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\begin{document}

\title{The Impact of Low Dose Aspirin on Markers of Inflammation and Placental
Function: An Ancillary Study of the ASPIRIN Trial}



\author[1]{Ramesh Araganji}%
\author[1]{Manjunath Somannavar}%
\author[2]{Sunil Vernekar}%
\author[3]{Avinash Kavi}%
\author[4]{Matthew Hoffman}%
\author[5]{Shivaprasad Goudar}%
\affil[1]{Jawaharlal Nehru Medical College}%
\affil[2]{JNMC}%
\affil[3]{1. KLE Academy of Higher Education and Researchs J N Medical College}%
\affil[4]{Christiana Care Health System}%
\affil[5]{KLE University Jawaharlal Nehru Medical College}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: To determine the impact of low dose aspirin (81mg) on markers
of maternal inflammation and placental function. Setting: Rural Southern
India Population: Nulliparous women with a singleton pregnancy dated by
ultrasound who were enrolled in the ASPIRIN (Aspirin Supplementation for
Pregnancy Indicated risk Reduction In Nulliparas) Trial. Methods: We
performed a case control study of women who delivered prematurely
compared to term controls in women enrolled in the ASPIRIN trial. Women
were prospectively enrolled in an ancillary observational trial wherein
maternal serum was collected and measured between 10 to 13 weeks and 17
to 21 weeks of gestation after initiation of aspirin or an identical
placebo. Our primary outcome was the impact of aspirin on markers of
placental function and maternal inflammation. Results: From 2016-18 with
a total of 666 n women enrolled in this ancillary trial of whom 269 were
selected for analyte analysis. Women who received low dose aspirin (LDA)
had lower levels of Alpha Feto-Protein (AFP) at 10 to 13 weeks than
women who received placebo (Placebo) (LDA 18.3 ng/mL vs 21.4 ng/mL -P
0.001). AFP was similar between the two groups at 17 to 21 weeks. No
other differences were seen in in C-Reactive protein or Anti-Mullerian
Hormone. Conclusion: Low dose aspirin administration lowers AFP early in
pregnancy and may be a marker of Aspirin efficacy. Keywords: maternal
serum alpha-fetoprotein (MSAFP), preterm birth, aspirin Tweetable
Abstract: Aspirin decreases AFP in the first trimester; a marker
associated with poor birth outcomes.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION:}

\textbf{Background:} The World Health Organization estimates that 15
million children are born prematurely each year resulting in the second
leading cause neonatal mortality throughout the world and in particular
low-middle income countries\textsuperscript{1,2}. In addition to its
significant contribution to mortality, the impact of preterm birth
amongst children born prematurely often continues throughout their
lifespan. Compared to children born at term, children born prematurely
have higher rates of cerebral palsy, milestone delay, impairment in
learning, visual disorders and higher rates of long-term physical health
problems\textsuperscript{3--5}.

Recently, the Aspirin Supplementation for Pregnancy Indicated Risk
Reduction In Nulliparas (ASPIRIN) trial demonstrated that nulliparous
women with no more than two previous first trimester pregnancy losses
treated with Low Dose Aspirin(LDA) 81mg daily beginning between 6 0/7
weeks and 13 6/7 weeks through 36 0/7 weeks gestational age have lower
rates of preterm birth from all causes and a decrease in perinatal
mortality\textsuperscript{6} .Though the ASPIRIN trial holds promise of
a therapeutic option for the prevention of preterm birth, the mechanism
by which it works has not been fully elucidated. LDA has been well
chronicled to affect both the COX-1 (thrombosis pathway) and the COX-2
(inflammatory pathway); however, the exact pathway through which it
exerts its affect remains uncler\textsuperscript{7,8}. We thus sought to
examine the impact of LDA on both inflammatory markers and established
markers of placental function amongst women who received either LDA or
placebo in the ASPIRIN trial.

\textbf{MATERIAL AND METHODS}

We performed a case control study of women enrolled within the study
within the ASPIRIN Trial conducted at the J N Medical College, Belagavi
Karnataka India. (JNMC Women's and Children's Health Research Unit;
Global Network for Women's and Children's Health Research).
Specifically, we identified women who delivered before 37 weeks (Cases)
and women who delivered at term (controls). As this analysis was
exploratory in nature with no prior data documenting differences due to
aspirin treatment in pregnancy, a power analysis was unable to be
calculate. We thus established a goal of including approximately 50
preterm birth cases and 150 term controls. Either sample limitations or
technical challenges in laboratory measurement, intermittently precluded
achieving the full 50/150 ratio. Due to sample limits, a separate either
preterm or control case was chosen rather than having a fixed cohort of
patients used for all specimens. The study protocol was approved by the
ethics committee of the institution and women were individually
consented for participation. As part of the primary study, women were
included if they were nulliparous with no more than 2 prior pregnancy
losses, pregnant with a singleton pregnancy between 6 weeks and 13 weeks
and 6 days as verified by ultrasound. Women with foetal anomalies or
medical conditions contraindicated to receive LDA were excluded.
Following randomization to either LDA or placebo, serum was obtained and
stored at -80 \textsuperscript{0}C degree until analysis. A second
sample was obtained at 17-21 weeks gestation and similarly stored. Women
who experienced an abortion prior to 16 weeks were excluded.

Measurements of the various analytes were performed using standardized
immunometric immunoassay (Alphafetoprotein {[}AFP{]}- R\&D Systems,
kit\# DAFP00; Anti-Mullerian Hormone {[}AMH{]}-Catalog Number: DY1737
R\&D Systems) and Immunoturbidimetric (C-Reactive Protein {[}CRP{]}-
Roche Diagnostics) methods in accordance with the kit manufacturers
protocol.

\textbf{Statistical analysis:}

Our primary outcome was preterm birth defined as delivery before 37
weeks. Secondary outcomes of interest were PTB \textless{}34 weeks and
hypertensive disorders of pregnancy. All continuous variables were
assessed for normality using the Shapiro Wilk test. Bivariate analysis
was performed using the Wilcoxon Rank Sum test where appropriate.
Additionally, we compared the impact of LDA on these biomarkers on these
analytes using a Wilcoxon Rank-Sum Test. All analyses were complete
using STATA v15.1 (Colleges Station, TX).

\textbf{RESULTS:}

A total of 666 women participated in this investigation of which a total
of 7 experienced an abortion prior to 16 weeks. A total of 269 women had
sample results that were able to be included (45 preterm and 224 term).
Demographic data of the total cohort are displayed in table 1. Maternal
demographics were noted to be similar between the two groups. Consistent
with the results of the parent trial, women who received Aspirin had
lower rates of preterm birth but this did not meet statistical
significance in this much smaller cohort enriched with preterm birth
cases. Similarly, birthweight tended to be greater in the Aspirin group
and conversely the rate of small for gestational age (SGA) and
birthweight \textless{}2500gm were lower in the Aspirin group. Of note
the rate of birthweight \textless{}1500gm was noted to be similar.

Results of the analytes are displayed in table 2. Notably none of the
values were normally distributed by the Sharipo-Wilk test and therefore
only Wilcoxon Rank-Sum tests are reported. No difference was seen in the
values of any of the analytes as they related to either preterm birth or
hypertensive disorders of pregnancy; excepting that AFP was found to be
lower amongst mothers who delivered before 34 weeks at the time of the
first blood draw. LDA use was also associated with markedly lower levels
of AFP at the first time point that blood was drawn. Neither of these
differences persisted at the second time point.

The relationship of the varied measured analytes on gestational age is
displayed in table 3. Only C reactive protein at the first visit was
shown to correlate with gestational age. This result was noted to be
positive suggesting that higher-Reactive Protein is associated with
longer gestational ages.

\textbf{DISCUSSION}

The results of our investigation suggest several interesting tenets
about how the role in Aspirin in pregnancy. First and foremost, we noted
that AFP is decreased at the time of the first blood draw amongst women
who took aspirin compared to those who did not take aspirin. This
difference was not noted at the second blood draw. AFP has been well
documented to be associated with poor obstetrical outcomes including
both preterm birth and ischemic placental
diseases\textsuperscript{9,1011--14}. Though our limited data did not
show a correlation of first trimester AFP with any obstetric outcomes,
this is probably a reflection of sample size. This data is suggestive
that aspirin plays an important role in facilitating deep
placentation\textsuperscript{15,16} and that it's early initiation is
important as this process occurs largely before 18 weeks. Several
meta-analyses have suggested that early initiation of aspirin is key to
avoidance of preeclampsia\textsuperscript{17,1819,20}. This would
suggest that measurement of AFP in the first trimester may be a useful
biomarker to understand the efficacy of LDA in pregnancy; however,
larger validation studies are necessary.

In contrast to AFP, we saw no differences in the levels of either AMH or
CRP at either gestational time points. It should be noted that AMH was
lower at both time points among women taking aspirin but neither was
statistically significant. AMH has been shown by others to be associated
with preterm birth; albeit it has mostly been evaluated in the setting
of women with infertility issues which may intersect with other medical
conditions\textsuperscript{21,22}. Finally, C-reactive protein is an
acute marker of inflammation and may not be predictive of obstetrical
conditions.

Our study has several strengths and weaknesses. First this is an
ancillary study on a well described prospectively phenotyped group of
women and masking to treatment allocation was maintained throughout the
study. Secondly, gestational age was validated using early ultrasound.
Weaknesses of our study include the fact that overall numbers of
specimens was variable based upon technical challenges with the assays.
Additionally, our overall sample size is limited and therefore we may
lack adequate power to detect meaningful differences.

In conclusion, our study suggests that AFP in the first trimester is
reduced by LDA therapy. Unfortunately, most likely due to sample size,
we are unable to demonstrate the predictive effects of AMH, AFP and CRP
on important obstetrical outcomes.

Acknowledgement:

Authors' contributions: RA conceived of the manuscript and wrote the
first draft with input from MSS, MKH and SSG. AK, RA, SSV, MSS and SSG
oversaw study implementation, data collection and quality monitoring.
RA, AK, and MSS performed the statistical analyses. All authors reviewed
and approved the final manuscript.

The authors report no conflict of interest

Financial Disclosure: No funding source was utilized for this report.

Clinical Trial Registration: ClinicalTrials.gov, NCT02409680, and the
Clinical

Trial Registry-India, CTRI/2016/05/006970.

Reprints: Reprints will not be provided

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Table 1: Maternal Demographics \& Birth Outcomes\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Aspirin (N= 129) & Placebo(N=146) & P-value\tabularnewline
Demographics & Demographics & Demographics & Demographics\tabularnewline
Age & 20.6+/-3.0 & 21.0 +/- 3.2 & 0.38\tabularnewline
Education & & &\tabularnewline
None & 0.8\% & 5.5\% &\tabularnewline
Primary & 3.1\% & 4.1\% &\tabularnewline
Secondary & 81.4\% & 77.4\% &\tabularnewline
University+ & 14.7\% & 13.0\% & 0.16*\tabularnewline
Height Cm & 151.8 +/- 5.5 & 151.7 +/- 5.4 & 0.90\tabularnewline
Weight Kg & 47.1 +/- 8.2 & 47.1 +/- 7.5 & 1.0\tabularnewline
BMI & 20.4 +/- 3.4 & 20.4 +/- 3.0 & 0.98\tabularnewline
Prior Abortion & 0.11 +/- 0.34 & 0.10 +/- 0.32 & 0.78\tabularnewline
Hb on enrollment & 11.6 +/- 1.4 & 11.4 +/- 1.4 & 0.28\tabularnewline
Gestational Age at sample 1 & 11.6 +/-2.6 & 11.7 +/-5.1 &
0.80\tabularnewline
Gestational Age at sample 2 & 18.7 +/-2.2 & 19.6 +/-3.8 &
0.16\tabularnewline
Birth Outcomes & Birth Outcomes & Birth Outcomes & Birth
Outcomes\tabularnewline
Gestational Age Weeks & 37.7 +/- 5.2 & 37.6 +/- 5.4 &
0.90\tabularnewline
Birth Weight (gm) & 2759 & 2588 & 0.005\tabularnewline
PTB \textless{}37 weeks & 12.1\% & 18.4\% & 0.18\tabularnewline
PTB \textless{}34 weeks & 7.8\% & 7.5\% & 0.94\tabularnewline
Stillbirth & 3.2\% & 5.7\% & 0.39*\tabularnewline
Hypertensive Disorders of Pregnancy (HDP) & 11.3\% & 10.6\% &
0.87\tabularnewline
Small for Gestational Age & 27.9\% & 45.0\% & 0.006\tabularnewline
\textless{}2500 gm & 15.7\% & 34.8\% & 0.001\tabularnewline
\textless{}1500 gm & 1.7\% & 4.4\% & 0.29*\tabularnewline
\bottomrule
\end{longtable}

*Fisher's Exact Test

Table 2: Serum Analytes\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& Preterm & N & Term & N & P-value\tabularnewline
AFP1 & 18.3 +/- 9.9 & 41 & 21.4 +/- 15.7 & 151 & 0.56\tabularnewline
AFP2 & 64.9 +/- 62.5 & 29 & 65.9 +/- 37.9 & 102 & 0.31\tabularnewline
CRP1 & 1.9 +/- 1.8 & 39 & 2.3 +/- 1.9 & 137 & 0.12\tabularnewline
CRP2 & 3.3 +/- 3.3 & 25 & 3.4 +/- 2.9 & 88 & 0.82\tabularnewline
AMH1 & 2.0 +/- 1.8 & 40 & 1.9 +/- 1.5 & 152 & 0.96\tabularnewline
AMH2 & 1.7 +/- 1.2 & 24 & 1.5 +/- 1.5 & 91 & 0.26\tabularnewline
& PTB\textless{}34 Weeks & & No PTB\emph{\textless{}}34 Weeks &
&\tabularnewline
AFP1 & 16.4 +/-6.9 & 15 & 21.1 & 177 & 0.48\tabularnewline
AFP2 & 65.7 +/- 41.0 & 9 & 66.9 +/- 44.6 & 122 & 0.82\tabularnewline
CRP1 & 1.4 +/- 0.8 & 13 & 2.3 +/- 1.9 & 163 & 0.21\tabularnewline
CRP2 & 3.7 +/- 4.2 & 8 & 3.3 +/- 2.8 & 105 & 0.91\tabularnewline
AMH1 & 2.2 +/- 1.6 & 14 & 1.9 +/- 1.5 & 178 & 0.51\tabularnewline
AMH2 & 1.5 +/- 1.1 & 9 & 1.55+/- 1.5 & 106 & 0.69\tabularnewline
& HDP & & No-HDP & &\tabularnewline
AFP1 & 22.3 +/-14.9 & 25 & 20.5 +/-14.8 & 167 & 0.44\tabularnewline
AFP2 & 67.8 +/-47.3 & 16 & 65.3 +/-44.4 & 115 & 0.87\tabularnewline
CRP1 & 2.1 +/-1.8 & 23 & 2.3 +/-1.9 & 153 & 0.65\tabularnewline
CRP2 & 3.4 +/-2.3 & 13 & 3.3 +/-2.9 & 100 & 0.62\tabularnewline
AMH1 & 1.7 +/-1.7 & 26 & 2.0+/-1.5 & 166 & 0.16\tabularnewline
AMH2 & 1.2 +/-1.2 & 14 & 1.6 +/-1.5 & 101 & 0.34\tabularnewline
& Aspirin & & Placebo & &\tabularnewline
AFP1 & 17.3 +/- 12.3 & 92 & 23.9 +/- 16.0 & 100 & 0.001\tabularnewline
AFP2 & 60.2 +/- 34.1 & 59 & 70.3 +/- 50.9 & 72 & 0.41\tabularnewline
CRP1 & 2.2 +/- 1.8 & 82 & 2.3 +/- 1.8 & 94 & 0.90\tabularnewline
CRP2 & 3.1 +/- 2.5 & 50 & 3.5 +/- 3.1 & 63 & 0.57\tabularnewline
AMH1 & 2.1 +/- 1.4 & 92 & 1.8 +/- 1.6 & 100 & 0.10\tabularnewline
AMH2 & 1.4 +/- 1.1 & 54 & 1.6 +/- 1.7 & 61 & 0.70\tabularnewline
NB: All P-values are Wilcoxon Ranks Sums & NB: All P-values are Wilcoxon
Ranks Sums & NB: All P-values are Wilcoxon Ranks Sums & NB: All P-values
are Wilcoxon Ranks Sums & NB: All P-values are Wilcoxon Ranks Sums & NB:
All P-values are Wilcoxon Ranks Sums\tabularnewline
\bottomrule
\end{longtable}

Table 3: Analytes and Gestational Age\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Analyte & Coefficient (weeks/unit) & 95\% CI & p-value\tabularnewline
AFP1 & 0.054 & -0.002 to 0.11 & 0.06\tabularnewline
CRP1 & 0.44 & 0.14 to 0.88 & 0.043\tabularnewline
AMH1 & -0.12 & -0.64 to 0.40 & 0.65\tabularnewline
AFP2 & 0.002 & -0.12 to 0.16 & 0.73\tabularnewline
CRP2 & -0.02 & -0.25 to0.21 & 0.87\tabularnewline
AMH2 & -0.033 & -0.51 to 0.45 & 0.89\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
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\end{document}

