First-trimester markers of aneuploidy in women.pdf

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First-trimester markers of aneuploidy in womenpositive for HIVMD Savvidou,a I Samuel,b A Syngelaki,c M Poulton,b KH Nicolaidesc

a Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital b Department of Sexual

Health and HIV c Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, London, UK

Correspondence: MD Savvidou, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster

Hospital, 369 Fulham Road, London SW10 9NH, UK. Email [email protected]

Accepted 17 September 2010. Published Online 10 November 2010.

Objective To investigate whether the sonographic and maternal

serum biochemical markers used in first-trimester screening for

chromosomal abnormalities are altered in pregnancies affected by

maternal HIV infection.

DesignNested casecontrol study.

Setting Routine antenatal visit in a teaching hospital.

PopulationNinety HIV-positive and 450 HIV-negative pregnant

women.

MethodsFindings from first-trimester antenatal visit for

calculation of the risk for chromosomal abnormalities were

compared between HIV-positive (treated and untreated) and

HIV-negative women.

Main outcome measuresFirst-trimester maternal serum free b

human chorionic gonadotrophin (free b-hCG) pregnancy-

associated plasma protein-A (PAPP-A) and fetal nuchal

translucency thickness (NT), were compared.

ResultsThere were no statistically significant differences

between the HIV-positive and HIV-negative women in the

median maternal levels of free b-hCG, PAPP-A and fetal NT.

However, within the HIV-positive group those receiving

antiretroviral treatment (n = 41) had a significantly lower

median multiple of the median (MoM) for free b-hCG (0.74,

interquartile range [IQR] 0.451.32 MoM) than HIV-positive

women on no treatment (1.03, IQR 0.761.85 MoM; P= 0.006)

and HIV-negative women (1.0, IQR 0.681.47 MoM;

P = 0.003). There was no correlation between the level

of free b-hCG or PAPP-A and maternal viral load or CD4+

count.

Conclusions Maternal levels of free b-hCG in treated HIV-positive

pregnant women were lower compared with those in non-treated

HIV-positive and HIV-negative women, whereas the PAPP-A

levels and fetal NT remained unaltered.

KeywordsChromosomal abnormalities, first trimester, free

b-human chorionic gonadotrophin, HIV, pregnancy,

pregnancy-associated plasma protein-A.

Please cite this paper as: Savvidou M, Samuel I, Syngelaki A, Poulton M, Nicolaides K. First-trimester markers of aneuploidy in women positive for HIV.

BJOG 2011;118:844848.

Introduction

In the past two decades, acquisition of human immunode-

ficiency virus (HIV) has reached epidemic levels globally,

as there are an estimated 33 million people living withHIV. Women account for half of these people and the

majority of them are of reproductive age.1 In the UK, the

introduction of routine antenatal screening, with 95% of

pregnant women accepting antenatal HIV testing, has

enabled the identification of the vast majority of HIV-posi-

tive pregnant women.2 Additionally, the introduction of

highly active anti-retroviral treatment in pregnancy has

reduced the risk of mother-to-child transmission to around

1%, leading to a rising number of pregnancies in these

women.3 As a result of these changes, the prevalence of

HIV among women giving birth in the UK has increased

five-fold over the past decade.2

Effective screening for chromosomal abnormalities in thefirst trimester of pregnancy is provided by assessment of a

combination of maternal age, measurement of fetal nuchal

translucency (NT), maternal serum free b-human chorionic

gonadotrophin (free b-hCG) and pregnancy-associated

plasma protein-A (PAPP-A).4 This method of screening,

which gives a detection rate for trisomy 21 of 90% for a

5% false-positive rate, is now recommended for all preg-

nant women in the UK.5 Free b-hCG and PAPP-A are

844 2010 The Authors Journal compilationRCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology

DOI: 10.1111/j.1471-0528.2010.02767.x

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known to be affected by maternal race, weight, smoking

status, gestational age, parity and method of conception.6,7

Conversely, little is known about the effect of the maternal

immune status, as regards HIV status, on their levels.812

The aim of the study was to assess whether the first-

trimester maternal serum levels of free b-hCG and PAPP-

A, used for the assessment of risk of chromosomal

abnormalities, are affected by the presence of maternal

HIV.

Methods

This was a casecontrol study from an ongoing prospective

study to identify potential biomarkers of pregnancy com-

plications in women attending for their routine first hospi-

tal visit in pregnancy at Kings College Hospital, UK. In

this visit, which is held at 11+013+6 weeks of gestation, all

women have an ultrasound scan, first, to confirm

gestational age from the measurement of the fetal crown

rump length (CRL); second, to diagnose any major fetalabnormalities; and third, to measure the fetal NT thickness

as part of screening for chromosomal abnormalities. In

addition, the maternal serum free b-hCG and PAPP-A are

determined and the results are combined with maternal age

and fetal NT to calculate the patient-specific risk for tri-

somy 21 and trisomy 13/18. All blood samples were pro-

cessed immediately and an automated machine that

provides reproducible results within 30 minutes, was used

to measure free b-hCG and PAPP-A (Delfia Express Sys-

tem; Perkin Elmer, Waltham, MA, USA). Maternal demo-

graphic characteristics, ultrasonographic measurements and

biochemical results were recorded in a computer database

where details on pregnancy outcomes were added as soon

as they became available.

The casecontrol study population comprised 90 HIV-

positive women with singleton pregnancies and a live birth.

For each HIV-positive woman, five HIV-negative women

were selected, matched according to the date of scan and

consequently the date of the biochemical measurements.

The study period was from March 2006 to August 2009

and during this period we examined 35 964 singleton preg-

nancies. Among the 90 HIV-positive women, 41 (45.5%)

were on anti-retroviral treatment (median duration of

treatment: 20 months) including 17 women (41.5%) on

nucleoside reverse transcriptase inhibitor (NRTIs) and aprotease inhibitor, 23 women (56%) on NRTIs and a non-

NRTI and one woman (2.5%) on monotherapy. Informa-

tion on the viral load and CD4+ count, at a date closest to

the scan date, was also obtained. Approval by the local

Research Ethics Committee was sought but was not

thought to be necessary under the terms of the Governance

Arrangements for Research Ethics Committees in the UK.

Furthermore, women in our centre routinely give written

informed consent for their data to be used for audit and

research purposes.

Statistical analysisIn the cases and controls the measured serum PAPP-A and

free b-hCG were converted to multiples of the expected

normal median (MoM) corrected for fetal CRL, maternal

weight, smoking, parity, racial origin and method of con-

ception as previously described.6 The measured NT was

expressed as a difference from the expected normal mean

for gestation (delta value).13 Normality of the data distribu-

tion was examined with the KolmogorovSmirnov test and

probability plots. Data were expressed as mean standard

deviation or as median and interquartile range (IQR) for

normally and non-normally distributed data, respectively.

Comparisons between groups were performed using

Students t test, MannWhitney U test or chi-square test

for numerical and categorical data, respectively. Power

calculation indicated that a sample of 90 HIV-positive and

450 HIV-negative women would have more than 80%power with an alpha 0.05 (two-tails) for the detection of a

mean difference of 0.25 MoM in free b-hCG (1:5 matched

case controls). The effect size was estimated from previous

publications.12 The statistical analyses were performed using

the SPSS (Version 12.0, SPSS Inc., Chicago, IL, USA).

Results

The maternal demographic and pregnancy characteristics

and outcomes of the 90 HIV positive and 450 HIV negative

women are given in Table 1. None of the neonates in this

study was affected by a chromosomal abnormality. The

HIV positive women, compared with the HIV-negative

group, were more likely to be black, heavier and non-

smokers and were more likely to deliver earlier and have

smaller neonates. There were no significant differences

between the HIV-positive and HIV-negative pregnancies in

fetal CRL and NT or in maternal adjusted levels of free

b-hCG and PAPP-A.

The maternal demographic and pregnancy characteristics

and outcome of the HIV-positive women depending on the

use of anti-retroviral treatment are also given in Table 1.

Women receiving anti-retroviral treatment (n = 41) were

more likely to be older and had a significantly lower med-

ian serum free b-hCG than HIV-positive women on notreatment and HIV-negative women (0.74, IQR 0.451.32

MoM versus 1.0, IQR 0.681.47 MoM; P= 0.003). In the

HIV group on treatment, there was no significant statistical

correlation between maternal serum free b-hCG and dura-

tion of treatment (P = 0.081). Similarly, there was no sig-

nificant difference in maternal median serum free b-hCG

between those receiving NRTIs together with a protease

inhibitor and those on a combination of NRTIs and a non-

Maternal levels of free b-hCG and PAPP-A in HIV

2010 The Authors Journal compilation RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology

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NRTI (0.82, IQR 0.421.44 MoM versus 0.74 IQR 0.51

1.26 MoM; P= 0.80). There were no statistically significant

differences between the HIV-positive women on treatment

and those on no treatment in fetal CRL, NT and levels of

PAPP-A. There was no statistically significant correlation

between maternal free b-hCG and maternal viral load

(P= 0.59) or CD4+ count (P = 0.77) even if women with

more severe infection, with CD4+ cell count/mm3


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especially considering the immunomodulatory properties of

b-hCG.15,16

From a clinical perspective, the differences that we

detected in free b-hCG levels are unlikely to be of clinical

significance but may have implications in the estimation of

individual risks of chromosomal abnormalities. In pregnan-

cies affected by trisomy 21, maternal serum free b-hCG isabout twice as high and PAPP-A is reduced to about half

compared with values in chromosomally normal pregnan-

cies.4,6,17 Conversely, pregnancies affected by trisomy 13/18

demonstrate low levels of both maternal free b-hCG and

PAPP-A.17 Consequently, lower levels of free b-hCG in

treated HIV-positive pregnant women may underestimate

the risk for trisomy 21 or overestimate the risk for trisomy

13/18. Nevertheless, this is a theoretical risk. A hypothetical

35-year-old woman, who is HIV-positive on treatment,

with fetal CRL of 65 mm, NT of 1.8 mm, PAPP-A levels of

1 MoM (all mean values of our study population) and free

b-hCG of 0.7 MoM, instead of 1 MoM, will not have a

different risk for chromosomal abnormalities compared

with an untreated HIV-positive woman or even an HIV-

negative woman with similar characteristics (Figures 1 and

2). For the majority of women this will have little impact

but may be crucial in women with intermediate risk when

small deviations may shift the balance between further

investigations in terms of invasive testing or not. This is

certainly, a parameter of which clinicians should be aware

and it should be taken into account in the estimation of

patient-specific risks for aneuploidies especially in view of

the theoretical increased risk of HIV vertical transmission

that is associated with early invasive diagnostic tech-

niques.18,19 Definitely, further larger studies will be required

to confirm our findings. The study did not include any

cases of chromosomal abnormalities and therefore, it is not

possible to comment on the levels of the maternal freeb-hCG and PAPP-A in these women.

Conclusion

In summary, we found that maternal levels of free b-hCG

in treated HIV-positive pregnant women are lower com-

pared with non-treated HIV-positive and HIV-negative

women, whereas the levels of PAPP-A are not significantly

altered.

Disclosure of interestsNone declared.

Contribution to authorshipMDS is the main corresponding author and she conceived

and designed the study. IS, AS and MP contributed to the

design and conduction of the study and interpretation of the

results. KHN is the main supervisor. All the authors partici-

pated in and contributed to the writing of the manuscript.

Details of ethics approvalApproval by the local Research Ethics Committee was

sought but was not thought to be necessary under the

terms of the Governance Arrangements for Research Ethics

Committees in the UK.

FundingThe study was supported by The Fetal Medicine Foundation

(UK Registered Charity number: 1037116).

AcknowledgementsThe study was supported by The Fetal Medicine Founda-

tion (UK Registered Charity number: 1037116).j

Risko

ftrisomy21

1/10000

1/5000

1/3333

1/2500

1/2000

1/1666

1/1428

1/1250

1/1111

0 0.5 1 1.5 2

0

Free -human chorionic gonadotrophin (MoM)

Figure 1. Scatter plot of the risk of trisomy 21 in a hypothetical

35-year-old pregnant woman, with fetal CRL 65 mm, NT 1.8 mm,

PAPP-A 1 MoM (all mean values of our study population), depending

on the maternal levels of free b-hCG.

Riskoftrisomy13/18

0

1/10000

1/5000

1/3333

1/2500

1/2000

1/1666

1/1428

1/1250

0 0.5 1 1.5 2

Free -human chorionic gonadotrophin (MoM)

Figure 2. Scatter plot of the risk of trisomy 13/18 in a hypothetical

35-year-old pregnant woman, with fetal CRL 65 mm, NT 1.8 mm,

PAPP-A 1 MoM (all mean values of our study population), depending

on the maternal levels of free b-hCG.

Maternal levels of free b-hCG and PAPP-A in HIV

2010 The Authors Journal compilation RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology

847


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First-trimester markers of aneuploidy in women.pdf