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Parental Age and the Risk of Gestational Hypertension

and Preeclampsia
Christopher Ortiz, DO, MS; Nancy U. Rondeau, MPH; Lisa E. Moore, MD; Zuber D. Mulla,

PhD South Med J. 2018;111(9):544-548.

Abstract and Introduction

Abstract

Objectives: To determine the effect of maternal age (MA) and paternal age (PA) on the risk of gestational
hypertension, preeclampsia, and eclampsia in women who delivered on the Texas–Mexico border.
Methods: A cohort study using birth certificate data (singleton pregnancies, years 2005–2010) from El Paso County, Texas,
was conducted. Six parental age–exposure categories were created with MA 20 to 34 years and PA younger than 35 years
serving as the referent. A directed acyclic graph was created. Adjusted risk ratios for the composite outcome of gestational
hypertension, preeclampsia, or eclampsia were calculated using Poisson regression.
Results: A total of 85,114 records were identified, with a majority of the mothers being of Hispanic ethnicity (89.2%). The
incidence of the composite outcome ranged from 2.8% in the MA 20 to 34 years old and PA 35 years and older group to 4.4% in
the MA younger than 20 years old and PA 35 years and older group. Compared to the MA 20 to 34 years old and PA younger
than 35 years group, women in the MA 35 years and older and PA 35 years and older groups were more likely to experience the
outcome (adjusted risk ratio 1.57, 95% confidence interval 1.39–1.77, P < 0.0001).
Conclusions: Couples in which both parents are 35 years old and older should be counseled on the increased risk of
gestational hypertension or preeclampsia/eclampsia.
Introduction
[1]
Preeclampsia is a multisystem disorder characterized by several features, including hypertension and proteinuria. Preeclampsia is
[1]
one of the leading causes globally of maternal and neonatal morbidity and mortality. A study of the temporal trend in the frequency of
[2]
preeclampsia in the United States noted that the prevalence was 3.4% in 1980 and 3.8% in 2010. Multiple risk factors for
[3]
preeclampsia have been identified, including advanced maternal age (MA; 35 years old and older) and obesity.
[4,5]
Across the developed world the proportion of births to women of advanced MA has increased over time. The first-birth rate for women 35
[5]
to 39 years old in the United States increased from 1970 to 2006. A registry-based study of primiparous women conducted in Finland found
a higher risk of preeclampsia in women of advanced MA than in women younger than 35 years old:
[6]
9.4% versus 6.4%. After controlling for parity, maternal body mass index (BMI), and other variables, investigators on the US– Mexico
border (in El Paso, Texas) reported an odds ratio (OR) of 2.55 for preeclampsia (95% confidence interval [CI] 1.04–6.28, P
[7]
= 0.04) for women 35 years old and older compared with women 20 to 24 years old. A retrospective cohort conducted in
Israel detected an adjusted OR of 2.45 (95% CI 1.03–5.85) for preeclampsia-eclampsia for primiparae aged 45 years old and
[8]
older compared with primiparae aged 30 to 35 years.
Although multiple studies have identified advanced MA as a risk factor for preeclampsia, to our knowledge only one investigation,
[9]
conducted by Harlap et al, focused on paternal age (PA) and the joint effect of MA and PA on the risk of preeclampsia. Harlap and
colleagues studied the frequency of preeclampsia in the Jerusalem Perinatal Study, a cohort of live births and stillbirths from 1964 to
[9]
1976. Their analysis of 81,213 deliveries detected adjusted ORs of 1.24 (95% CI 1.05–1.46) and 1.80 (95% CI 1.40– 2.31) for
preeclampsia for fathers who were 35 to 44 years old and 45 years old and older, respectively, when compared with fathers who were
25 to 34 years old. A limitation of this study was the lack of information on the subjects' BMI.

To account for the gap in the literature on the effect of PA, and the joint effect of MA and PA, on the risk of
gestational hypertension and preeclampsia, a retrospective cohort study was conducted using birth certificate data.

Methods

The study protocol was deemed exempt from formal review by the Institutional Review Board for the Protection of
Human Subjects at the Texas Tech University Health Sciences Center El Paso.
Inclusion and Exclusion Criteria

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Birth certificate data for El Paso County, Texas, containing nonsensitive data for the years 2005 through 2010 were analyzed. El
Paso County is located on the Texas–Mexico border. In 2010 the county had a population of 800,647 residents, 82.2% of
[10]
which were Hispanic.
Our sample was restricted to singleton births. The records of pregnancies that resulted from infertility treatments, including artificial
insemination and assisted reproductive technology, were excluded. Additional selection criteria are noted in the Figure.

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Figure.

Identification of the birth certificate records included in the study sample, El Paso County, Texas, 2005–2010.
Data Analysis

Data were analyzed using SAS version 9.3 (SAS Institute, Cary, NC). The birth certificate database did not contain a single
variable for the occurrence of preeclampsia; however, it did contain a gestational hypertension variable that captured the
presence of preeclampsia. Using the combined gestational hypertension-preeclampsia variable and a second variable
recording the occurrence of eclampsia, a composite outcome was created: gestational hypertension, preeclampsia, or
2
eclampsia. Initially, contingency tables were created, frequencies were calculated, and χ tests were performed.
Adjusted risk ratios (RRs) for the composite outcome were estimated from generalized linear models, specifically Poisson
[11]
regression with robust variance, and reported along with 95% CIs. The main exposure variable was parental age. Six groups
based on MA and PA were formed: MA younger than 20 years and PA younger than 35 years, MA 20 to 34 years and PA
younger than 35 years (the referent category), MA 35 years old and older and PA younger than 35 years, MA younger than 20
years and PA 35 years old and older, MA 20 to 34 years and PA 35 years old and older, and MA 35 years old and older and PA
35 years old and older.
A directed acyclic graph was created to assist in determining which predictor variables would be included in the final regression
[12–14]
model. RRs were adjusted for the following dichotomous variables: any maternal smoking during pregnancy, receipt of any
2
prenatal care, ethnicity (Hispanic vs non-Hispanic), obesity (defined as a BMI of ≥30 kg/m ), and nulliparity (nulliparous
vs parous).
[9]
To facilitate a comparison of the results of our study with those of the one conducted by Harlap and colleagues, adjusted RRs
for the composite outcome also were calculated for three paternal age groups (≤24, 35–44, and ≥45 years) with the 25- to 34-
year-old age group serving as the referent category. These three RRs were adjusted for maternal age (a continuous variable, as
Harlap et al had done), any maternal smoking during pregnancy, receipt of any prenatal care, ethnicity (Hispanic vs non-
2
Hispanic), obesity (defined as a BMI of ≥30 kg/m ), and nulliparity (nulliparous vs parous).

Results

A total of 85,114 singleton births were included in our sample (Figure). The majority of the mothers in each parental age group
were of Hispanic ethnicity () and, overall, 89.2% of the mothers were Hispanic. The prevalence of nulliparity varied from 13.4%
in the MA 35 years old and older and PA 35 years old and older groups to 80.2% in the MA younger than 20 years and PA
younger than 35 years groups. The risk of the composite outcome (gestational hypertension, preeclampsia, or eclampsia) was
highest in the MA 35 years old and older and PA 35 years old and older groups (4.0%) and in the MA younger than 20 years
and PA 35 years old and older groups (4.4%).
Table 1. Characteristics of the 85,114 singleton births by MA-PA group, El Paso County, TX, 2005–2010

MA <20, PA MA 20–34, MA ≥35, MA <20, MA 20–34, MA ≥35,

<35 (N = PA <35 (N = PA <35 (N PA ≥35 (N PA ≥35 (N = PA ≥35 (N
Characteristic n (%) 11,157) 54,037) = 2153) = 68) 9946) = 7753) P
Mother of Hispanic ethnicity 10,581 47,763 1921 64 (94.1) 8816 (88.6) 6791 <0.0001
(94.8) (88.4) (89.2) (87.6)
Any prenatal care 10,586 52,119 2072 62 (91.2) 9594 (96.5) 7494 <0.0001
(94.9) (96.5) (96.2) (96.7)
Any smoking during pregnancy 102 (0.9) 651 (1.2) 26 (1.2) 2 (2.9) 112 (1.1) 66 (0.9) 0.01
Obese (pregnancy BMI ≥30 836 (7.5) 10,484 483 (22.4) 10 (14.7) 2243 (22.6) 1981 <0.0001
2
kg/m ) (19.4) (25.6)
Nulliparous 8946 (80.2) 18,864 377 (17.5) 42 (61.8) 2158 (21.7) 1040 <0.0001
(34.9) (13.4)
Pregnancy complicated by 352 (3.2) 1589 (2.9) 72 (3.3) 3 (4.4) 276 (2.8) 312 (4.0) <0.0001
gestational hypertension,
preeclampsia, or eclampsia

MA ranged from 12 to 49 y, whereas PA ranged from 14 to 86 y. BMI, body mass index; MA, maternal age; PA, paternal age.

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Adjusted RRs for the composite endpoint are reported in . Compared with the MA 20- to 34-years-old and the PA younger than
35 years old groups, women in the MA 35 years old and older and PA 35 years old and older groups were more likely to
experience the outcome (adjusted RR 1.57, 95% CI 1.39–1.77). Pregnancies in which the mother was younger than 20 years old
and the father was younger than 35 years old were less likely than pregnancies in the referent category to be complicated by
gestational hypertension, preeclampsia, or eclampsia ().
Table 2. Adjusted RRs for gestational hypertension, preeclampsia, or eclampsia in 85,114 singleton pregnancies in El
Paso County, TX, 2005–2010

Possible risk factor Adjusted RR 95% CI P

MA-PA group, y
MA <20, PA <35 0.88 0.78–0.99 0.03
MA 20–34, PA <35 1 Ref. —
MA ≥35, PA <35 1.31 1.04–1.65 0.02
MA <20, PA ≥35 1.33 0.45–3.99 0.61
MA 20–34, PA ≥35 1.03 0.91–1.17 0.60
MA ≥35, PA ≥35 1.57 1.39–1.77 <0.0001
Dichotomous variables (present vs absent)
Smoking during pregnancy 0.46 0.29–0.74 0.001
Any prenatal care 0.81 0.67–0.98 0.03
Hispanic ethnicity 0.60 0.54–0.66 <0.0001
Obese (prepregnancy BMI ≥30) 1.91 1.76–2.08 <0.0001
Nulliparous 2.20 2.03–2.39 <0.0001

Each RR is adjusted for the remaining variables found in the table. BMI, body mass index; CI, confidence interval; MA,
maternal age; A, paternal age; Ref., referent; RR, risk atio.
Table 2. Adjusted RRs for gestational hypertension, preeclampsia, or eclampsia in 85,114 singleton pregnancies in El
Paso County, TX, 2005–2010

Possible risk factor Adjusted RR 95% CI P

MA-PA group, y
MA <20, PA <35 0.88 0.78–0.99 0.03
MA 20–34, PA <35 1 Ref. —
MA ≥35, PA <35 1.31 1.04–1.65 0.02
MA <20, PA ≥35 1.33 0.45–3.99 0.61
MA 20–34, PA ≥35 1.03 0.91–1.17 0.60
MA ≥35, PA ≥35 1.57 1.39–1.77 <0.0001
Dichotomous variables (present vs absent)
Smoking during pregnancy 0.46 0.29–0.74 0.001
Any prenatal care 0.81 0.67–0.98 0.03
Hispanic ethnicity 0.60 0.54–0.66 <0.0001
Obese (prepregnancy BMI ≥30) 1.91 1.76–2.08 <0.0001
Nulliparous 2.20 2.03–2.39 <0.0001

Each RR is adjusted for the remaining variables found in the table. BMI, body mass index; CI, confidence interval; MA,
maternal age; A, paternal age; Ref., referent; RR, risk atio.
Unadjusted risk estimates of the composite outcome by PA group are shown in . The incidence of the composite outcome was highest in
the group of pregnancies in which the fathers were 45 years old and older. A statistically significant association between

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PA and the outcome was not detected after controlling for MA, maternal smoking, prenatal care, Hispanic ethnicity,
maternal obesity, and parity.
Table 3. Risk of gestational hypertension, preeclampsia, or eclampsia by PA in 85,114 singleton pregnancies in El
Paso County, TX, 2005–2010

† a
PA group, y No. deliveries Risk (%) Adjusted RR 95% CI P
≤24 25,922 3.1 1.11 0.997–1.24 0.06
25–34 41,425 2.9 1 Ref. —
35–44 15,581 3.2 1.04 0.93–1.17 0.50
≥45 2186 4.0 1.20 0.96–1.50 0.12
a
Adjusted for MA (continuous), smoking during pregnancy, prenatal care, Hispanic ethnicity, maternal obesity, and parity.
CI, confidence interval; MA, maternal age; PA, paternal age; Ref., referent; RR, risk ratio.

Discussion

In this retrospective cohort study we detected an elevated risk of gestational hypertension, preeclampsia, or eclampsia in women who
were in the oldest joint parental age group (MA 35 years old and older and PA 35 years old and older) when compared with women in
the MA 20- to 34-years-old and PA younger than 35 years old groups (adjusted RR 1.57). To our knowledge, the only other large study
[9]
of PA and preeclampsia was conducted by Harlap et al. Harlap and colleagues reported adjusted ORs for preeclampsia for several
[9]
PA groups with a PA of 25 to 34 years being the reference category. Among pregnancies in which the mother's age was 35 years
old and older, they found an OR of 1.05 (95% CI 0.66–1.68) for pregnancies fathered by men who were aged 35 to 44 years and an
OR of 1.51 (95% CI 0.92–2.47) for fathers 45 years old and older.
Although both the investigation conducted by Harlap et al and the present study each included >80,000 deliveries and
controlled for multiple factors, a direct comparison between the two studies is complicated by the fact that the ethnic
[9]
distributions of the two cohorts are not similar. Harlap and colleagues analyzed data from the Jerusalem Perinatal Study
[9]
which captured all births to Israelis who resided in the city of Jerusalem and its rural county. In contrast, approximately 89%
of the deliveries in our cohort were to mothers of Hispanic ethnicity (data not shown).
A positive correlation between the father's age and the risk of preeclampsia is biologically plausible. Micronuclei in mammalian cells
[15]
arise from chromosomal fragments and entire chromosomes lagging behind in anaphase. It has been noted that the frequency
[16,17]
of spermatid micronuclei increase with advancing age in mice and Armenian hamsters. Advanced PA may increase the risk
[16]
of chromosomal abnormalities in male germ cells. A review of the literature by Fenech states that an abnormally high
[15]
prevalence of micronuclei in peripheral blood lymphocytes may be associated with preeclampsia.
A strength of the present study was the use of a directed acyclic graph, which guided us in determining which variables should be
[12–14]
included in the final multiple Poisson regression model. We adjusted our RRs for maternal smoking and several other
possible confounders. A protective effect of smoking was noted in our cohort. This inverse association between smoking and
[18,19]
preeclampsia has been reported elsewhere. We chose not to control for diabetes mellitus because it may have been an
intermediate variable between maternal obesity and the outcome of interest. Controlling for an intermediate variable may lead
[13]
to overadjustment bias.
A limitation of our study is the possible misclassification of the preexisting maternal medical conditions and pregnancy
complications that are recorded on the birth certificate. To our knowledge there are no published reports on the accuracy of the
coding of gestational hypertension and preeclampsia on Texas birth certificates. Lydon-Rochelle and colleagues conducted a
validation study of the reporting of preexisting maternal medical conditions and complications of pregnancy that were noted in
live-birth certificate and hospital discharge data using a stratified random sample drawn from 19 nonfederal short-stay hospitals
[20]
in Washington State. Using the patient's medical record as the gold standard, Lydon-Rochelle et al found a true-positive
fraction of the reporting of pregnancy-induced hypertension in birth certificate data, hospital discharge data, and both sources
[20]
combined of 48.6% (95% CI 40.4–56.7), 70.6% (95% CI 61.4–79.7), and 73.5% (95% CI 63.8–83.3), respectively. Similarly,
linking birth certificate data from El Paso County, Texas, with the Texas Hospital Inpatient Public Use Data File (PUDF) may
have resulted in a study with less misclassification of key maternal health conditions and complications of pregnancy; however,
the Data Use Agreement for the PUDF prohibits the licensee from attempting to link the PUDF with personally identifiable records
[21]
from any other source.
Another limitation of our investigation is the unknown accuracy of the reporting of the father's age. Confusion as to paternity may
lead to the recording of an erroneous age for the father in the live-birth certificate. Discordance between the apparent father of a
[22,23]
child and the actual (biological) father is known as nonpaternity or paternal discrepancy. A review of 17 studies by Bellis
[23]
and colleagues revealed that the rate of paternal discrepancy varied between 0.8% and 30%, with a median of 3.7%.

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The usefulness of weak associations detected by observational studies has been a topic of interest for some years in the health
[24,25]
sciences. Healthcare providers are bombarded with an increasing volume of study results and must identify those
associations that have both statistical and clinical significance. For risk factors (exposures) that increase the probability of an
[24]
adverse outcome, an RR that is <3 identifies the presence of a weak or moderate association rather than a strong one.
Our study detected an RR of 1.57 associated with the exposure of advanced MA and PA compared with the referent. A statistic
that combines information on the RR and how common the risk factor is in the population (the prevalence of the exposure) is the population
[26,27]
attributable risk. The population attributable risk is the excess risk of disease in the total population of exposed
[26]
and nonexposed individuals that is attributable to that exposure. A moderate RR coupled with a high prevalence can result in
a high population attributable risk. A high population attributable risk indicates that the risk factor is of importance to the health of
[27] [28]
the population. Given the increase in delayed childbearing worldwide, future studies of the impact of parental age on the
risk of preeclampsia should strive to report confounder-adjusted estimates of population attributable risk in addition to adjusted
RRs.

Conclusions

Our investigation adds to the literature on parental age and the frequency of hypertensive disorders of pregnancy. Couples in
which both parents are 35 years old and older should be counseled on the increased risk of gestational hypertension or
preeclampsia/eclampsia. Prenatal care with close observation by an obstetrician is especially important in women of advanced
[29]
maternal age to promptly detect and manage preeclampsia. In the setting of potential or actual morbidity, referral to a
maternal-fetal medicine specialist may be indicated. Younger women who intend to delay childbearing may consider elective
[28]
oocyte cryopreservation. Similarly, young men who plan to delay paternity can cryopreserve sperm; however, they should
[30]
be aware of the cost and the possible deleterious effects that cryopreservation may have on semen.

Sidebar
Key Points

There is a gap in knowledge with regard to the effect of advanced paternal age on the risk of hypertensive disorders
of pregnancy.
Six parental age groups were created with pregnancies in which the mother was 20 to 34 years old and the father
was younger than 35 years old serving as the comparison group.
Pregnancies in which both parents were 35 years old or older were 57% more likely than pregnancies in the
comparison group to be complicated by gestational hypertension or preeclampsia (adjusted risk ratio 1.57, 95%
confidence interval 1.39–1.77, P < 0.0001).
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