Vet and Hormonal Contraception

8/9/2019 Vet and Hormonal Contraception

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Blood Coagulation, Fibrinolysis and Cellular Haemostasis 1

Combined hormonal contraception and risk of venous

thromboembolism within the first year following pregnancy

Danish nationwide historical cohort 199!"##9

$esper Friis %etersen

1

& 'homas Bergholt

1

& (nne )ristine *ielsen

1

& +ichael $ %aidas

"

& -llen Christine . ./kkegaard

1

1Department of Gynecology and Obstetrics, Hillerød Hospital, Hillerød, University of Copenhagen, Denmark;

Department of Obstetrics, Gynecology, and

!eprod"ctive #ciences, $ale %omen and Children&s Center for 'lood Disorders, $ale University #chool of (edicine, )e* Haven, Connetic"t, U#+

maryting the risk of veno"s thromboembolism -./0 associated *ith combined hormonal

ceptives follo*ing early terminated pregnancies or birth, a Danish nation*ide retrospective

observing a oneyear follo*"p *as defined "sing three "ni2"e registries3 +ll Danish

n *ith confirmed pregnancies aged 14567 d"ring the period of 17745887 *ere incl"ded3

ain o"tcomes *ere relative and absol"te risks of first time veno"s thromboembolism in

as *ell as non"sers of combined hormonal contraceptives3 9n 7:4,47 personyears, 47:

s thromboembolisms *ere recorded3 +fter early terminated pregnancies and births,tively, 11< and 6:4 events occ"rred in 1,44 and ==


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espondence to Financial support

er @riis Aetersen, (D /he st"dy *as f"nded by the research fo"ndation at Hillerød Hospital3 /he f"nding

rtment of Gynecology and Obstetrics organisation had no role in the st"dy planning, data collection, analysis, *riting of

rsity of Copenhagen, Hillerød Hospital the article, or in the decision to s"bmit the article for p"blication3 +ll a"thors held

haveveB 7,


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" %etersen et al :isk of ;'- by contraceptives followingpregnancy

'able 1 Characteristics of

populations with different

pregnancy out6comes

childbirth or early

terminated pregnancy!es"lts indicate the

n"mbers of person years

-A$0 and veno"s

thromboembolisms -./0;

the incidence rate -9!0 *as

calc"lated ./-A$188803

Childbirth

%< +ge -years0

14 :,74

8 :1,:6=

4 4:,681


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The primary outcome

was VTE during the first

year following pregnancy.

This outcome included

deep venous thrombosis

of the lower e,tremities%

pulmonary embolism%

cerebral venous throm-bosis% and portal vein

thrombosis. /iagnoses

were obtained from codes

used specifically for

pregnant women and

from additional% general

codes. 9pecific codes

from the 45/-1 were

either in-cluded or

e,cluded. 45/-; (1066-

100&) was used to

e,clude pre-vious venousthromboembolism (see

#ppendi,). #ll records

were subdivided into two

groups for analysis: i)

early terminated preg-

nancies% which were

terminated before

wee!s of gestation (in-

duced abortions%

miscarriages% hydatiform

mole% ectopic pregnan-cy%

and un!nown location of

the foetus) and ii)

childbirths.

The use of combined

hormonal

contraceptives was

considered a time-

varying covariate in

multivariate > ?

1@(incidence rate of

combined hormonal

contraceptive users A incidence rate of

>*>-users).

9tatistics were

conducted with

9#9@9T#T (9#9

4nc.% 5ary% >5% B9#)

software.

The study was

approved by The

/anish /ata

o.: 1-"1-

"66;). >o ethical

approval was

reuired for regis-

try-based studies in

/enmar!.

:esults

The one-year observation period

following pregnancycomprised 0;&%&0 person years.

Early terminated

pregnancies accounted

for 1%&& person

years. *f these%

1"%63 were

attributed to induced

abortions$ &0%3" were

miscarriages$ 0"

were caused by

hydatiform moles$

/hrombosisandHaemostasis1131816

F

#chatta"er816


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%etersen et al, :isk of ;'- by contraceptives following pregnanc

6%"0; were ectopic pregnancies$and 1%;"3 had an un!nown lo-

cation of the pregnancy. *ver thefirst year after the early termin-ated pregnancies% 113 casesdeveloped first-time occurrencesof VTE.

5hildbirths accounted for a total of

663%16 person years. #mong these% ";&

cases developed first-time occurrences

of VTE.

7aternal age and calendar year

were similarly distributed across the

two populations ( Table 1). owever%

higher edu-cation% normal bodyweight% and no smo!ing tended to be

associ-ated with reduced rates of

VTE.

/uring the initial seven wee!s of

the observation period% &8 (n?;) of

the total number of events were

diagnosed after early terminated

pregnancies% and ;8 (n?30) were

diagnosed after childbirth. /uring the

subseuent time intervals (6-13% 1"-

% 6-30% and "-& wee!s)%

(108)% " (18)% 3 (68)% and nine

(;8) events% respectively% were

diagnosed after early terminated

pregnancies and 30 (;8) " (08)% "1

(;8)% and 3" (68)% respect-ively%

were diagnosed after childbirths.

#s illustrated by the incidence

rates% for individuals that did or did

not use combined hormonal

contraceptives% the ris! of VTE was

high in the early postpartum period%

and it decreased later ( Table ). >o

differences were found in the ris! of

VTE associ-ated with use of

combined hormonal contraceptives

between the two outcome groups

(early terminated pregnancies and

birth) over the various time intervals (

Table ).

The

influence of

combined

hormonal

contraceptive

use on the ris!

of VTE was

assessed with

rate ratios

('') ad=usted

for ma-ternal

age% calendar

year%

education%

74% and

smo!ing for each time

interval. #fter

early

terminated

pregnancies%

the use of

com-bined

hormonal

contraceptives

conferred an

increased ris!

after seven

wee!s ('':

.3% 0&8 54:

1.-&.") (

Table ).

2ollowing

childbirth% the

use of

combined

hormonal

contraceptives

was as-

sociated with

increased ris! after 1" wee!s

('': .;% 0&8

54: 1.&-&.3) (

Table ).

The crudeincidencerates for progesteroneonlyformulations

during theentire

follow-upwere

.3@1% person-yearsand pro-gesteroneintrauterinedevices at.1@1% person-years%indicat-inglow ris!.

2or the

group with

early

terminated pregnancies%

the estimated

numbers

needed to

harm indicated

no significant

change in ris!

over the entire

year of

observation. 4n

contrast% for

the group thatgave birth% the

number

needed to

harm was

much lower

during the

early

postpartum

period (-

wee!s) than

during the

remain-ing

observation

period ( Table

3).

Discussion

This study

showed anincreased ris!

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of VTE in the postpartum period%

consistent with previous studies (&% 6-

1). 4n this

popu-

'able " :isk of venous

thromboembolism =;'->

following pregnancy in

groups with different

pregnancy outcomes /he

incidence rates -per 1,888

person years0 and rate ratiosare sho*n for individ"als that

"sed combined hormonal

contraceptives -CHC0

compared to those that did

not "se CHC, *ith 74K

confidence intervals -C903

!es"lts *ere adB"sted for the

covariates listed in /able 13

'old font indicates a

significant effect of CHC3


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?eeks @se of %erson6 ;'- ncidence :ate ratiofollowing CHC years rate =9A C>

pregnancy =9A C>

Childbirth 85 )o 76,=8


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8 %etersen et al :isk of ;'- by contraceptives followingpregnancy

'able 51 -stimated numbers needed to harm =**H>,

fects of combined hormonal contraceptives d"ring the indicated time intervals -*eeks0 for gro"ps *ith different pregnancy o"tcomes3 ))H L 1G-inci

dence rate of combined hormonal contraceptive "sers 5 incidence rate of

non"sers03

%regnancy ?eeks following pregnancy

outcome #!4

Childbirth :

arly terminated 16=:

Aregnancy

lation% the vast ma=ority of cases occurred during the initial sevenwee!s postpartum. The use of combined hormonal contraceptivesdid not increase this relatively elevated ris! observed in the proco-

agulative postpartum state (the first 1" wee!s following birth).Thereafter% the well-!nown association between combined hor-monal contraceptives and VTE became evident (11% 1). 5onse-uently% treatment of only ; persons per year with combinedhormonal contraceptives (number needed to harm) was necessaryto detect one incident of VTE in the early interval following birth.Cater% the ris! declined% as e,pected. 2ollowing early terminatedpregnancies% the number needed to harm was 1%"6; per detectableevent in the early interval% with no changes in later intervals.

Dac!son et al. reviewed the ris! of VTE in the postpartum peri-od (&) and identified 1& articles from 13 studies. 4n those studies%the reference groups comprised women that were not pregnant or

postpartum. 5ompared to that group% the ris! of VTE increased by.&- to ;"-fold when combined hormonal contraceptives wereused during the initial si, wee!s after childbirth. 5onseuently% a* group changed the recommendation regarding initiation of combined hormonal contraceptives following childbirth (). 4n the

present study% we e,amined the ris! associated with combined hor-

?hat is known about this topic

1•'oth pregnancy andthe "se of combinedhormonal contracepVTE postpartum(1"). 4n light of thisevidence% it would bereason-tives areestablished asindependent riskfactors of veno"sthrom able torecommend theinitiation of combined hormonalcontra-


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boembolism -./03

• +n interactionbet*eentheseseparaterisks hasbeen

s"ggested; ho*ever,researchaddressing

the matter islimited3

?hat doesthis paperadd

1•)ointeractionof combinedhormonalcontraceptives andthe already

biologicallyincreasedrisk of ./ in theearlypostpart"m period*asobserved3

2•)"mbersneeded toharm by"se of combinedhormonal

contraceptives*ere lo*,s"ggestingrel"ctancein their "se in theearlypostpart"m period3

3• +fter earlyterminatedpregnancies, bydifferent

indications,the "se of

combined hormonalcontraceptives did notincrease the absol"terisk of ./3

ceptivesdirectlyfollowingearlyterminated pregnancies$however%we

observedwideconfidence limits%due to thelimitednumber of cases% andthuscliniciansshouldconductanindividualassessment in allinstances.

The

present

study had

some

limitations.

2irst% the

low number

of

individualsthat used

contraceptiv

es early

after

pregnancy

might have

produced

misleading

results. The

conclusions

might differ

when testedin a larger

cohort.

owever%

this type of

study design

might be the

only way to

assess this

serious

complicatio

n of

contraceptiv

e use$

therefore%

the authors

recommend

that addi-

tional

research

should be

conducted in

other

countrieswhere these

registries are

available.

The validity

of the

registry data

in The

>ational

'egistry of


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%etersen et al, :isk of ;'- by contraceptives following pregnanc

(ppendi3 CD6 and 61# codes used =black> and e3cluded =grey> for identification of incident ;'-

CD6 CD61#

./ in nonpregnant *omen

648 D9 A"lmonary embolism

D9:81 Ahlebitis and thrombophlebitis of femoral vein

641,8: D9:8 Ahlebitis and thrombophlebitis of other deep vessels of lo*er e>tremities

641 D9:8< Ahlebitis and thrombophlebitis of lo*er e>tremities, "nspecified

64 D9:1 Aortal vein thrombosis

64


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Haemostasis 1131816


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4 %etersen et al :isk of ;'- by contraceptives followingpregnancy

mation or underestimation

of the number of cases%

depending on whether a

superficial event was

coded as a VTE (leadingto overes-timation) or as a

subclinical event (leading

to underestimation).

2inally% the results were

based on the assumption

that filled pre-scriptions

implied actual use of

combined hormonal

contracep-tives.

*verestimation of the use

of combined hormonal

contracep-tives couldoccur when women

decided not to ta!e the

pills% des-pite the filled

prescription. *n the other

hand% underestimation

could occur when women

used an old pac!age of

combined hor-monal

contraceptives before

filling a new prescription.

The ma=or strength of

the study was the large

number of pa-tients.

This was due to the

nationwide databases%

which included all

pregnancies that

occurred in women aged

1&-"0 throughout a 1&-

year period.

#dditionally% the register

approach eliminated po-

tential recall or non-

responder biases

compared to different

meth-ods. This study

was one of the first to

e,amine the ris!

associated with the use

of combined hormonal

contraceptives during

the postpartum period.

Conclusion

4n our national setting%this study illustrated an

increased ris! of

VTE during the

initial seven wee!s

postpartum.

#ttempting to e,-

plain this% our study

distinguished between the

biologically in-

creased ris! due to

pregnancy and the

ris! imposed by the

use of combined

hormonal

contraceptives. >o

addition to the

already biologically

increased ris! was

observed whenadding the use of

combined hormonal

contraceptives.

owever% because of

the low numbers

needed to harm in the

early postpartum

period% our re-sults

supported the

recently altered

recommendations

from *

suggesting a pause of at least si, wee!s

before commencing

hor-monal

contraception.

2ollowing early

terminated

pregnancies% the

numbers needed to

harm showed no

ma=or changes

throughout the

follow-up peri-od$this result suggested

that combined

hormonal

contraceptives were

relatively safe to use

under these

conditions supporting

the clinical option of

immediate

commencement.

Conflicts ofinterest

>one declared.

:eferences

1. od!er % vidman

C% eber T% et al.

7aternal deaths in

/enmar! -.

#cta *bstet ynecol

9cand 0$ ;;: &&-

&.

2. 5hang D% Elam-Evans

C/% erg 5D% et al.


13/13

5E% Dames #% et al.

Trends in the incidence

of venous

thromboembolism during

pregnancy or postpartum:

a 3-year population-

based study. #nn 4ntern

7ed &$ 1"3: 06-6.

8. 7c5oll 7/% 'amsay DE%

Tait '5% et al. 'is! factors

for pregnancy associated

ve-nous thromboembolism.Thromb aemost 1006$

6;: 11;3-11;;.

9. 9alonen 'os % Cichtenstein

Vet and Hormonal Contraception

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