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Am J Obstet Gynecol. Author manuscript; available in PMC 2022 September 01.
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Published in final edited form as:

Am J Obstet Gynecol. 2021 September ; 225(3): 280.e1–280.e11. doi:10.1016/j.ajog.2021.03.048.

Metabolic Syndrome in Obesity: Treatment Success and Adverse

Pregnancy Outcomes with Ovulation Induction in Polycystic
Ovary Syndrome
Sushila Aryaa, Karl R. Hansena, Jennifer D. Pecka,b, Robert A. Wilda,b NICHD’s
Reproductive Medicine Network
aDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center,
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Oklahoma City, OK
bDepartment of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center

Abstract
Objective: Obesity is common in women with polycystic ovary syndrome (PCOS). PCOS and
obesity are associated with reduced fertility. Metabolic syndrome’s (MetS) effect on infertility
treatment success and pregnancy outcomes in women with PCOS undergoing ovulation induction
(OI) has not been investigated. The objectives of this study were to determine the associations of
MetS with OI live birth rate and pregnancy complications in obese women with PCOS, and to see
if these outcomes differ by specific agent used for OI.

Study Design: This prospective cohort analysis was from data collected from participants
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in the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) clinical trial conducted by the
Reproductive Medicine Network. In PPCOSII, 750 women with PCOS and infertility were
randomized to either clomiphene citrate or letrozole for OI for 1-5 cycles or until pregnancy
occurred. Cox regression and modified Poisson regression, Chi-square and Student’s t or
Wilcoxon tests were applied. Outcomes of interest were live birth and clinical pregnancy rates,
and pregnancy complications. Having MetS was defined by the presence of at least 3 out of 5
cardiometabolic risk factors (waist circumference > 88cm, low high-density lipoprotein cholesterol
< 50mg/dL, triglycerides ≥ 150mg/dL, systolic BP ≥ 130 or diastolic BP ≥ 85 mmHg, and fasting
glucose > 100mg/dl). We also used a continuous MetS Z-score. BMI categories were defined as
normal (BMI < 25 kg/m2), high (25 to 35 kg/m2), and very high (> 35 kg/m2).

Results: Fewer women achieved a clinical pregnancy (20.5% vs. 29.7%, p=.007) or had a live
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birth (16.5% vs. 27%, p=.001) in the presence of MetS. Early pregnancy losses were not different
by MetS status. At least one pregnancy complication occurred more often with MetS, 61.9%
(26/42) compared to 44.4% (59/133) (p=.05) without it. Gestational diabetes (35.7% vs. 18.2 %,
p=.02) and macrosomia (21.4% vs. 8.3%, p=.02) were more common in the presence of MetS.
After adjustment for other potential confounders, the live birth rate ratio for a one-unit change in
the MetS z-score was 0.89 (95% CI 0.79, 1.00, p=.04) for those whose BMI was 25-35 kg/m2 .
For the very high BMI subgroup (>35 kg/m2) the independent effects of MetS from obesity were

Corresponding author: Robert A. Wild, Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center,
800 Stanton L. Young Blvd., AAT 2400, Oklahoma City, OK 73104, (405)271-8787 (work), (405)271-8547 (fax).
 Arya et al. Page 2

harder to discern. The live birth rate was higher with letrozole, although MetS had a different
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detrimental effect by medication given. The overall incidence of pregnancy complications was
high (≃ 49%) in PPCOSII, and similar with either agent. Letrozole was associated with more
obstetrical complications in the presence of MetS and clomiphene was associated with a lower live
birth rate when MetS was present.

Conclusions: MetS is a risk factor that lowers the live birth rate with OI for women with PCOS
independent of obesity, and it is particularly associated with a lower live birth rate for clomiphene
compared to letrozole users. It is also a risk factor for pregnancy complications for obese letrozole
users. Having the MetS is a risk factor for gestational diabetes and macrosomia.
Condensation:
Metabolic syndrome affects live birth and pregnancy complication rates differently for women
with polycystic ovary syndrome after letrozole or clomiphene citrate treatment for ovulation
induction.
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Keywords
Metabolic syndrome (MetS); polycystic ovary syndrome (PCOS); ovulation induction (OI);
pregnancy complications

Introduction
Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in
women of reproductive age, and the most common cause of anovulatory infertility. Up
to 15% of women are affected. 1 Obesity is prevalent in women with PCOS, particularly
in the U.S., although prevalence varies widely depending on ethnicity and region. Insulin
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resistance (IR) and dyslipidemia are common with PCOS, even in women of normal
weight.2–4 Obesity, IR and dyslipidemia all increase the likelihood of a diagnosis of
metabolic syndrome (MetS).5 MetS components include abdominal obesity, dyslipidemia
(elevated triglycerides and lowered high-density lipoprotein cholesterol (HDL-C), elevated
glucose and high blood pressure.6 The age-adjusted prevalence from the general population
is increasing for women (25.3% to 34.2% from 1988 through 2012 - NHANES).7

In PCOS, oligo-ovulation and obesity both reduce fertility. Added obesity contributes
to a lower success rate with in vitro fertilization (IVF).8, 9 Folliculogenesis is altered
by various pathways (e.g. abnormal signaling of follicles by regulators such as Anti
Mullerian Hormone, insulin-like growth factors and sex steroids) leading to an arrest of
antral follicles.10, 11 Poor oocyte quality, smaller size of mature oocytes, more abnormal
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spindles, and chromosome misalignment are found with obesity.12 Poorer IVF performance
(higher dose, longer duration of gonadotropins, fewer retrieved oocytes, and fewer available
embryos) and a decreased cumulative live birth rate is found in patients with PCOS with
MetS compared to those without MetS. 13

Ovulation induction (OI) with letrozole is now the first choice treatment for anovulation
in PCOS-related infertility.14 Older age, a higher BMI, and a longer duration of infertility
are associated with poorer success with OI.15 Interventions targeting insulin resistance

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(metformin, rosiglitazone, pioglitazone and d-chiro-inositol) and lifestyle changes (diet and
exercise) to improve fertility outcomes in PCOS are less successful than OI.16–18 Targeting
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insulin resistance may improve ovulation and IR but does not necessarily improve fertility
outcomes. 19 Our understanding of how MetS affects treatment success with OI for women
with PCOS is limited.

In general, women with PCOS are at increased risk of pregnancy related hypertensive
diseases, gestational diabetes mellitus, preterm delivery, intrauterine growth retardation
(IUGR), and/or fetal macrosomia.1, 20, 21 Metabolic abnormalities in PCOS, such as
hyperandrogenism, obesity and IR may contribute to more pregnancy complications.1

The impact of MetS on fertility treatment success and subsequent adverse pregnancy
outcomes in women with PCOS undergoing OI has not been investigated. We hypothesized
that MetS in women with PCOS adversely affects conception rates, live birth rates and
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pregnancy complications independent of body mass index (BMI). We wished to determine

if results differ by which medication is used for OI. Data collected during the multicenter,
randomized controlled clinical trial, Pregnancy in Polycystic Ovary Syndrome II (PPCOSII)
trial 14, 22 offered an opportunity to assess our objectives.

Materials and Methods

Study Design
The PPCOS II trial was a multicenter, randomized controlled, double-blind clinical trial
conducted at 11 clinical sites across the United States to study OI live birth rates after
clomiphene citrate or letrozole treatment for anovulatory infertility due to PCOS. Although
750 infertile women underwent OI for up to five treatment cycles (1:1 ratio of letrozole and
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CC), 158 withdrew after a varying number (1-4) of unsuccessful attempts.

Participants were 18 to 40 years of age, without significant comorbidities. They had to

have had at least one patent fallopian tube, a normal uterine cavity, and the male partner
had to have a sperm concentration of at least 14 million per milliliter with documented
motility according to World Health Organization cutoff points 23 in at least one ejaculate in
the past year. The partners agreed to have regular intercourse with the intent of conception
during the study. The design, baseline characteristics, and outcomes of the original study
are published.14, 22, 24, 6 Institutional Review Board approval was obtained at each study
site. The Reproductive Medicine Network conducted the trial (ClinicalTrials.gov number:
NCT00719186).

Participant characteristics and relevant laboratory analysis

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Participants in the PPCOSII trial fulfilled modified Rotterdam criteria for PCOS. 24
Other disorders that mimic PCOS, including thyroid disease and hyperprolactinemia were
excluded.25 All measurements in this analysis were collected at screening prior to OI.
A standardized protocol for all measurements was in place. A transvaginal ultrasound
evaluated the ovaries for polycystic ovarian morphology.

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The fasting blood samples were analyzed in batch, including glucose, lipid profile, and other
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biomarkers, at the core lab at the University of Virginia (Ligand Assay and Analysis Core
of the Specialized Cooperative Centers Program in Reproduction and Infertility Research).22
The intra and inter-assay coefficients of variation (CV) were below 10% for each assay.
Lipid profiles, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL),
and triglycerides (TG), were measured using the Abbott Architect c16000 automated
analyzer. Low-density lipoprotein (LDL) cholesterol was estimated with the Friedewald
equation.22, 24

Outcome variables and MetS

MetS was defined categorically (binary yes or no) as the presence or absence of at least
3 of 5 risk factors:1 1. Waist circumference > 88cm; 2. low high-density lipoprotein
cholesterol (HDL-C < 50mg/dL); 3. hypertriglyceridemia (TG > 150mg/dL); 4. hypertension
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(Systolic BP ≥ 130 or diastolic BP ≥ 85 mmHg); and 5. fasting hyperglycemia (fasting

glucose > 100mg/dl).6 A Z- score was calculated by first standardizing the individual
MetS variables (e.g., waist circumference, systolic BP, glucose, HDL-C, and log of TG by
subtracting the study population mean from the study participant’s value and dividing by the
study population standard deviation. Since the standardized HDL-C is inversely related to
metabolic risk, it was multiplied by −1. The standardized values of each MetS component
are summed to create the Z-score.26 BMI was categorized as normal (< 25 kg/m2), high (25–
35 kg/m2), or very high (>35 kg/m2). A clinical pregnancy was defined as documentation
of a fetal heart beat by vaginal ultrasound. A live birth was defined as the delivery of a
viable infant. Pregnancy complications included preeclampsia, gestational diabetes, preterm
delivery, IUGR, macrosomia or any complication (at least one). Pregnancy outcomes were
tracked through review of maternal and infant medical records.
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Statistical Analysis
Comparisons of means or medians of the continuous variables were by Student’s t test or
Mann-Whitney U test based on the normalcy of the distributions. Chi-Square or Fisher’s
Exact tests were used to compare frequencies of patient characteristics and pregnancy
outcomes by presence or absence of MetS. The cumulative incidence of pregnancy success
was compared using the log rank test. Cox regression was used to compare the live birth
rates for all the patients who entered the PPCOSII trial and had complete data available for
MetS (n= 746). Participants who did not conceive and did not complete all treatment cycles
were censored at the time of last patient contact. MetS z-score was assessed as a continuous
variable within BMI strata. Unadjusted and BMI-adjusted rate ratios and 95% confidence
intervals (CI) are reported for a one-unit change in MetS Z-score stratified for high (25–35
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kg/m2) and very high (>35 kg/m2) BMI categories. Rate ratios were adjusted for BMI, age
and smoking status. We also applied Poisson regression models with a robust error variance,
27 to examine the consistency of conclusions when using an alternative method to estimate

risk ratios for live birth for those who continued in the study to completion. We calculated
risk ratios and 95% CIs for those with complete follow-up data (n=592). Because patients
were randomly assigned to clomiphene citrate or letrozole treatment for OI in the original
clinical trial, we further examined how live birth rates differed by MetS and BMI when
stratified by these two OI agents. Due to sparse numbers across strata, this assessment is

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limited to unadjusted comparisons of proportions using Chi-square and Fisher’s exact tests.
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A p-value of < 0.05 was considered statistically significant. All analyses were performed by
using the Statistical Analysis System V9.4 (SAS Institute, Cary, NC) and NCSS Salt Lake
City, Utah.

Results
Table 1 illustrates the demographic characteristics of the study population by presence of
MetS. The majority were obese 84% (627/746). MetS was present in 34% (254/746). Those
with MetS were slightly older and heavier. Only one patient in the BMI category <25 kg/m2
met criteria for MetS. The fasting glucose, blood pressure and lipid profiles reflect their
MetS status. Those who had MetS were more likely to be current smokers. They gained
less weight during pregnancy and there was no difference in alcohol consumption, income,
education level or ovulated cycles (data not shown). Those with MetS had a longer duration
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of infertility. There was no difference in the percent who received clomiphene or letrozole.

Figure 1 illustrates the cumulative incidence of live births for the whole cohort (A); for those
whose BMI was 25-35 kg/m2 (B); and for those whose BMI was > 35 kg/m2 (C). MetS was
associated with a lower cumulative live birthrate when the BMI was 25-35 kg/m2.

With MetS fewer women achieved a clinical pregnancy 20.5% (52/254) vs. 29.7%
(146/492), p=.007 or had a live birth [16.5% (42/254) vs. 27% (133/492), p=.001; with MetS
vs. without, respectively. The incidences of gestational diabetes 35.6% (16/45) vs. 17.9%
(24/134), p=.014 and macrosomia 21.4% (9/42) vs. 8.3% (11/132), p=.019 were higher with
MetS (both obesity strata combined).

Table 2 demonstrates the pregnancy outcomes and complication rates contrasting those with
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and without MetS stratified within the three BMI categories. Fewer women with MetS
achieved a pregnancy or had a singleton live birth when their BMI was 25-35 kg/m2
compared to those who did not have MetS. When their BMI was >35 kg/m2 there was no
statistical difference. For those who had a BMI of 25-35 kg/m2, MetS was associated with
more gestational diabetes and macrosomia but not statistically different within BMI stratum.
Comparisons are hampered by small numbers within strata.

Table 3 shows the regression results for live births for the entire cohort stratified by obesity
BMI categories. Cox regression analysis (n=746 evaluable data) found that the rate ratio
for live births for those with PCOS in BMI 25-35 kg/m2 was 0.89 (95% CI 0.79, 1.00),
p=0.04 for the MetS Z-score, when adjusted for BMI, age and current smoking status and
the adjusted risk ratio was 0.91(95% CI 0.83, 1.00) using modified Poisson Regression .
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There is a 10-11% lower live birth rate with a one-unit increase in the MetS z-score
independent of BMI in those whose BMI was 25-35 kg/m2 adjusted for BMI and other
potential confounders.

Risk ratios of similar magnitude were observed in the analysis of those who completed
study follow up. The prevalence of obesity remained similar in this restricted sample 82.2%
(484/589).

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Table 4 compares the effects of MetS on live birth rates and pregnancy complications
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by type of OI medication used and by MetS status. Live birth rates were higher with
letrozole. The detrimental effects of having MetS on live birth rates can be seen for all BMI
groups and more clearly in the BMI category 25-35 kg/m2 (p=.03), more clearly shown
in clomiphene users. Overall complication rates were not different by which OI agent was
used. However, having MetS was associated with more obstetrical complications in letrozole
users compared to those who did not have MetS.

Comments
Principal findings of the study
Having MetS in the presence of obesity was associated with a reduced live birth rate and is
a risk factor for gestational diabetes and macrosomia for women with PCOS who underwent
OI in the PPCSOII trial. Obesity, with and without MetS, was very prevalent among women
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in PPCOSII as was the incidence of a subsequent pregnancy complication for those who
conceived. Letrozole had a higher live birth rate, but it was associated with a higher rate of
pregnancy complications in the presence of MetS. Clomiphene users had fewer live births in
the presence of the MetS. Overall, pregnancy complication rates were not different between
the two OI medications

Results of the study in the context of other observations

The overall prevalence of MetS was 34% (254/746) in our study. This is similar to the
overall prevalence in the United States by NHANES report.7 Of interest, a study from China
reported a lower prevalence (27%) of MetS in infertile women undergoing IVF for PCOS
than we found in this US cohort.13 Lim et al. reported an increased prevalence of MetS in
overweight and obese women with PCOS OR 1.88 ( 95% 1.16, 3.04) compared to women
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without PCOS in their meta-analysis.28 They also found a higher prevalence of MetS with
older age, Hispanic ethnicity and lower socioeconomic status. 7

Severe obesity is associated with systemic chronic inflammation. We hypothesize that

obesity and MetS are both risk factors for lower live birth rates with OI and likely contribute
to the higher rates of gestational diabetes and macrosomia. This is easier to delineate in
those whose BMI was 25-35 kg/m2. Separate effects of MetS from obesity were very
difficult to disentangle when the BMI was >35 kg/m2 in PPCOSII. In a recent study of
PCOS women who had IVF treatment in China, they found a lower cumulative live birth
rate in PCOS women with MetS than those without MetS. The prevalence of obesity was
significantly lower in their cohort.13 There is limited literature on the impact of MetS on
fertility treatment success following OI in an obese population to compare to our findings.
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The women with PCOS in the PPCOSII trial who had MetS also reported longer times
trying to conceive before they entered the PPCOSII trial. This begs the question - for
women with PCOS trying to conceive, not participating in a research study, who never seek
out medical attention to get pregnant, how does having MetS affect time to conception?
Our findings suggest that reducing metabolic dysfunction before pregnancy might make a
difference.

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The use of the MetS Z-score as a continuous predictor was helpful. It provided more power
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to discern effects in this relatively small sample size. It is possible that with a larger data set
the effects of MetS may have been easier to separate from the potential effects of obesity
across the spectrum of BMIs.

The overall risk of GDM in this cohort was 22.3% (39/175). This is higher than often
reported (approximately 9%) in the United States.29 Our findings are consistent with other
studies that have reported a 2-3 fold higher risk of GDM in women with PCOS.30, 31 Chanzi
et al, in a cohort of 508 pregnant women in Greece, reported MetS increased the risk of
GDM RR=3.17 (95% CI 1.06-9.50). 32

Excessive weight gain in pregnancy is associated with an increased the risk of preeclampsia
and eclampsia. 33 Of interest, the women with MetS in PPCOSII gained less weight during
their pregnancy than those without it. The precise cause of preeclampsia is not completely.
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Some have suggested a significant role of generalized inflammatory response and metabolic
dysfunction.34 It is possible that lower weight gain in the MetS group during pregnancy
in our study somewhat blunted the association. In a case-control study by Palomba et al.,
women with PCOS had more preeclampsia compared to women without (8% versus 2%).35
Naver et al. reported preeclampsia in women with PCOS who had hyperandrogenism, but
not in PCOS women without hyperandrogenism, even after adjusting for BMI and parity. 36

The increased susceptibility of women with PCOS for higher pregnancy complications
might be explained by various mechanisms, possibly including obesity, hyperandrogenism,
more insulin resistance and lipid abnormalities. Hyperandrogenism is associated with
microscopic alterations in early trophoblast invasion and placentation.37 Hyperinsulinemia
is common in PCOS and is considered a contributor. 38 Hyperlipidemia may contribute
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to maternal and fetal morbidity, increased fetal adiposity, higher birth weight, and greater
risk of GDM and preeclampsia.39–41, 42 With limited hepatic de novo lipogenesis in fetus
43, maternal lipids provide an important fuel for fetal fat accretion 44. However excess

highly atherogenic cardiometabolic lipids are detrimental. Elevated maternal triglycerides

and associated elevated free fatty acids contribute to macrosomia. 45, 46

Weight gain in pregnancy is a risk factor for pregnancy complications. 35, 47 The observation
that the women with MetS in PPCOS gained less weight during pregnancy might be
explained by patient’s compliance with weight gain recommendations by the Institute of
Medicine (IOM). Lower weight gain is recommended for higher BMI groups to minimize
pregnancy complications.48 Women who gain more weight than IOM guidelines exhibit a
higher risk of maternal and neonatal morbidity, irrespective of their pre-pregnancy weight.
33. Metabolic abnormalities vary among different PCOS phenotypes, so to fairly compare
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various studies reporting associations between PCOS and pregnancy complications, it is

important to consider which diagnostic criteria for PCOS were utilized.1, 49

Strengths and limitations

The major strength of this analysis is its prospective design, and that fasting serum
was collected for cardiometabolic dysfunction parameters pre-conception. All serum
analyses were batched and performed at a single core lab. Recruitment for participants

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of PPCOSII was from 11 centers in the USA. This adds to the diversity and increases
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the generalizability. In most other studies examining the associations between metabolic
markers with pregnancy outcome, samples were collected during pregnancy instead of
pre-conception. Obtaining measurements while a patient is pregnant might not necessarily
reflect metabolic dysfunction at the time a pregnancy is established.

Our analysis has some important limitations. People who volunteer for a clinical trial are
different from those who do not. Women were excluded from PPCOSII if they had diabetes
mellitus or other uncontrolled chronic medical conditions. This provides a lower prevalence
and possibly a less severe metabolic dysfunction in this cohort. The majority (66.5%)
were non-Hispanic White, and this may affect generalization. Women diagnosed using NIH
criteria (both androgen excess and anovulation) are more likely to have severe insulin
resistance and more prevalent MetS.50 The PPCOSII trial used the Rotterdam criteria for
PCOS and this definition may not include women at the same heightened risk of metabolic
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dysfunction as likely found with NIH criteria. This is a relatively small sample size cohort,
and we might not have adequate power to detect some differences. Multiple comparisons in
the studied sample could have resulted in spurious associations. Survival analysis methods
considers total duration of persons ‘at risk of pregnancy’ and provides options for censoring
those who were lost to follow up yet attempted some cycles. Those lost to follow up had
higher BMIs, were older, were more likely non-Hispanic Black, Hispanic and/or of lower
socioeconomic status. These are risk factors for higher rates of pregnancy complications. 51
It is possible that the true detrimental effect size of MetS for success or complications is
larger than we found. Although we conducted our analysis using stratification by BMI, and
adjusted for potential confounders; there can always be unknown confounders.

Conclusions and clinical implications

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Obesity and MetS were prevalent in women with PCOS in PCOSII, as was the incidence
of pregnancy complications after OI. MetS was associated with a lower live birth rate
after OI and more gestational diabetes and macrosomia. Detrimental effects of having this
cardiometabolic phenotype on live birth rates could be discerned independent of obesity
(and likely additive) most clearly for those with a BMI >25-35 kg/m2. Although having
MetS was associated with more pregnancy complications, overall letrozole users had more
live births. The obstetrical complication rate was no different compared to clomiphene.
For clomiphene users, having MetS was associated with fewer live births. MetS is a risk
factor for poorer OI outcomes in PCOS. Our findings stress the importance of recognizing
MetS in PCOS women desiring infertility treatments, and suggest that diagnosing this
cardiometabolic syndrome and reversing it before infertility treatments is desirable.
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Disclosure Summary:
SA has no conflict of interest.

Dr. Hansen reports grants from Roche Diagnostics and Ferring International Pharma science Center US outside the submitted
work.

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 Arya et al. Page 9

Dr. Peck reports support from Ferring Pharmaceuticals outside the submitted work.
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Dr. Wild reports grants from Quest Diagnostics, AbbVie, Amgen, and the NICHD outside the submitted work
SA has no conflict of interest.

Dr. Hansen reports grants from Roche Diagnostics and Ferring International Pharma science Center US outside the
submitted work.

Dr. Peck reports support from Ferring Pharmaceuticals outside the submitted work.

Dr. Wild reports grants from Quest Diagnostics, AbbVie, Amgen, and the NICHD outside the submitted work

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD077680) and the National
Institute of General Medical Sciences (U54GM104938). The Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) clinical
trial was supported by grants from the NICHD (U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD38998,
U10 HD055936, U10 HD055942, U10 HD055944, and U54-HD29834)
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The Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD077680) and the
National Institute of General Medical Sciences (U54GM104938). The Pregnancy in Polycystic Ovary Syndrome II
(PPCOSII) clinical trial was supported by grants from the NICHD (U10 HD27049, U10 HD38992, U10HD055925,
U10 HD39005, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944, and U54-HD29834)

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AJOG at a Glance:
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• Why was this study conducted: To determine if metabolic syndrome,

independent of obesity, affects ovulation induction live birth and pregnancy
complication rates in women with the polycystic ovary syndrome in the
PPCOSII trial, and to determine if there are differences by which ovulation
inducing agent was used.

• What are the key findings: Presence of metabolic syndrome in obese women
with polycystic ovary syndrome reduces live birth success with ovulation
induction.

• What does this study add to what is already known: Metabolic syndrome,
prevalent in obese women with polycystic ovary syndrome, is an independent
and likely an additive risk factor that reduces the live birth rate following
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ovulation induction.

• Effects of metabolic syndrome independent of obesity were most easily

shown for persons whose BMI was 25-35 kg/m2.

• Letrozole had a higher live birth rate than clomiphene with or without the
metabolic syndrome.

• Pregnancies achieved with letrozole were more likely to experience

obstetrical complications in the presence of metabolic syndrome. However,
overall, they were not different by which ovulation induction medication was
used.
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Figure 1.
ABC illustrates the cumulative incidence of live births for the whole cohort (A); for those
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whose BMI was 25-35 kg/m2 (B); and for those whose BMI was > 35 kg/m2 (C). Metabolic
syndrome was associated with a lower cumulative live birth rate when the BMI was 25-35
kg/m2 (p = 0.014).
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Table 1.

Demographic Characteristics of PPCOSII Cohort by Metabolic Syndrome Status

Mean (SD) Metabolic Syndrome No Metabolic Syndrome p-value

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Median(95%CI) N=254 N= 492

Chi-square or Fisher’s
Student’s t
Mann-Whitney U or Wilcoxon sum
Rank-Sum

Age (years) 29.6 (4.1) 28.5 (4.3) <0.01

Weight (kg) 104.3 (102, 108)) 86.1 (80.4, 89.1) <.01

Height (cm) 164.2 (6.1) 164.0 (6.6) 0.60

Waist circumference (cm) 117 (114, 119) 100 (97, 102) <.01

Systolic blood pressure (mmHg) 126.3 (13.7) 116.2 (11.0) <.01

Diastolic blood pressure (mmHg) 82.1 (9.2) 74.5 (8.4) <.01

BMI at Screen ( kg/m2) 38.8 (38, 41) 32.9 (30, 33) <.01

BMI Category <.01

<25 kg/m2 0.39% 24%

25-35 kg/m2 30% 36%

>35 kg/m2 69% 40.5%

Race

Hispanic 21.3% 14.8% 0.03

White 35.6% 64.4% 0.85

Black 9.5% 15.5% 0.02

Asian 2.97% 3.9% 0.19

American Indian 1.2% 0.8% 0.62

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Native Hawaiian 0.39% 0.0% 0.34

Mixed Race 4.7% 3.1% 0.25

Fasting Glucose mg/dL 90.5 (89, 92) 84.3 (83, 86) <.01

HDL Cholesterol mg/dL 34 (32, 35) 39 (38, 40) <.01

Triglycerides mg/dL 167 (157, 173) 87 (82, 91) <.01

Hs-CRP mg/L 6.4 (5, 7) 3.1 (3, 4) <.01

Current Smokers 18.5% 12.8% 0.04

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Current alcohol users 63.8% 62.6% 0.75

Education 0.31

High school or less 22.9% 23.4%

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Some College 69.3% 63.2%

Graduate school 7.9% 13.4%

Prior pregnancy loss 24.4% 22/3%

History of pregnancy 40.2% 34.6% 0.13

Prior pregnancy loss 24.4% 22.6% 0.57

Duration of infertility 36 (30, 48) 24 (24, 24) <.01

Treatment 0.76

Clomiphene 50.8% 49.6%

Letrozole 49.2% 50.4%

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Table 2

Pregnancy Outcomes by Metabolic Syndrome and Obesity Status

Outcome BMI <25 kg/m2 BMI 25-35 kg/m2 BMI >35 kg/m2
Arya et al.

MetS No MetS Mets No MetS MetS No MetS P Value

Live Births 1/1 42/118 11/77 52/175 30/176 39/199 0.04*
(100%) (35.6%) (14.3%) (29.7%) (17.1%) (19.5%)
0.52**

Singleton 1/1 39/118 11/77 50/175 28/176 37/199 0.03*

(100%) (33.1%) (14.3%) (28.6%) (15.9%) (18.6%)
0.49**

Twins 0/1 3/118 0/77 2/175 2/176 2/199 0.47*

(0.0%) 2.54% (0.00%) (1.1%) (1.1%) (1.0%)
0.90**

Achieved Pregnancy 1/1 58/118 22/77 71/175 47/176 58/199 0.14*

(100%) (49.2%) (28.6%) (40.6%) (26.7%) (29.2%)
0.60**

Clinical Pregnancy 1/1 44/58 15/22 57/71 36/47 45/58 0.24*

(100%) (75.9%) (68.2%) (80.3%) (76.6%) (77.6%)
0.90**

Loss in first trimester 0/1 16/58 9/22 18/71 15/47 16/58 0.16*
(0.0%) (27.6%) (40.9%) (25.4%) (31.9%) (27.6%)
0.63**

Biochemical 0/1 7/118 2/77 5/175 6/176 6/199 0.82*

(0.0%) (5.93%) (2.6%) (2.9%) (3.4%) (3.0%)
0.91**

Miscarriage 0/1 7/58 6/22 11/67 9/47 11/57 0.26*

(0.0%) (12.1%) (27.3%) (16.4%) (19.2%) (19.3%)
0.99**

Ectopic 0/1 2/58 1/22 1/71 2/47 1/58 0.38*

(0.0%) (3.5%) (4.6%) (1.4%) (4.3%) (1.7%)
0.44**

Loss in second or third trimester 0/1 0/58 0/22 1/71 2/47 2/58 0.58*
(0.0%) (0.0%) (0.0%) (1.4%) (4.3%) (3.5%)
0.83**

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Preterm Labor 0/1 7/42 1/11 5/52 5/30 5/38 0.66*
(0.0%) (16.7%) (9.1) (9.6%) (16.7%) (13.2%)
0.69**

Gestational diabetes 0/1 4/41 4/11 8/52 11/30 12/39 0.11*

(0.0%) (9.8%) (36.4%) (16.4%) (36.7%) (30.8%)
0.61**

Preeclampsia 0/1 4/42 0/11 7/52 8/30 12/39 0.20*

(0.0%) (9.5%) (0.0%) (13.5%) (12.7%) (30.8%)
0.71**
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Outcome BMI <25 kg/m2 BMI 25-35 kg/m2 BMI >35 kg/m2

MetS No MetS Mets No MetS MetS No MetS P Value

IUGR 0/1 1/42 0/10 2/52 0/30 3/39 0.53*
(0.0%) (2.4%) (0.0%) (3.9%) (0.0%) (7.50%)
0.25**
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Macrosomia 0/1 0/42 2/11 7/52 7/29 4/39 0.68*

(0.0%) (0.0%) (18.2%) (13.5%) (24.1%) (10.3%)
0.12**

Cesarean Section 0/11 11/45 4/11 14/55 18/32 21/40 0.46*

(0.0%) (24.4%) (36.4%) (25.5%) (56.3%) (52.5%)
0.75**

Any Pregnancy Complication 0/1 14/42 5/11 22/52 21/30 23/39 0.89*
(0.00%) (33.3%) (45.5%) (42.3%) (70.0%) (59.0%)
0.36**

Chi-square or Fischer’s Exact test.

*
Metabolic syndrome effect within BMI category 25-35 25 kg/m2;
**
Metabolic syndrome effect within BMI category >35 25 kg/m2.

Only 1 person had metabolic syndrome in BMI category 25 kg/m2. Pregnancy losses before 20 weeks is per achieved pregnancy except biochemical pregnancies. Complications of pregnancy is per live
birth.

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Table 3.

Live births for full cohort

Using Cox Regression

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BMI category Metabolic Syndrome No Metabolic Syndrome RR Adjusted * p- value

(n= 254) (n=492) (95% CI) RR
(95% CI)
# 11/77 52/175 0.83 0.89 0.04
25-35 kg/m2 (14.3%) (29.7%) (0.75, 0.93) a
(0.79, 1.00 )

>35 kg/m2 30/176 39/199 1.02 1.04 0.50

(17.1%) (19.6%) (0.92, 1.13) (0.93, 1.15)

Using Modified Poisson Regression

BMI category Metabolic Syndrome No Metabolic Syndrome RR Adjusted * p- value

(n= 254) (n=492) (95% CI) RR
(95% CI)
# 11/77 52/175 0.86 0.92 0.04
BMI (14.3%) (29.7%) (0.79, 0.93) (0.83, 0.99)
25-35

BMI 30/176 39/199 1.02 1.04 0.34

>35 (17.1%) (19.6%) (0.94, 1.11) (0.96, 1.13)

*
Rate Ratio for one-unit change in MetS z-score adjusted for BMI
#
Rate Ratio for adjusted BMI, age, current smoking = 0.89(0.79, 1.00)
a
Upper bound of confidence interval rounded from value of 0.997
*
Risk ratio for one-unit change in MetS z-score adjusted for BMI
#
Risk ratio adjusted for BMI, age, current smoking = 0.91 (0.83, 1.00)

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Table 4

Effects of metabolic syndrome (MetS) on live birth rates and pregnancy complications by ovulation induction medication in PPCOSII

Live Births
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Letrozole P* Clomiphene Citrate P* P**

BMI 16.7-67.5 0.06 <.01

No MetS 76/248(30.7%) 57/245(23.3%) 0.06

MetS 27/125(21.6%) 15/129(11.6%) 0.03

Obese BMI >25 kg/m2 81/314(25.8%) 0.17 51/313(16.3%) 0.03 <0.01

No MetS 54/189 (28.6%) 37/185 (20.0%) 0.06

MetS 27/125 (21.6%) 14/128 (10.9%) 0.02

BMI 25-35 kg/m2 36/128(28.1%) 0.14 27/123 (22.0%) 0.03 0.26

No MetS 29/91 (31.8%) 23/83 (27.7%) 0.55

MetS 7/37 (18.9%) 4/40 (10.0%) 0.34

BMI > 35 kg/m2 45/186(24.2%) 0.66 24/190(12.6%) 0.63 <0.01

No MetS 25/98 (25.5%) 14/102 (13.7%) 0.04
MetS 20/88 (22.7%) 10/88 (11.4%) 0.05

Pregnancy Complication

Letrozole P* Clomiphene Citrate P* P**

All BMI 35/72(48.6%) 0.01 50/103(48.5%) 0.87 0.99

No MetS 31/76(40.8%) 28/57(49.1%) 0.33

MetS 19/27(70.4%) 7/15(46.7%) 0.19

Obese BMI >25 kg/m2 44/81(54.3%) 0.04 27/51 (52.9%) 0.16 0.88

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No MetS 25/54(46.3%) 20/37 (54.1%) 0.47

MetS 19/27(70.4% ) 7/14 (50.0%) 0.20

BMI 25-35 kg/m2 13/36(36.1%) 0.20 14/27 (51.8%) 0.33 0.21

No MetS 9/29(31.0%) 13/23 (56.5%) 0.09

MetS 4/7(57.1%) 1/ 4 (25.0%) 0.55

BMI > 35 kg/m2 31/45(68.9%) 0.43 13/24(54.2%) 0.77 0.23

No MetS 16/25(64.0%) 7/14(50.0%) 0.40

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Live Births

Letrozole P* Clomiphene Citrate P* P**

MetS 15/20(75.0%) 6/10(60.0%) 0.43
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Chi-Square or Fisher’s Exact test.

*
P-value within medication for MetS.(categorical)
**
P-value between medications.

Pregnancy complications are limited to those with a live birth and refer to having had a complication during pregnancy (any). This includes preterm labor, preeclampsia, hyperemesis, gestational diabetes,
IUGR, incompetent cervix, premature rupture of the membranes, and/or other

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