The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Trisomy 13 and the risk of gestational

hypertensive disorders: A population-based study

Sarah K Dotters-Katz, Whitney M. Humphrey, Kayli L. Senz, Vanessa R. Lee,

Brian L. Shaffer, Jeffrey A. Kuller & Aaron B. Caughey

To cite this article: Sarah K Dotters-Katz, Whitney M. Humphrey, Kayli L. Senz, Vanessa R.
Lee, Brian L. Shaffer, Jeffrey A. Kuller & Aaron B. Caughey (2017): Trisomy 13 and the risk of
gestational hypertensive disorders: A population-based study, The Journal of Maternal-Fetal &
Neonatal Medicine, DOI: 10.1080/14767058.2017.1332037

To link to this article: http://dx.doi.org/10.1080/14767058.2017.1332037

Accepted author version posted online: 17

May 2017.

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Trisomy 13 and the risk of gestational hypertensive disorders: A population-based study

Running Head: T13 and preeclampsia risk

Sarah K DOTTERS-KATZ, MD1; Whitney M. HUMPHREY, MD2; Kayli L. SENZ, MD3;

Vanessa R. LEE, MD, MPH4; Brian L. SHAFFER, MD4; Jeffrey A. Kuller, MD5; Aaron B.

CAUGHEY, MD, PhD4

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Division of Maternal Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill,

North Carolina
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2
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan

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Department of Obstetrics and Gynecology, Case Western Reserve University, Cleveland, Ohio
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Division of Maternal Fetal Medicine, Oregon Health & Sciences University, Portland, Oregon

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Division of Maternal Fetal Medicine, Duke University, Durham, North Carolina
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Disclosure: The authors report no conflict of interest

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Funding: None

Prior presentation: This paper was presented in part at the 36th annual Society of Maternal Fetal

Medicine Meeting in 2016, Atlanta, Georgia as a poster presentation.

Corresponding Author:

Sarah Dotters-Katz, MD

Division of Maternal-Fetal Medicine, University of North Carolina

3010 Old Clinic Building, CB # 7516,

Chapel Hill, NC 27599-7516

Phone: 919-966-4103 / Fax: 919-966-6377 / Email: sarahdk@med.unc.edu

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Abstract word count: 193

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Main text word count: 1929 EP
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Abstract:

Purpose: To describe the rate and severity of gestational hypertensive disorders (GHD) in

pregnancies complicated by trisomy 13 (T13).

Materials and Methods: Retrospective cohort study of singleton deliveries in California from

2005-2008 using vital statistics and ICD-9 data. We were interested in gestational hypertension

(gHTN), preeclampsia with and without severe features (sPREX and PREX), and gestational age

at delivery. Pregnancies and maternal complications affected by prenatally diagnosed T13 were

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compared to unaffected pregnancies. Regression models were used to compute adjusted odds

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ratios for pregnancy outcomes by T13 status.

Results: Of the 2,029,004 deliveries, 142 women had prenatally diagnosed T13. A diagnosis of
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GHD occurred in 26.8% of the T13 pregnancies versus 6% of the non-T13

pregnancies(p<0.001). This remained true for gHTN (9.2% vs 3.2%,p=0.001), PREX (12% vs
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2.2%,p<0.001), and sPREX (8.5% vs 0.9%,p<0.001). After adjusting for confounders, T13
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pregnancies were 6.3-times more likely to be affected by GHD, and 12.5-times more likely to

have sPREX. Delivery <37 and <32 weeks in the setting of GHD was 14.1-times and 11.2-times
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likely among women with T13.

Conclusion: Women with T13 pregnancies were significantly more likely to have gHTN,
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preeclampsia, sPREX, and to deliver <32 weeks.

Key words: Trisomy 13, Patau syndrome, Maternal outcomes, gestational hypertension,

preeclampsia
Introduction:

Trisomy 13 (T13), also known as Patau Syndrome, is uncommon, occurring in 1 in

5,000-10,000 live births, as it commonly results in spontaneous abortion.[1, 2, 3] It is the third

most common trisomy in live born babies and is associated with increasing maternal age. This

life-limiting condition is characterized most commonly by cardiac defects, holoprosencephaly,

growth restriction, rocker bottom feet, and cleft lip and palate; though a variety of other

anomalies have been associated with it.[1, 4, 5, 6] Most commonly, trisomy 13 is due to a de

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novo nondisjunction of chromosome 13, but it can also be due to an unbalanced translocation

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inherited from a parent with a balanced translocation.[7]

Trisomy 13 has been associated with an increased risk of preeclampsia; in small series,
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the incidence of preeclampsia in women with a fetus with T13 ranged between 25-40%;

suggesting an increased risk by 2-20 fold.[8, 9, 10, 11, 12] Due to the small size of these series,
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all with 25 or fewer cases, a detailed understanding of the severity of preeclampsia was
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precluded. It was unclear if the preeclampsia associated with trisomy 13 was mostly mild disease

that presented at term or more likely to be severe disease presenting very early in gestation.

Due to this dearth of knowledge, this important aspect of the trisomy 13 is often omitted
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or glossed over in maternal counseling, with the main focus of counseling on neonatal survival

and outcomes. However, given the maternal danger that can be associated with gestational
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hypertensive disease, a better understanding of this risk is critical. Thus, the objective of this

study was to better describe the rate and severity of hypertensive disorders in pregnancies

complicated by trisomy 13. We also sought to define the risk of maternal complications in this

setting.
Materials and Methods:

After approval from the Institutional Review Boards at Oregon Health & Science

University and the State of California, we conducted a retrospective cohort study using

California Vital Statistics Birth Certificate Data, California Patient Discharge Data, Vital

Statistics Death Certificate, and Vital Statistics Fetal Death File data. These linked datasets

describe maternal and child data from all pregnancies in California from 2005-2008.

Using the Internal Classification of Diseases, 9th Revision code for fetal trisomy 13

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(758.1), coded during the delivery admission, we identified women with a pregnancy

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complicated by a prenatal diagnosis of T13. Women with multiple gestations, other aneuploidies,

other major fetal anomalies not associated with trisomy 13, and those who delivered at <23 or
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>43 weeks were excluded. These datasets include no patient identifiers. Therefore, informed

consent was not necessary.

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Maternal demographics and antepartum complications, specifically any gestational

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hypertensive disorder (GHD), gestational hypertension (gHTN), preeclampsia without severe

features (PREX), preeclampsia with severe features (sPREX), eclampsia, and gestational
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diabetes was collected. Delivery and postpartum information including delivery prior to 37

weeks, delivery prior to 32 weeks, cesarean delivery, abruption, postpartum hemorrhage, red cell
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transfusion, platelet transfusion, and maternal length of stay were also obtained.

Women with a T13 fetus were compared to those with an unaffected fetus using bivariate

analysis, including chi-squared and student’s t-tests as appropriate. A planned sub-group analysis

of women with a prenatal diagnosis of T13 to those with an unaffected infant among only

women with a diagnosis of any GHD was also performed. The analyses were performed using
Stata software (version 11; Stata Corporation, College Station, TX). Multivariable logistic

regression was performed to control for potential confounders, including maternal age (≥35 or

<35 years), maternal race/ethnicity, educational level (≥12th grade or <12th grade), less than 5

prenatal visits, parity, diabetes, gestational diabetes, chronic hypertension, and insurance (public

vs private). A p-value of less than 0.01 and 95% confidence intervals (CIs) were used to

determine statistical significance due to the large sample size and to reduce the risk of spurious

associations.

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Results:

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The study population included 2,029,004 singleton pregnancies, including 142 that

carried a prenatal diagnosis of trisomy 13. In this population, the overall prevalence of known
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T13 was 0.007% or 7 per 100,000 live births. Women with a prenatal diagnosis of T13 were

more likely to be aged 35 or older and nulliparous (Table1).

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Women with fetal T13 were four times more likely to have any GHD (27% vs 6%,

p<0.001). They were significantly more likely to have gHTN, PREX, and sPREX, but not

eclampsia, (Table 2). Preterm delivery less than 37 weeks occurred in 51% of women with fetal
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T13 and only 9.9% of those without T13, (p<0.001). Women with a T13 fetus were also more

likely to delivery at less than 32 weeks (14.1% vs 1.4%, p<0.001). Cesarean delivery and
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cesarean delivery in a nulliparous woman were also more common among women with fetal T13

(Table 2). However, abruption, postpartum hemorrhage, and product transfusion were not more

common in pregnancies with T13 compared to those without T13, (Table 2).

Thirty-eight of the 142 of women (27%) with T13 developed some GHD, compared to

6% of women without a T13 fetus. When considered only women with a diagnosis of gestational
hypertensive disorder, cesarean delivery occurred in 60.5% of those with T13, but only 46.5% of

those without T13, (p=0.082). Among women with T13 and any GHD, 76% delivered prior to 37

weeks, with 34% delivering less than 32 weeks, compared to 23% and 4% respectively in

women without a T13 fetus, (p<0.001 for both). Rates of postpartum hemorrhage, abruption,

and blood transfusion did not differ between among women with GHD by fetal T13 status (data

not shown). When considering women with preeclampsia with severe features, 83% of those

with a T13 fetus delivered less than 37 weeks, compared to 53% of those without a T13 fetus

(p=0.035); and 50% with a T13 fetus but only 14% of those with a normal fetus delivered less

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than 32 weeks (p<0.001).

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After controlling for maternal age (≥35 or <35 years), maternal race/ethnicity,
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educational level (≥12th grade or <12th grade), less than 5 prenatal visits, parity, diabetes,

gestational diabetes, chronic hypertension, and insurance (public vs private), pregnancies

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complicated by fetal T13 were associated with a 6-fold higher odds of developing any gestational
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hypertensive disorder (95% CI 4.17, 9.51), a 9-fold higher odds of developing PREX, and 12.5-

fold higher odds of developing preeclampsia with severe features (Table 3). Among women with

T13 and a gestational hypertensive disorder, there was also a significantly increased odds ratio of
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delivery at less than 37 and 32 weeks, (aOR 14.1 95% CI 5.77, 34.3 and aOR 11.2 95% CI 5.24,

23.9 respectively). Maternal complications such as abruption and platelet transfusion approached
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but did not reach significance (Table 3).

Discussion:

In this study, a diagnosis of any gestational hypertensive disorder was made in 27% of

women with carrying a fetus with trisomy 13. Among women with T13, 27% developed

preeclampsia, and 9% developed preeclampsia with severe features. Women with a T13 fetus

had a 9-fold higher odds of developing PREX, and 12.5-fold higher odds of developing

preeclampsia with severe features compared to those without a T13 fetus. Among women with

any gestational hypertensive disorder, women with a T13 fetus were 3.4 times and 8.6 times

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more likely to deliver as less than 37 and 32 weeks respectively, and 2.5 times increased odds of

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cesarean delivery.

To our knowledge, this is the first study to specifically examine the relationship between
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a diagnosis of fetal trisomy 13 and the spectrum of gestational hypertensive disorders, as well as

the first population based study of this topic. Case control studies looking at risk of preeclampsia
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in general are limited in size, with the largest having 25 cases.[8, 11, 12] The incidence of
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gestational hypertensive disorders in these case-control studies ranged from 25-40%; our cohort

showed a similar incidence.[8, 11, 12] It should also be noted, that though T13 and trisomy 18
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are often grouped in studies, there does not appear to be similar increased incidence of

gestational hypertensive disorder associated with trisomy 18.[13]

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There are many strengths of this study. Because this dataset comprises such a sizable

population, we are able to study rare conditions and outcomes. This present study is the largest

cohort of trisomy 13 neonates, and the only study specifically designed to define the relationship,

timing, and complications of preeclampsia in the setting of trisomy 13. However, there are also

limitations to this study as well. First, we are reliant on coders to correctly identify and code our

primary exposure, fetal T13, as well as our outcomes variables. This does increase the risk of
underreporting. However, most commonly a misclassification bias is generally towards the null.

In other words, if this were the case, it suggests that the findings of this study underestimate

lower the actual relationship between preeclampsia and trisomy 13. As this study was

specifically looking at women who continued their pregnancies, we only included women who

delivered after 23 weeks and 0 days, and thus did not include women who elected termination of

pregnancy or had a spontaneous loss prior to that time. We were also limited by available codes in

the dataset, such as lack of coding for admission to the intensive care unit or maternal death. We

also could not assess if any T13 diagnoses were made during or after delivery for an infant

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originally in the non-affected group, in the case of a woman with a positive screening test who

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did not pursue diagnostic testing. However, it is very unusual for a fetus to have trisomy 13 to

not have major anomalies (and thus not be brought to attention by prenatal ultrasound), and we
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did exclude fetuses without a trisomy 13 diagnosis who had major anomalies. Additionally, there

is no way to account for mosaicism within this cohort. Though this cohort only includes those
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fetuses with a prenatal diagnosis, thus if a family did not pursue diagnostic testing, that fetus
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would not have been included. Most mosaic fetuses have more mild phenotype, again biasing the

study toward the null. From a maternal perspective, data regarding maternal history of
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preeclampsia, a known risk factor for the development of preeclampsia in a subsequent

pregnancy, was not available. Finally, due to the retrospective nature, we are unable to assess
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causation, but can only describe an association of trisomy 13 with gestational hypertensive

disorders and other obstetric outcomes. Future prospective studies could focus on more specifics

of maternal outcomes among with trisomy 13 and preeclampsia.

In summary, given that 1 in 3 women with a T13 pregnancy will develop some

gestational hypertensive disorder and 1 in 10 will develop severe disease, the clinician must
consider incorporating the risk of gestational hypertensive disorders into counseling for women

and couples with a prenatal diagnosis of Trisomy 13. While future study is needed to better

understand the reasons for this association as well as the maternal outcomes associated with this

range of gestational hypertensive disorders, the provider must be cognizant of the increased risk

and counsel/manage the patient accordingly.

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References:
1. Bruns D. Birth history, physical characteristics, and medical conditions in long-term
survivors with full trisomy 13. American journal of medical genetics Part A. 2011;155A:2634-40.
Epub 2011/10/13.
2. Morris JK, Savva GM. The risk of fetal loss following a prenatal diagnosis of trisomy 13 or
trisomy 18. American journal of medical genetics Part A. 2008;146A:827-32. Epub 2008/03/26.
3. Wladimiroff JW, Stewart PA, Reuss A, Sachs ES. Cardiac and extra-cardiac anomalies as
indicators for trisomies 13 and 18: a prenatal ultrasound study. Prenatal diagnosis. 1989;9:515-20.
4. Dotters-Katz SK, Kuller JA, Grace MR, Laifer SA, Strauss RA. Management Considerations for
Ongoing Pregnancies Complicated by Trisomy 13 and 18. Obstet Gynecol Surv. 2016;71:295-300.
5. Maeda J, Yamagishi H, Furutani Y, Kamisago M, Waragai T, Oana S, Kajino H, Matsuura H,
Mori K, Matsuoka R, Nakanishi T. The impact of cardiac surgery in patients with trisomy 18 and
trisomy 13 in Japan. American journal of medical genetics Part A. 2011;155A:2641-6. Epub
2011/10/13.
6. Nelson KE, Rosella LC, Mahant S, Guttmann A. Survival and Surgical Interventions for
Children With Trisomy 13 and 18. JAMA. 2016;316:420-8.

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7. Jacobs PA, Hassold TJ, Henry A, Pettay D, Takaesu N. Trisomy 13 ascertained in a survey of
spontaneous abortions. Journal of medical genetics. 1987;24:721-4.

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8. Bower C, Stanley F, Walters BN. Pre-eclampsia and trisomy 13. Lancet. 1987;2:1032.
9. Evers J, Seelen J, Blankenborg G. Severe toxemia, hydramnios and trisomy 13-15. Ned
Tijdschr Verloskd Gynaecol. 1967;67:395-7.
10. Silasi M, Rana S, Powe C, Cohen B, Lim KH, Zsengeller ZK, Karumanchi SA, Stillman IE.
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Placental expression of angiogenic factors in Trisomy 13. Am J Obstet Gynecol. 2011;204:546 e1-4.
11. Tuohy JF, James DK. Pre-eclampsia and trisomy 13. British journal of obstetrics and
gynaecology. 1992;99:891-4. Epub 1992/11/01.
12. Boyd PA, Lindenbaum RH, Redman C. Pre-eclampsia and trisomy 13: a possible association.
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Lancet. 1987;2:425-7.
13. Dotters-Katz S, Kuller J, Heine RP. Parasitic infections in pregnancy. Obstet Gynecol Surv.
2011;66:515-25.
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Table 1: Maternal Demographics of pregnancies with a prenatal diagnosis of Trisomy 13 vs
the control population
Variable T13 Diagnosis No T13 Diagnosis p-value
% (n=142) % (n=2,028,862)
Maternal age ≥35yrs 37.3 (53) 20.9 (350,333) <0.001
Race 0.087
African American 6.3 (9) 5.1 (103,841)
White 18.3 (26) 26.6 (538,781)
Hispanic 64.8 (92) 54.5 (1,103,587)

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Asian / Pacific 9.2 (13) 11.9 (241,906)
Islander

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Other 1.4 (2) 1.9 (38,412)
Education, grade 0.080
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<12 62.9 (83) 55.1 (1,087,040)
≥12 27.1 (49) 44.9 (882,821)
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Public Insurance 56.6 (81) 48.4 (982,232) 0.044
Nulliparous 25.5 (36) 39.9 (807,319) <0.001
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Less than 5 prenatal 7.9 (11) 3.9 (78,199) 0.026

visits
Chronic Hypertension 2.8 (4) 1.1 (23,124) 0.080
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Diabetes Mellitus 1.4 (2) 0.80 (16,058) 0.310

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Table 2: Unadjusted incidence of maternal complications in pregnancies affected by
prenatally diagnosed T13 vs control population
Variable T13 Diagnosis No T13 Diagnosis p-value
% (n=142) % (n=2,028,862)
Gestational Diabetes 7.8 (11) 6.5 (132,015) 0.50
Gestational hypertension 9.2 (13) 3.2 (65,726) 0.001
Preeclampsia w/o SF 12.0 (17) 2.2 (44,073) <0.001
Severe preeclampsia 8.5 (12) 0.91 (17,520) <0.001
Eclampsia 0 0.07 (1,437) >0.99
Any gestational 26.8 (38) 6.0 (122,068) <0.001

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hypertensive disorder

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Preterm delivery <37wks 50.7 (72) 9.9 (2000,971) <0.001
Preterm delivery <32 wks 14.1 (20) 1.4 (28,795) <0.001
Intrauterine fetal demise 0.70 (1) 0.28 (5,659) 0.327
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Any cesarean delivery 53.5 (76) 30.2 (612,736) <0.001
Primary cesarean delivery 61.1 (20) 29.7 (239,661) <0.001
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in nulliparous patient
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Abruption 2.8 (4) 0.87 (17,708) 0.037

Postpartum hemorrhage 1.4 (2) 2.9 (58,503) 0.45
Platelet transfusion 0.7 (1) 0.06 (1,144) 0.077
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Blood transfusion 2.1 (3) 0.63 (12,825) 0.062

Length of stay 3.3 +/- 3.95 2.5 +/- 3.55 0.006
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Mean cost of maternal 9,982 ± 11,905 7,727 ± 6872 <0.001

delivery hospitalization,
±SDb
b
Cost in US dollars
Table 3: Adjusted odds ratios for outcomes of pregnancies with a prenatal diagnosis T13 vs
control populationa
Outcome Adjusted Odds 95% confidence p-value
ratio interval

Gestational Hypertension 3.22 (1.70, 6.09) <0.001

Preeclampsia 8.84 (5.64, 13.9) <0.001
Preeclampsia with severe 12.5 (6.58, 23.7) <0.001
features
Any gestational hypertensive 6.3 (4.17, 9.51) <0.001
disorder

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Gestational hypertensive 14.1 (5.77, 34.3) <0.001
disorder and delivery <37wk

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Gestational hypertensive 11.2 (5.24, 23.9) <0.001
disorder and delivery <32wk
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Any cesarean delivery 2.50 (1.76, 3.55) <0.001
Postpartum hemorrhage 0.53 (0.13, 2.16) 0.38
Abruption 3.11 (1.15, 8.47) 0.026
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Platelet transfusion 11.4 (1.58, 81.9) 0.016

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Blood transfusion 3.17 (1.01, 10.0) 0.049

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Adjusted for maternal age (≥35 or <35 years), maternal race/ethnicity, educational level (≥12th
grade or <12th grade), less than 5 prenatal visits, parity, diabetes, gestational diabetes, chronic
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hypertension, and insurance (public vs private).

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