(Characteristic Coparison 1 Coparison 2
-ithout chronichypertension
#reated chronichypertension
-ithout chronichypertension
#reated chronichypertension
#otal 19,F1/ />= 9F,F9F 00,F/
4ge group, y
0= 0>1 7F.28 F>1 7D.18 2>2= 70/.28 1>29 708
1>;1F FD=> 70=.28 0D91 70=.28 0>,0D 71=.28 9F9F 71=.=8
1D;1= 2=20 71=./8 1911 71=./8 =>F 712.F8 1=D/ 71D.8
9>;9F 20/ 712.F8 1>>2 71D./8 D92= 70D.28 0/=9 70D.28
9D;9= 9D29 70D.18 00/ 70D.18 1== 7.F8 =F 7.98
JF> 0>D9 7F.D8 92> 7F.28 1 71.F8 19 71.D8
RaceBethnicity
-hite, non;5ispanic /== 79F.08 1DD 799.08 09,921 79.8 F909 79/.28
lack, non;5ispanic 00,/=9 7D>.98 9=2/ 7D>.8 0D,F1D 7FF.8 D0/D 7FD.08
5ispanic 1>1D 7.28 2// 7./8 91>D 7=.98 000> 7=./8
4sian F0 71.08 0D 71.F8 29= 70.=8 1D/ 71.18
Other 2=1 7908 1F0 79.08 0D/ 79.F8 F>1 79.D8
(nknown FF/ 70.=8 0DF 718 2F2 70.=8 110 70.=8
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atients characteristics
ree&isting )3 F9/D 70./8 0DD9 70=.=8 F/ 709.=8 022D 70F.D8
+estational )3 DFD 719.98 0/0 711.8 229= 70=.98 110F 70=.98
Chronic renal disease =2 7F.18 90= 7F.08 0F>1 7F.08 D0F 7F.D8
#obacco use 01/ 7/.8 291 7.08 1==1 7./8 0>>/ 7.8
3edication e&posure
Insulin 12/1 700.F8 =2 701.28 1F9 7.98 0>>0 7./8
Oral diabetesmedications
92= 70D.8 09= 70/.=8 1292 7/./8 0>>2 7.8
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% Ta$le 3 The association $et)een chronic hypertension *treated and
untreated+ and congenital alforations copared
% )ith norotensi!e controlsCharacteristics Treated chronic hypertension 'nreated chronic hypertension
(nad?usted ' matched (nad?usted ' matched
Composite congenitalmalformations
0./ 70.2K0.=8 0.9 70.1K0.D8 0.D 70.FK0.28 0.1 70.0K0.98
Organ; specific malformations
Central nervoussystem malformations
1.> 70.9K98 0.F 7>.K1.98 0.F 7>.=K1.08 0.1 7>./K0.=8
3alformations of theeye, ear, neck, or face
>.= 7>.DK0./8 >. 7>.FK0.8 0.0 7>./K0.=8 0.1 7>./K1.08
Cardiac malformations 1.2 71.9K98 0.2 70.FK0.=8 1.0 70.=K1.98 0.D 70.9K0./8
Respiratory malformations 0. 70.1K1./8 0.D 7>.=K1.F8 0.F 7>.=K18 0.9 7>.K1.08
Cleft palate and lip 0.9 7>./K1.98 0.9 7>.2K1.28 0.0 7>./K0.=8 0.0 7>.2K1.08
+astrointestinal malformations 0.0 7>.K0.D8 0.> 7>./K0.D8 0.0 7>.=K0.F8 0.> 7>./K0.98
+enitourinary malformations 0.F 70.0K0.8 0.0 7>.K0.D8 0.9 70.0K0./8 0.0 7>.=K0.D8
3usculoskeletal malformations 0.0 7>.=K0.F8 >.= 7>./K0.18 0.> 7>.K0.18 >. 7>./K0.08
Other malformations 0. 70.9K1.F8 0.2 70.0K1.98 0.0 7>.K0.D8 0.> 7>./K0.F8
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% Ta$le #ensiti!ity and exploratory analyses
Characteristic Treated chronic hypertension 'ntreated chronic hypertension
'ensitivity analysis 0, e&cluding )3,
+)3, insulin, and diabetes medication Composite congenital malformations 0.1 70.>K0.F8 0.1 70.0K0.98
Cardiac malformations 0.D 70.1K0.8 0.D 70.1K0./8
'ensitivity analysis 1, e&cluding pretermdeliveries
Composite congenital malformations 0.9 70.0K0.28 0.0 70.>K0.98
Cardiac malformations 0.D 70.1K0.=8 0.0 7>.=K0.F8
'ensitivity analysis 9 7all covariatesdefined based on trimester 08
Composite congenital malformations 0.9 70.1K0.28 0.1 7>.=K0.28
Cardiac malformations 0.2 70.9K0.=8 0.9 7>.=K0.=8
'ensitivity analysis F 7outcome definedby a single diagnostic code in the infantrecord8
Composite congenital malformations 0.1 70.0K0.98 0.1 70.0K0.98
Cardiac malformations 0.F 70.9K0.28 0.D 70.9K0.28
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"&ploratory analysis of specific cardiacmalformations
$entricular septal defect 0.F 70.>K1.>8 0.0 7>.K0.D8
Right ventricular septal defect 0.1 7>.1K2.18 0.9 7>.FK9.D8
'ingle ventricle 9.> 7>.FK10.98 F.D 7>.K12.=8
'ecundum atrial septal defect 0.D 70.>K1.F8 0.9 7>.=K0.=8
Conotruncal defect 0./ 7>.K9.D8 >.= 7>.FK0.8
Left ventricular outflow obstruction 0. 7>.KF.08 0.0 7>.DK1.18
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CO33"#
% #here are few studies that have e&ploredthe role of hypertension in conferringrisk of
congenital malformations in the offspring.
% Our findings confirm and e&tend theseobservations from previous studies.
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%irst, we e&amined the role specifically ofchronic hypertension in conferring the risk of
malformations, whereas prior studies e&amined
all pregnancy;related hypertensive disorders
together.% 'econd, our study e&amined a full range of
organ;specific congenital malformations in
relation to hypertension, finding that chronic
hypertension is associated most strongly withcardiac malformations.
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%#hird, our study carefully controlled for a widerange of potential confounders of the association
between chronic hypertension and congenital
malformations including comorbid conditions as
well as other relevant medication e&posures andmarkers of overall health status and health care
utiliAation.
% inally, the large siAe of our cohort allowed us to
make relatively precise estimates with regard tothe risk of malformations associated with treated
and untreated hypertension.
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% 4lthough we were careful to identify potential
confounders of the association between chronic
hypertension and malformations using maternal
inpatient and outpatient diagnostic claims,
medications, and health care utiliAation variables, it
remains possible that residual bias is present
because of unmeasured or unknown confounders.
% Our study also cannot directly address whether
treatment of chronic hypertension in pregnancy willdecrease the risk of malformations.
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% 4lthough the estimate of risk of malformations
was similar for both treated and untreated
chronic hypertension, our study cannot e&clude
the possibility that certain antihypertensives are
teratogenic.% 4s in all observational studies, we cannot
e&clude the possibility of residual confounding
and additional studies replicating these findings
are necessary before chronic hypertensionshould be considered an established risk factor
for congenital malformations.
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COCL('IO
% #here is a similar increase in the risk ofcongenital malformations 7particularly cardiacmalformations8 associated with treated anduntreated chronic hypertension that isindependent of measured confounders.
% 'tudies evaluating the teratogenic potential ofantihypertensive medications must control forconfounding by indication.
% etuses and neonates of mothers with chronic
hypertension should be carefully evaluated forpotential malformations, particularly cardiacdefects.
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CRI#IC4L 4R4I'4L-uestions .ns)ers Explanation
0. 'tudy design,
survey or registrationM
'urvey #he control group consisted of /F
healthy pregnant women and =>patients with diagnosed pre;eclampsia.#otal R4 was isolated from placentaand the mR4 level of e&amined geneswas to determine using real;time CR.
1. Inductive ordeductive reasoningM
)eductive7theory Nprediction Nobservation Nconclusions8
#heory: -riters e&plained the theory ofchronic hypertension in coferring risk ofcongenital malformation.rediction: Chronic hypertension alonemay be related to development ofcongenital malformation in the
offspring.Conclusions: #here is a similarincrease in the risk of congenitalmalformations associated with treatedand untreated chronic hypertension.
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-uestions .ns)ers Explanation
9 and F #ype andscales of eachvariables in this study
)ependent variables: Chronichypertension 7nominal8 and congenitalmalformation 7nominal8
Independent $ariables:4ge 7ratio8RaceBethnicity 7nominal8atient characteristics 7nominal83edication e&posure 7nominal8
D. #ype of data,primary, secondary or
tertiary resourcesM
'econdary )ata was derived from 3edicaid4nalytic e6tract 73468
2. +roup or ungroupdataM
+roup
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-uestions .ns)ers Explanation
/. 4d hoc or routinedataM
4d hoc )ata was collected for some period oftime during study
. 3easures of Central
#endency, ositionand )ispersion
ot
mentioned
=. #ables that wasused to present resultsof this study
reuencytables
'ee page D,2, / and
0>. +raph used in thispaper
'catter;plot 'ee page =
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CRI#IC4L 4R4I'4L
-uestions .ns)ers Explanation
00. uality of researchdata
5igh uality 0. (sed primary data1. +ood operational definition9. (sing valid measurement techniue
01. ias Low risk of
bias
4lmost all known confounding
factors was controlled
09. 'ample siAecalculation for thisstudy
otmentioned
0F. 'amplingtechniue
#otalsampling
4ll studies that met inclusion ande&clusion criteria were included inthis study
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-uestions .ns)ers Explanation
0D and 02. 'tatisticalanalysis
ivariateanalysis: one;way 4O$4test tocomparemean values
#he e&perimental data were analyAedusing the ''' 0/.> for -indowssoftware. 3ean values were comparedby one;way 4O$4 test. #he value of pP >.>D was considered as statisticallysignificant.
0/. "rror to concludestatistical analysisresults
one
0. 5ow was the
presentation of resultsin this paperM
+ood -riters clearly e&plained
background, methods and results inthis study. #hey compare resultswith another study and e&plainlimitation of this study
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T/.0 O'