Adjustment of Serum Markers in First Trimester Screening

Abstract

First trimester combined screening can be performed using maternal serum pregnancy-associated plasma protein A, total human chorionic gonadotropin (hCG) and ultrasound measurement of nuchal translucency at 11–13 weeks of pregnancy. Our objective was to explore the effects of covariates on total hCG in the first trimester. First trimester total hCG levels were significantly increased in twins (median = 1.87 MoM), mildly increased in pregnancies achieved by in vitro fertilization (1.04 MoM) and decreased in smokers (0.80 MoM).

Introduction

The levels of first and second trimester serum markers used in Down's syndrome screening can be influenced by covariates, such as multiple gestation, insulin-dependent diabetes mellitus (IDDM), in vitro fertilization (IVF), smoking and race/ethnicity. Screening in the first trimester was originally reported using free beta hCG measurements, ¹ but testing for this analyte is not widely available in the United States. Total hCG is an acceptable alternative when used in combination with pregnancy-associated plasma protein A (PAPP-A) and ultrasound assessment of nuchal translucency, and when measured between 11–13 weeks’ gestation. ² There are no published data regarding the effects of covariates on first trimester total hCG levels.

Methods

We examined the median analyte values (expressed as the multiple of the median; MoM) for first trimester PAPP-A and total hCG over a three-year time period (2006–2008) for tests performed at Women and Infants Hospital, Providence, RL PAPP-A assays were performed using a manual method (Diagnostic Systems Laboratories/Beckman Coulter, Webster, TX) and total hCG levels were measured on the Immulite (Siemens, Los Angeles CA) or Dxl (Beckman Coulter, Inc., Chaska, MN). Serum marker levels were adjusted for gestational age (by ultrasound) and maternal weight for calculation of MoMs using Alpha software (Logical Medical Systems, London UK).

A total of 14,816 observations from singleton, non-IDDM, non-LVF, non-smoking, non-Black women were available for analysis. The observed median PAPP-A and total hCG levels in this group were 1.05 and 1.00 MoM, respectively. There were additional records for women with a twin pregnancy (n = 147), IDDM (n = 114), LVF (n = 545), or who smoked (n = 381). The median MoM values were calculated for each of these groups and adjusted by dividing by the corresponding level in controls. The 95% confidence intervals (CI) for the distributions of PAPP-A and total hCG in each group were estimated using the SURUSS logarithmic standard deviations ³ for each marker.

Results

As expected, PAPP-A and total hCG MoM levels in twin gestations were almost twice that in singletons. PAPP-A levels were lower in smokers and LVF pregnancies. Total hCG levels were also lower in smokers, but were somewhat increased in LVF pregnancies. First trimester marker levels were not significantly altered in pregnant women with pre-existing IDDM (Table 1).

Table 1

Median MoM levels for first trimester maternal serum pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG) in various groups of pregnant women

Group (sample size)	PAPP-A ratio *	Total hCG ratio
Twins (147)	1.75 (1.63 to 1.88)	1.87 (1.74 to 2.01)
Diabetic (114)	0.99 (0.91 to 1.09)	0.95 (0.87 to 1.03)
IVF † (547)	0.91 (0.88 to 0.94)	1.04 (1.00 to 1.08)
Smokers (381)	0.86 (0.82 to 0.90)	0.80 (0.76 to 0.84)

*

Expressed as a ratio of observed MoM in the sample group divided by the observed MoM in the control group (with 95% CI)

†

IVF = in vitro fertilization

Discussion

Our findings for the effects of covariates on PAPP-A agree with published reports. It has been previously shown that PAPP-A is almost double in twins (1.86 MoM), ⁴ not significantly changed in IDDM (1.02 MoM), ⁵ modestly reduced in IVF pregnancies (0.94 MoM), ⁶ and markedly reduced in smokers (0.81 MoM). ⁷

This report is intended to guide the adjustment for covariates in screening programmes that use first trimester total hCG measurements. The present results in twins, diabetics, smokers and IVF pregnancy agree well with both first trimester free beta hCG and second trimester total hCG results.^6–9 Investigation of the effect of Black race on first trimester total hCG is underway. At minimum, total hCG should be adjusted in the first trimester for twin pregnancy.