ORIGINAL ARTICLE: EARLY PREGNANCY

Ectopic pregnancy and outcomes

of future intrauterine pregnancy
Me
lanie Chouinard, M.P.H.,a Marie-He
le
ne Mayrand, M.D., Ph.D.,a,b,c Aimina Ayoub, M.Sc.,b,d

s, M.P.H.,b,d and Nathalie Auger, M.D., M.Sc.a,b,d,e
Jessica Healy-Profito
a
Department of Social and Preventive Medicine, School of Public Health, University of Montreal; b University of Montreal


Hospital Research Centre; c Department of Obstetrics and Gynecology, University of Montreal; d Institut national de sante
publique du Que
bec; e Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal,
Quebec, Canada

Objective: To provide information on the birth outcomes of future intrauterine pregnancies in women whose first pregnancy was
ectopic.
Design: Population-based longitudinal cohort study.
Setting: All hospitals in Quebec, Canada, 1989–2013.
Patient(s): Group surgically treated for an ectopic first pregnancy: 15,823 women; comparison group with an intrauterine first preg-
nancy: 1,101,748 women.
Intervention(s): Not applicable.
Main Outcome Measure(s): Repeat ectopic pregnancy, future delivery of a live infant, stillbirth, cesarean delivery, preterm birth, low
birth weight, preeclampsia, gestational diabetes, and postpartum hemorrhage as well as other outcomes of pregnancy.
Result(s): The overall prevalence of ectopic first pregnancy was 14.2 per 1,000 women, of whom 10% of women with an ectopic first
pregnancy had a future ectopic. Regardless of age, women with ectopic first pregnancies had an increased risk of adverse birth outcomes
at future intrauterine pregnancies, including 1.27 times the risk of preterm birth (95% confidence interval [CI], 1.18–1.37), 1.20 times the
risk of low birth weight (95% CI, 1.10–1.31), 1.21 times the risk of placental abruption (95% CI, 1.04–1.41), and 1.45 times the risk of
placenta previa (95% CI, 1.10–1.91). Older women with a prior ectopic pregnancy had particularly elevated risks of placental abruption
(risk ratio 1.42; 95% CI, 1.16–1.69).
Conclusion(s): Women with ectopic first pregnancies have an increased risk of adverse birth outcomes during subsequent intrauterine
pregnancies. These women may benefit from closer clinical management in pregnancy to prevent adverse birth outcomes. (Fertil SterilÒ
2019;112:112–9. Ó2019 by American Society for Reproductive Medicine.)
El resumen está disponible en Español al final del artículo.
Key Words: Cohort study, ectopic, fertility, pregnancy, pregnancy outcome

Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/45605-27613

U
p to 2% of clinically recognized known on the outcomes of future availability of assisted reproductive
pregnancies are ectopic (1–3). intrauterine pregnancies. Most technologies have increased the
Ectopic pregnancy occurs research has focused on the ability of likelihood that women with a history
when a fertilized ovum implants women with a previous ectopic of ectopic pregnancy will achieve a
outside the uterine cavity, usually in pregnancy to achieve an intrauterine future intrauterine pregnancy (4). Yet
the fallopian tubes (1–3). Although pregnancy (4, 5) or on optimizing the lack of data on birth outcomes in
women with a history of ectopic treatment methods to preserve fertility future pregnancies does not allow us
pregnancy are at risk for repeated (3, 6). Improvements in diagnosis and to identify the pregnancy disorders
ectopic pregnancies (1–3), little is treatment and the increased that should be targeted for prevention
(7, 8).
Received January 9, 2019; revised February 27, 2019; accepted March 11, 2019; published online May The lack of data is compounded by
2, 2019.
M.C. has nothing to disclose. M.-H.M. has nothing to disclose. A.A. has nothing to disclose. J.H.-P. has the changing demographics of preg-
nothing to disclose. N.A. has nothing to disclose. nant women as delayed childbearing
Funded by the Canadian Institutes of Health Research (PJT-156062) and the Fonds de Recherche du
Que
bec - Sante

(career award 34695). becomes more common (9). Advanced
Reprint requests: Nathalie Auger, M.D., M.Sc., 190 Cremazie Blvd E., Montreal, Quebec H2P 1E2, Can- age is a risk factor for ectopic preg-
ada (E-mail: nathalie.auger@inspq.qc.ca).
nancy (1, 2). With more women
Fertility and Sterility® Vol. 112, No. 1, July 2019 0015-0282/$36.00 attempting their first pregnancy at
Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. older ages (10), ectopic pregnancies
https://doi.org/10.1016/j.fertnstert.2019.03.019

112 VOL. 112 NO. 1 / JULY 2019


are becoming more frequent later in life (5). Older maternal
age is also a risk factor for adverse outcomes such as
preterm birth, low birth weight, and cesarean delivery as
well as infertility (10). Older women who have an ectopic
first pregnancy may therefore be particularly concerned
about their future reproductive outcomes (3, 6). There is,
however, little evidence available in the literature to guide
physicians in counseling these women. The purpose of this
study was to determine how ectopic first pregnancy is
associated with the risk of adverse outcomes in future
intrauterine pregnancies, including how the associations
vary according to maternal age.
MATERIALS AND METHODS
Study Design and Population
We designed a population-based retrospective cohort study of
1,117,571 women who were pregnant in Quebec, Canada, be-
tween 1989 and 2013. We used the Maintenance and Use of
Data for the Study of Hospital Clientele registry, an adminis-
trative data set of discharge abstracts from all hospitalizations
in the province (11). We classified each woman's first preg-
nancy as either ectopic or intrauterine. The cohort included
two groups: [1] women who had a surgically treated ectopic
first pregnancy (n ¼ 15,823) and [2] women with an intrauter-
ine first pregnancy and no prior ectopic surgery (n ¼
1,101,748). Information on intrauterine pregnancies that mis-
carried or were terminated before 20 weeks' gestation was not
available in the cohort. We evaluated the women's records
over time to characterize subsequent reproductive events
before March 31, 2013, the end of study. Women with invalid
medical insurance numbers were not included because their
information could not be followed through time.
Ectopic Pregnancy
We used codes from the 9th and 10th revisions of the Interna-
tional Classification of Diseases (ICD 633, O00), Canadian
Classification of Diagnostic, Therapeutic, and Surgical Pro-
cedures (78.52, 81.21), and Canadian Classification of Health
Interventions (5.CA.93) to identify women who had a surgi-
cally treated ectopic first pregnancy. Although we could
determine the surgical method (salpingectomy, salpingos-
tomy, unspecified), women whose ectopic pregnancy was
medically treated in ambulatory clinics could not be identi-
fied. The comparison group included all women whose first
pregnancy was intrauterine, defined as a pregnancy that led
to a live birth or stillbirth after 20 weeks' gestation.
Outcomes
We examined two outcomes capturing the site of the second
pregnancy, defined as either ectopic or intrauterine. We sub-
sequently examined several adverse birth outcomes at the
first intrauterine pregnancy, including preterm birth at
<37 weeks' gestation, low birth weight <2,500 g, multiple
birth, stillbirth, preeclampsia, gestational diabetes, placental
abruption, placenta previa, cesarean delivery, intensive care
unit admission, shock, oligohydramnios, sepsis and other
infection (chorioamnionitis, genital tract and pelvic infection,
VOL. 112 NO. 1 / JULY 2019
Fertility and Sterility®
shock, systemic inflammatory response syndrome, puerperal
infection), thromboembolism, antepartum hemorrhage, post-
partum hemorrhage, and blood transfusion. These outcomes
are commonly examined in epidemiologic analyses of
pregnancy (12–15). We coded the outcomes as binary
variables based on diagnostic and procedure codes
(Supplemental Table 1, available online). For most women
with ectopic pregnancy, the first intrauterine pregnancy
corresponded to the second pregnancy, but a proportion of
women had two or more ectopic pregancies before the first
intrauterine pregnancy (28.2%).
Covariates
We accounted for covariates that could be confounders of
the association between ectopic pregnancy and future reproduc-
tive outcomes (see Supplemental Table 1). We used ICD codes to
identify women with comorbidity defined as preexisting hyper-
tension, type 1 or 2 diabetes, morbid obesity, or substance use
(illicit drug, alcohol, or tobacco). We accounted for abdomino-
pelvic pathology including endometriosis, pelvic inflammatory
disease, polycystic ovary syndrome, and previous abdominopel-
vic surgery. We considered maternal age (<20, 20–24, 25–29,
30–34, R35 years), assisted reproductive technology, socioeco-
nomic status (advantaged, moderate-advantaged, moderate,
moderate-disadvantaged, disadvantaged, unspecified), place of
residence (rural, urban, unspecified), and time period (1989–
1996, 1997–2004, 2005–2012). Information on assisted repro-
ductive technology was available only for women who had an
intrauterine pregnancy that led to a delivery beyond 20 weeks.
Socioeconomic status was assigned based on a composite score
of mean income, education level, and employment rate for
neighborhoods in the Canada Census (16).
Data Analysis
We computed the prevalence of ectopic first pregnancy per
1,000 women with 95% confidence intervals (CI). We calculated
rates of ectopic and intrauterine second pregnancies stratified
by age and site of first pregnancy. We estimated risk ratios
(RR) and 95% CIs using log-binomial regression models to
determine the association of an ectopic first pregnancy with
an ectopic or intrauterine second pregnancy. In these models,
we compared women whose first pregnancy was ectopic
(exposed) with women whose first pregnancy was intrauterine
(unexposed) and adjusted for maternal age, comorbidity, ab-
dominopelvic pathology, socioeconomic status, place of resi-
dence, and time period. We ran additional models with the
data stratified by maternal age at first pregnancy and type of
surgical procedure (salpingectomy vs. salpingostomy).
In the analysis of adverse birth outcomes, we restricted
the data to women who had at least one intrauterine preg-
nancy. We assessed birth outcomes at the first intrauterine
pregnancy in both exposed and unexposed women to ensure
that women were comparable. In parous women, the out-
comes of a second intrauterine pregnancy may not be compa-
rable to women with a history of ectopic pregnancy who
essentially are nulliparous. To avoid selection bias, it is pref-
erable to compare exposed nulliparous women with
113
ORIGINAL ARTICLE: EARLY PREGNANCY

TABLE 1

Prevalence of ectopic first pregnancy according to maternal characteristics.

Ectopic first Prevalence rate per
Characteristics N pregnancy (n) 1,000 (95% CI)
Age (y)a
<20 64,459 924 14.3 (13.4–15.3)
20–24 244,275 2,615 10.7 (10.3–11.1)
25–29 414,413 4,576 11.0 (10.7–11.4)
30–34 278,191 4,319 15.5 (15.1–16.0)
R35 116,233 3,389 29.2 (28.2–30.1)
Comorbidityb
Yes 41,068 563 13.7 (12.6–14.8)
No 1,076,503 15,260 14.2 (14.0–14.4)
Abdominopelvic pathologyc
Yes 89,716 3,200 35.7 (34.5–36.9)
No 1,027,855 12,623 12.3 (12.1–12.5)
ARTd
Yes 5,243 168 32.0 (27.3–36.8)
No 1,103,358 6,685 6.1 (5.9–6.2)
Socioeconomic status
Advantaged 196,824 2,644 13.4 (12.9–13.9)
Moderate-advantaged 205,461 2,832 13.8 (13.3–14.3)
Moderate 206,483 2,915 14.1 (13.6–14.6)
Moderate-disadvantaged 207,619 2,923 14.1 (13.6–14.6)
Disadvantaged 210,903 3,053 14.5 (14.0–15.0)
Place of residence
Rural 191,747 2,582 13.5 (12.9–14.0)
Urban 867,603 12,282 14.2 (13.9–14.4)
Time period
1989–1996 611,921 8,824 17.6 (17.3–18.0)
1997–2004 381,566 3,868 13.3 (12.9–13.7)
2005–2012 124,084 3,131 9.6 (9.3–9.9)
Total 1,117,571 15,823 14.2 (13.9–14.4)
Note: ART ¼ assisted reproductive technology; CI ¼ confidence interval.
a
Age at first pregnancy (ectopic or intrauterine).
b
Preexisting hypertension, type 1 or 2 diabetes, obesity, and drug, alcohol, or tobacco use at the first intrauterine pregnancy (or at the first ectopic if there was no future intrauterine pregnancy).
c
Endometriosis, pelvic inflammatory disease, polycystic ovary syndrome, and abdominopelvic surgery.
d
Information on assisted reproduction was available only for women who had an intrauterine pregnancy (N ¼ 1,108,601).
Chouinard. Outcomes of ectopic pregnancy. Fertil Steril 2019.

unexposed nulliparous women. The exposed group included
women who had at least one surgically treated ectopic preg-
nancy before the first intrauterine pregnancy. The unexposed
group included women with no prior surgically treated
ectopic pregnancy. We estimated the association between
ectopic pregnancy and the future risk of adverse birth out-
comes in log-binomial regression models adjusted for assisted
reproductive techniques and the remainder of the study cova-
riates. We further stratified the analysis by maternal age at
delivery (<30 vs. R30 years) to determine whether the risk
of adverse outcomes was greater among older women.
In the sensitivity analyses we stratified women with an
ectopic first pregnancy by type of surgery to determine
whether the method affected the associations with adverse
birth outcomes. We restricted the analysis to women who
had follow-up observation until 45 years of age to ensure
that the results were robust in women who had completed
childbearing. We ran models without adjusting for assisted
reproductive technology, which may be an intermediate be-
tween ectopic first pregnancy and future outcomes of intra-
uterine pregnancy. We examined the impact of excluding
women who had multiple ectopic pregnancies before their
first intrauterine pregnancy because these women may have
different underlying risk factors for adverse birth outcomes.
Finally, because diagnostic and treatment procedures may
have changed during the study, we compared outcomes in
the first period (1989–1996) with the last (2005–2012).
We performed the analyses in SAS v9.4 (SAS Institute Inc.).
We used 95% CIs to determine statistical significance. Confi-
dence intervals provide information on the precision and range
of potential effect estimates in the population. Because data
from hospital discharge abstracts are anonymized, the institu-
tional review board of the University of Montreal Hospital
Centre determined that ethical review was not necessary.
RESULTS
In this cohort of 1,117,571 women, there were 15,823 women
with a surgically treated ectopic first pregnancy, for a preva-
lence of 14.2 per 1,000 (Table 1). The prevalence of ectopic
first pregnancy increased with age in a dose–response
manner, with the greatest prevalence in women R35 years
(29.2 per 1,000 women). Women with an ectopic first preg-
nancy tended to live in urban areas and be socioeconomically
disadvantaged but did not have more comorbidity. When
compared with women whose first pregnancy was intrauter-
ine, women with an ectopic first pregnancy had lower rates
of an intrauterine second pregnancy (40.5 vs. 54.5 per 100

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TABLE 2

Prevalence of ectopic and intrauterine second pregnancy.

Ectopic second pregnancy Intrauterine second pregnancy
Rate per 100 Rate per 100
First pregnancy N n women (95% CI) n women (95% CI)
Site
Ectopica 15,823 1,594 10.1 (9.6–10.5) 6,404 40.5 (39.7–41.2)
Salpingectomy 8,924 755 8.5 (7.9–9.0) 3,072 34.4 (33.4–35.4)
Salpingostomy 2,062 253 12.3 (10.9–13.7) 919 44.6 (42.4–46.7)
Intrauterine 1,101,748 6,346 0.6 (0.6–0.6) 600,326 54.5 (54.4–54.6)
By age (y)
Ectopic
<20 924 65 7.0 (5.4–8.7) 576 62.3 (59.2–65.5)
20–24 2,615 278 10.6 (9.4–11.8) 1,549 59.2 (57.4–61.1)
25–29 4,576 557 12.2 (11.2–13.1) 2,392 52.3 (50.8–53.7)
30–34 4,319 503 11.6 (10.7–12.6) 1,434 33.2 (31.8–34.6)
R35 3,389 191 5.6 (4.9–6.4) 453 13.4 (12.2–14.5)
Intrauterine
<20 64,667 612 0.9 (0.9–1.0) 45,399 70.2 (69.9–70.6)
20–24 243,465 1,778 0.7 (0.7–0.8) 165,009 67.8 (67.6–68.0)
25–29 410,221 2,286 0.6 (0.5–0.6) 247,810 60.4 (60.3–60.6)
30–34 272,253 1,331 0.5 (0.5–0.5) 117,884 43.3 (43.1–43.5)
R35 111,142 339 0.3 (0.3–0.3) 24,224 21.8 (21.6–22.0)
Note: CI ¼ confidence interval.
a
Information on method used for surgical removal was unspecified for 30.6% of women with an ectopic first pregnancy.
Chouinard. Outcomes of ectopic pregnancy. Fertil Steril 2019.

women) and higher rates of an ectopic second pregnancy
(10.1 vs. 0.6 per 100 women) (Table 2). Compared with salpin-
gostomy, women treated with salpingectomy had lower rates
of an ectopic second pregnancy but also lower rates of an in-
trauterine second pregnancy.
In adjusted models, women with an ectopic first preg-
nancy had over 16 times the risk of having a surgically treated
ectopic at the second pregnancy, compared with women
whose first pregnancy was intrauterine (RR 16.33; 95% CI,
15.43–17.29), and were 19% less likely to have an intrauterine
second pregnancy (RR 0.81; 95% CI, 0.79–0.83) (Table 3).
Relative to no surgery, salpingostomy was associated with a
higher risk of a repeat ectopic pregnancy at second pregnancy
(RR 21.93; 95% CI, 19.31–24.89) than salpingectomy (RR
14.04; 95% CI, 12.99–15.17). Salpingostomy was, however,
associated with a more favorable chance of achieving an in-
trauterine second pregnancy (RR 0.89; 95% CI, 0.84–0.95)
than salpingectomy (RR 0.72; 95% CI, 0.70–0.75). Advanced
maternal age was associated with a lower chance of a subse-
quent intrauterine pregnancy with salpingectomy, and a
greater risk of repeat ectopic pregnancy with salpingostomy.
These associations were weaker in younger women.
Women with an ectopic first pregnancy who achieved a
future intrauterine pregnancy had a greater risk of adverse
pregnancy outcomes (Table 4). Compared with no ectopic pre-
gancy, women with a prior ectopic pregnancy had 1.27 times
the risk of preterm birth (95% CI, 1.18–1.37), 1.20 times the
risk of low birth weight (95% CI, 1.10–1.31), and 1.17 times
the risk of cesarean delivery (95% CI, 1.12–1.21) at their first
intrauterine pregnancy. Ectopic first pregnancy was also

TABLE 3

Association of ectopic first pregnancy with risk of ectopic and probability of intrauterine second pregnancy by age and type of surgery.
Risk ratio (95% CI) for Risk ratio (95% CI) for
ectopic second pregnancya intrauterine second pregnancya
Age groups (y) Any surgery Salpingectomy Salpingostomy Any surgery Salpingectomy Salpingostomy
Allb 16.33 (15.43–17.29) 14.04 (12.99–15.17) 21.93 (19.31–24.89) 0.81 (0.79–0.83) 0.72 (0.70–0.75) 0.89 (0.84–0.95)
At first
pregnancyc
<20 7.43 (5.76–9.60) 5.85 (3.82–8.95) 11.31 (6.64–19.27) 0.90 (0.86–0.94) 0.85 (0.74–0.97) 0.90 (0.73–1.12)
20–24 14.56 (12.83–16.52) 13.20 (11.06–15.75) 17.38 (12.99–23.26) 0.86 (0.84–0.89) 0.83 (0.77–0.89) 0.91 (0.80–1.03)
25–29 21.84 (19.91–23.96) 17.53 (15.43–19.92) 23.18 (18.66–28.81) 0.87 (0.84–0.89) 0.79 (0.75–0.84) 0.91 (0.82–1.01)
30–34 23.82 (21.50–26.40) 15.57 (13.51–17.94) 25.55 (20.10–32.46) 0.78 (0.75–0.81) 0.67 (0.63–0.72) 0.94 (0.82–1.08)
R35 15.39 (12.82–18.46) 11.03 (8.76–13.89) 39.32 (27.53–56.16) 0.61 (0.56–0.67) 0.49 (0.44–0.56) 0.78 (0.58–1.04)
a
Risk ratio adjusted for comorbidity, abdominopelvic pathology, socioeconomic status, place of residence, and time period.
b
Additionally adjusted for age at first pregnancy.
c
Stratified analysis, comparing ectopic first pregnancy relative to intrauterine first pregnancy by age group.
Chouinard. Outcomes of ectopic pregnancy. Fertil Steril 2019.

VOL. 112 NO. 1 / JULY 2019 115

ORIGINAL ARTICLE: EARLY PREGNANCY

TABLE 4

Association of ectopic first pregnancy with adverse outcomes at first intrauterine pregnancy.
Ectopic first pregnancy No ectopic pregnancy Adjusted risk ratio (95% CI)a
Rate per Rate per
Adverse outcomes n 1,000 women n 1,000 women All ages <30 y ‡30 y
Preterm birth, <37 wk b
686 100.1 82,391 74.8 1.27 (1.18–1.37) 1.28 (1.15–1.41) 1.31 (1.14–1.41)
LBW, <2,500 gc 525 76.6 66,633 60.5 1.20 (1.10–1.31) 1.14 (1.00–1.29) 1.29 (1.12–1.41)
Multiple birth 143 21.0 14,597 13.5 1.15 (0.98–1.36) 0.96 (0.71–1.30) 1.31 (1.04–1.55)
Stillbirth 24 3.5 5,299 4.8 0.69 (0.46–1.02) 0.86 (0.51–1.46) 0.54 (0.28–0.99)
Preeclampsia 359 52.4 51,990 47.2 1.18 (1.06–1.31) 1.23 (1.07–1.41) 1.16 (0.98–1.34)
Gestational diabetes 376 54.9 44,873 40.7 1.25 (1.13–1.38) 1.34 (1.14–1.58) 1.22 (1.05–1.36)
Placental abruption 166 24.2 20,954 19.0 1.21 (1.04–1.41) 0.97 (0.75–1.25) 1.42 (1.16–1.69)
Placenta previa 51 7.4 4,550 4.1 1.45 (1.10–1.91) 1.50 (0.90–2.49) 1.48 (1.04–1.99)
Cesarean delivery 1,769 258.1 231,929 210.5 1.17 (1.12–1.21) 1.13 (1.06–1.12) 1.20 (1.14–1.26)
ICU admission 28 4.1 3,325 3.0 1.48 (1.02–2.15) 2.12 (1.37–3.29) 0.84 (0.42–1.68)
Shock 6 0.9 875 0.8 1.12 (0.50–2.50) 1.85 (0.77–4.46) 0.38 (0.05–2.74)
Oligohydramnios 116 16.9 17,125 15.5 1.11 (0.93–1.34) 1.28 (1.00–1.64) 0.96 (0.74–1.25)
Sepsis and other infection 427 62.3 64,493 58.5 1.06 (0.97–1.16) 0.99 (0.86–1.13) 1.12 (0.99–1.27)
Thromboembolism <5 0.6 580 0.5 0.91 (0.34–2.44) 1.75 (0.56–5.45) 0.38 (0.05–2.70)
Hemorrhage
Antepartum 237 34.6 27,295 24.8 1.27 (1.12–1.44) 1.07 (0.86–1.32) 1.41 (1.21–1.64)
Postpartum 399 58.2 61,603 55.9 1.08 (0.98–1.19) 1.01 (0.89–1.15) 1.17 (1.02–1.34)
Transfusion 49 7.2 5,678 5.2 1.44 (1.09–1.91) 1.59 (1.09–2.33) 1.31 (0.86–1.99)
Note: CI ¼ confidence interval; ICU ¼ intensive care unit; LBW ¼ low birth weight.
a
Adjusted for age at first intrauterine pregnancy, comorbidity, abdominopelvic pathology, assisted reproductive technology, socioeconomic status, place of residence, and time period. We strat-
ified women by <30 versus R30 years as the average age of first delivery is 29 years in Quebec.
b
Excludes 80 women with missing data for gestational age.
c
Excludes 185 women with missing data for birth weight.
Chouinard. Outcomes of ectopic pregnancy. Fertil Steril 2019.

associated with preeclampsia, placenta previa, multiple birth,
intensive care unit admission, blood transfusion, and gesta-
tional diabetes. Women with an ectopic first pregnancy did
not have an increased risk of stillbirth, shock, thromboembo-
lism, or postpartum hemorrhage.
The risks of adverse birth outcomes were present in both
older and younger women with a prior ectopic pregnancy, but
some associations were stronger in older women (see Table 4).
Compared with women of the same age, women with a prior
ectopic pregnancy who were 30 years or older at their first de-
livery had a 42% greater risk of placental abruption (RR 1.42;
95% CI, 1.16–1.69), whereas women younger than 30 years
had no increased risk (RR 0.97; 95% CI, 0.75–1.25). Older
women with a prior ectopic pregnancy also had an increased
risk of multiple birth, antepartum hemorrhage, and post-
partum hemorrhage. The risks of preterm birth, low birth
weight, and cesarean delivery were similar for both older
and younger women.
In sensitivity analyses, salpingectomy was associated
with a slightly greater risk of adverse birth outcomes than sal-
pingostomy, but the CIs overlapped (Supplemental Table 2,
available online). When we restricted our analyses to women
who had follow-up observation until 45 years of age, the
prevalence of ectopic second pregnancy was slightly higher
at 11.2 per 100 (95% CI, 10.6–11.9), and the rate of intrauter-
ine second pregnancy was lower at 31.2 per 100 (95% CI,
30.2–32.1). However, the association of ectopic first preg-
nancy with repeat ectopic pregnancy, intrauterine second
pregnancy, and adverse birth outcomes persisted. Removing
assisted reproductive technology from the regression models
slightly strengthened the associations between ectopic first
pregnancy and future adverse birth outcomes. Excluding
women who had two or more ectopic pregnancies before their
first intrauterine pregnancy did not statistically significantly
change the results. When we compared the last study period
(2005–2012) with the first (1989–1996), the rates of ectopic
first pregnancy and repeat ectopic pregnancy were lower.
Women aged 30 years or older at an ectopic first pregnancy
had a higher rate of intrauterine second pregnancy in the
last period.
DISCUSSION
In this study of 15,823 women with surgically treated ectopic
first pregnancies, the risk of repeat ectopic pregnancy
increased with age while the chance of an intrauterine second
pregnancy decreased. Women with ectopic pregnancy who
later achieved an intrauterine pregnancy had higher risks of
adverse outcomes such as preterm birth, low birth weight,
placental disorders, and cesarean delivery. Adverse outcomes
of intrauterine pregnancy were present regardless of age,
although older women were at greater risk of multiple birth,
placental abruption, and placenta previa. Risks were indepen-
dent of the use of assisted reproductive technology and ab-
dominopelvic pathology. These findings suggest that older
women with ectopic first pregnancies have a decreased
chance of a subsequent intrauterine pregnancy, particularly
if they are treated with salpingectomy, and a higher risk of
adverse outcomes if they do achieve an intrauterine
pregnancy.
Little is known about the future birth outcomes of women
with ectopic pregnancies. To our knowledge, only two prior

116 VOL. 112 NO. 1 / JULY 2019


studies examined associations between a history of ectopic
pregnancy and adverse birth outcomes during a later preg-
nancy (7, 8). An analysis of Scottish national data found
that women with an ectopic first pregnancy who had an
intrauterine second pregnancy had higher risks of
preeclampsia, preterm delivery, and emergency cesarean
delivery compared with unexposed women at their second
intrauterine pregnancy (7). However, compared with
unexposed women at their first intrauterine pregnancy,
having a prior ectopic pregnancy was not associated with
an added risk of adverse birth outcomes (7). These findings
differ from ours, as we found that ectopic first pregnancy
was associated with a range of adverse birth outcomes at
the first intrauterine pregnancy. This discrepancy may be
related to differences in study design, as the Scottish study
used women who never had a second pregnancy as the
comparison group, rather than all women at their first
pregnancy regardless of final parity. In another study,
researchers found no increased risk of preterm birth in
women with a prior interstitial ectopic pregnancy (8).
Interstitial ectopic pregnancy is caused by an embryo that
implants in the myometrium near where the fallopian tube
connects to the uterus (8). Interstitial ectopic pregnancy is
rare and accounts for only 2% to 4% of all ectopic
pregnancies (8), so the study may not generalize to the
majority of women.
It is not clear why women with ectopic pregnancy may
have an increased risk of adverse birth outcomes in future
pregnancies, but several factors could contribute. Ectopic
pregnancy is associated with lower fertility (17, 18), and
women with unexplained or subfertility have an increased
risk of many of the same adverse birth outcomes in our
study, particularly placentation disorders (12, 19). In a
prospective study of Danish women planning pregnancy,
the investigators concluded that longer time to conception
was independently associated with poor placentation, a
problem also associated with preterm birth, low birth
weight, antepartum hemorrhage, and cesarean delivery
(12). The researchers found that assisted reproductive
technology did not explain the association between a
longer time to pregnancy and adverse birth outcomes.
Although the role of subfertility and assisted reproductive
technology in the risk of adverse birth outcomes is not
fully understood (13), research has suggested that they
could be linked through hormonal and/or inflammatory
pathways (19, 20).
Risk factors such as previous pelvic surgery or endometri-
osis may also contribute to the association of ectopic preg-
nancy with adverse birth outcomes in subsequent
pregnancies (1, 2). The women with ectopic pregnancy in
our study were all surgically treated, and it is possible that
the surgery itself is linked to the increased risk of adverse
birth outcomes. Surgery is also used to diagnose
reproductive disorders such as endometriosis (20), a risk
factor for ectopic pregnancy that is itself associated with
adverse birth outcomes (19, 21). Most women, however, do
not have identifiable risk factors for ectopic pregnancy (1,
2), and adjusting for some of these disorders did not remove
associations, making it challenging to determine whether
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Fertility and Sterility®
reproductive disorders explain the association with adverse
birth outcomes.
As many ectopic pregnancies require medical interven-
tion (2, 22), the type of management may have a role in the
pathway between ectopic pregnancy and the risk of future
adverse birth outcomes. Our sensitivity analyses pointed to
a slightly increased risk of adverse birth outcomes for
salpingectomy than salpingostomy. Women who have
undergone salpingectomy may have characteristics that
predispose them to more invasive ectopic pregnancies and
adverse birth outcomes. The choice of surgical procedure is
also determined by factors such as surgeon's preference
(22). Although we did not have information on use of
methotrexate, a U.K. study found no difference between
medical and surgical treatment in time to next pregnancy,
and the rates of intrauterine pregnancy and miscarriage (23).
Advanced maternal age is unlikely to contribute to the
findings, despite its association with adverse birth outcomes
(10, 14, 15, 24). Our results indicated that women with an
ectopic first pregnancy had a greater risk of adverse birth
outcomes at their first intrauterine pregnancy regardless of
age, although some associations were stronger in older
women. This was true for placentation disorders such as
abruption and previa among women 30 years and older.
Older women with a previous ectopic pregnancy had a 42%
greater risk of placental abruption compared with no ectopic
pregnancy, whereas no association was present for younger
women. Although the results suggest that older women with
a previous ectopic pregnancy may be at particular risk of
placentation disorders, older women did not have a
disproportionately greater risk of most other adverse birth
outcomes compared with unexposed women of similar age.
The remainder of our findings are compatible with the
current literature on age at ectopic first pregnancy and later
fertility outcomes. Studies have shown that women with a
prior ectopic pregnancy have a higher risk of repeat ectopic
pregnancy and lower rates of intrauterine pregnancy (3, 5, 7),
and that maternal age contributes (3). A French study of the
Auvergne Ectopic Registry found that the chance of
intrauterine pregnancy after an ectopic pregnancy decreased
with age, particularly for women 30 years or older (3). A
Danish study found that the probability of intrauterine
pregnancy increased over time for women with an ectopic
first pregnancy (5), a finding compatible with the trends in
the last time period of our study. Advancements in both
treatment of ectopic pregnancy and assisted reproductive
technology have likely improved the ability of women to
achieve an intrauterine pregnancy (1, 2, 4, 5).
Limitations
Our results should be considered in light of changes in
the availability of assisted reproduction technology over
time and of medical treatment of ectopic pregnancy. In the
latter part of the study, assisted reproductive technology
was fully or partially funded by provincial health insurance
(25), which may have increased the proportion of pregnancies
from these therapies. However, we were limited by lack of
data on assisted reproductive technology for women who
117
ORIGINAL ARTICLE: EARLY PREGNANCY
did not achieve an intrauterine pregnancy. Medical treatment
with methotrexate became more common over time, espe-
cially for women with a previously treated ectopic pregnancy
(22). Methotrexate use nearly doubled in the United States
between 2006 and 2015 (22). Thus, our study is not represen-
tative of all women with a history of ectopic pregnancy
(2, 26, 27). Lack of information on the use of methotrexate
could result in the misclassification of women as having
no repeat ectopic pregnancy in later years of the study, or if
used for ectopic first pregnancies, misclassification of
women as unexposed. Both forms of misclassification may
lead to underestimation of risk ratios and prevent us from
confirming whether the decrease in ectopic pregnancy over
time was due to management or an actual decrease in
numbers.
In addition to time trends, we did not have information
on several risk factors for ectopic pregnancy that could be
confounders, such as sexually transmitted infections or
prenatal exposure to diethylstilbestrol (1, 2). We adjusted
for smoking, but complete smoking history is likely
underestimated. We did not know whether women were
actively trying to conceive or used birth control, and we did
not have information on miscarriages or terminations
before 20 weeks' gestation. Finally, the results most likely
generalize to areas where health insurance is publicly
financed; it is unclear whether these findings would be
similar in other health care delivery settings.
CONCLUSION
Women with ectopic first pregnancies have an increased risk
of adverse birth outcomes in future intrauterine pregnancies,
such as preterm birth, low birth weight, and cesarean delivery.
The risks are present regardless of age. However, women who
have had an ectopic pregnancy who are 30 years or older have
a particularly elevated risk of placental disorders. More study
is needed to determine whether this relationship is present in
other settings. These findings point to new routes for investi-
gation into the shared causes of ectopic pregnancy and
adverse birth outcomes.
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Embarazo ect
opico y resultados del futuro embarazo intrauterino

Objetivo: Proporcionar informaci

on sobre los resultados del nacimiento de futuros embarazos intrauterinos en mujeres cuyo primer
embarazo fue ect

opico.
~o: Estudio de cortes longitudinal basado en la poblaci

Disen on.
Lugar: Todos los hospitales en Quebec, Canad
a, 1989–2013.
Paciente (s): Grupo tratado quir

urgicamente por un primer embarazo ect

opico: 15.823 mujeres; Grupo de comparaci

on con un primer
embarazo intrauterino: 1.101,748 mujeres.
Intervenci
on (es): No aplicable.
Principales medidas de resultado: Embarazo ect
opico repetido, futuro parto de un beb
e vivo, muerte fetal, ces
area, parto prematuro,
bajo peso al nacer, preeclampsia, diabetes gestacional y hemorragia posparto, así como otros resultados del embarazo.
Resultado (s): La prevalencia general del primer embarazo ect
opico fue de 14,2 por cada 1.000 mujeres, de las cuales el 10% de las
mujeres con un primer embarazo ect
opico tuvo un siguiente embarazo ect
opico. Independientemente de la edad, las mujeres con pri-
meros embarazos ect
opicos tuvieron un mayor riesgo de resultados adversos en el parto en futuros embarazos intrauterinos, que in-
cluyen 1,27 veces el riesgo de parto prematuro (intervalo de confianza [IC] del 95%, 1,18–1,37), 1,20 veces el riesgo de bajo peso al
nacer (IC 95%, 1,10–1,31), 1,21 veces el riesgo de desprendimiento de la placenta (IC 95%, 1,04–1,41) y 1,45 veces mayor que el riesgo
de placenta previa (IC 95%, 1,10–1,91). Las mujeres mayores con embarazos ect
opicos anteriores tuvieron particularmente elevado
riesgo de desprendimiento de placenta (tasa de riesgo 1,42; CI 95%, 1,16-1,69).
Conclusi
on (es: ): Las mujeres con primeros embarazos ect

opicos tuvieron un mayor riesgo de resultados adversos en el parto y durante
el siguiente embarazo intrauterino. Estas mujeres pueden beneficiarse de un manejo clínico m
as cercano en el embarazo para prevenir
resultados de nacimiento adversos.

VOL. 112 NO. 1 / JULY 2019 119