The effect of weight and body mass

index on serum progesterone values

and live birth rate in cryopreserved
in vitro fertilization cycles
Rachel M. Whynott, M.D., Karen M. Summers, M.P.H., Margurite Jakubiak, B.S., Bradley J. Van Voorhis, M.D.,
and Rachel B. Mejia, D.O.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa Carver
College of Medicine, Iowa City, Iowa

Objective: To determine if weight or body mass index (BMI) affects the serum progesterone level at the time of the pregnancy test in
cryopreserved blastocyst transfer cycles and to determine if those serum progesterone levels affect live births.
Design: Retrospective cohort study.
Setting: US academic medical center.
Patient(s): Six hundred thirty-three patients undergoing their first cryopreserved embryo transfer cycle.
Intervention(s): None.
Main Outcome Measure(s): The primary outcome was the serum progesterone level on the day of the pregnancy test by patient weight
and BMI. Our secondary analysis assessed the serum progesterone effect on live birth rate (LBR) in a clinic where progesterone supple-
mentation was increased if the progesterone level was <15 ng/mL on the day of the pregnancy test.
Results(s): There was a strong negative correlation between serum progesterone level and both BMI and weight, with BMI accounting
for 27% and weight accounting for 29% of the variance in progesterone level. Serum progesterone level on the day of the pregnancy test
was <15 ng/mL in 3% of women weighing <68 kg compared with 29% of women weighing R90.7 kg. Among women weighing R90.7
kg, live birth occurred in 47% whose serum progesterone level was <15 ng/mL on the day of the pregnancy test compared with 49% in
those with serum progesterone level of 15–19 ng/mL and 44% in those with serum progesterone level of R20 ng/mL.
Conclusion(s): Body weight was a significant factor in serum progesterone level at the time of the pregnancy test, with nearly 30% of
patients weighing R90.7 kg having serum progesterone level of <15 ng/mL, a value associated with lower LBRs in prior studies. How-
ever, we found no effect of low progesterone levels on LBR after cryopreserved embryo transfer cycles in a clinic where progesterone
dosing was increased if serum progesterone levels were <15 ng/mL. (Fertil Steril RepÒ 2021;2:195–200. Ó2021 by American Society for
Reproductive Medicine.)
Key Words: Body mass index, obesity, IVF, in vitro fertilization, progesterone, infertility
Discuss: You can discuss this article with its authors and other readers at [Link]

A
s of 2016, there were 93.3 including issues with reproduction. Obesity is often diagnosed by us-
million adults affected by Obesity is thought to impact fertility ing a patient’s height and weight to
obesity in the United States through effects on ovulation, oocyte calculate their body mass index
(1). There is a high rate of reproductive numbers and quality, as well as miscar- (BMI). Physical characteristics and
age women meeting the criterion for riage rates (3–8). Assisted reproductive pharmacokinetics vary in overweight
obesity—34.8% of women aged 20–34 technology success is also negatively and obese patients (10). For example,
years and 43.4% of women aged 35– impacted by obesity, even when using a 2014 study by Shah et al. (11) re-
44 years (2). A multitude of health top-quality autologous blastocysts or vealed that standard 1.5-inch (3.81
problems are linked to obesity, using donor oocytes (7, 9). cm) needles for intramuscular injec-
tions did not reach the gluteal muscle
Received September 11, 2020; revised February 14, 2021; accepted February 15, 2021.
R.M.W., K.M.S., M.J., B.J.V.V. and R.B.M. have nothing to disclose. in 36.3% of the obesity study partici-
Reprint requests: Rachel M. Whynott, M.D., 1360 North Dodge Street, Office 1408, Iowa City, Iowa pants. Additionally, it is known that
52245 (E-mail: [Link]@[Link]).
obese patients require larger doses of
Fertil Steril Rep® Vol. 2, No. 2, June 2021 2666-3341 gonadotropins in comparison with
© 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Reproductive Med- their normal-weight counterparts
icine. This is an open access article under the CC BY-NC-ND license ([Link]
licenses/by-nc-nd/4.0/). (3, 9, 12). Bioavailability and serum
[Link]

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levels of both exogenous and endogenous human chorionic at 8 PM. Patients were included if their initial dose of supple-
gonadotropin are negatively affected by increasing BMI mental progesterone was 50 mg intramuscular daily.
and body weight in obese individuals (11, 13, 14). Patients were excluded if their weight or serum progesterone
Just as gonadotropins and human chorionic gonado- level on the day of the pregnancy test were unavailable. The
tropin are affected by obesity, so is progesterone. Progester- serum progesterone levels on the day of the pregnancy test
one supplementation is important for mimicking the natural were measured using an electrochemiluminescence
cycle, stabilizing the endometrium, supporting early preg- immunoassay.
nancy, improving pregnancy rates, as well as decreasing uter- The primary objective was to stratify the serum progester-
ine contractions at the time of embryo transfer to help reduce one level on the day of the pregnancy test by weight and BMI
the likelihood of embryo displacement from the uterine cavity and to determine which might be more impactful on the
(15–17). Nonpregnant women with obesity have been shown serum progesterone level. We decided to look at both weight
to have luteal progesterone levels approximately 75%–80% and BMI because a prior study by Mejia et al. (14) found that
lower than those of normal-weight women (18). Pregnant weight had a greater effect than BMI on hormone levels in
women with obesity have serum progesterone levels inversely early pregnancy. We used the same weight stratifications as
related to their BMI, and it has been postulated that this may were published in that article (14). Our secondary objective
influence the increased miscarriage rate noted among obese was to determine the effect of serum progesterone levels on
pregnant women (19, 20). Overweight and obese patients us- live birth rate (LBR) in a clinic that increased the dose of pro-
ing progesterone supplementation during fresh donor in vitro gesterone supplementation to 75 mg in response to a serum
fertilization (IVF)/intracytoplasmic sperm injection cycles progesterone level of <15 ng/mL on the day of the pregnancy
required increases in the progesterone dosage, because they test. We also examined the effect of the serum progesterone
were shown to have lower progesterone levels in comparison level on miscarriage and ectopic and biochemical
with those of their normal-weight counterparts (21). Addi- pregnancies.
tionally, a study revealed that increasing body weight was Chi-square test, Student’s t test, and Kruskal-Wallis test
associated with lower levels of progesterone in early preg- were used to compare demographics, serum progesterone
nancy after blastocyst transfer (14). level, and pregnancy outcome data between groups. Ectopic
Much of the research regarding progesterone supplemen- pregnancy, biochemical pregnancy, and miscarriage were
tation for IVF/ intracytoplasmic sperm injection cycles has grouped together as ‘‘abnormal pregnancy’’ because of low
focused on dosage and route of administration for the general numbers. Spearman’s rank correlation was used to assess
infertility population but has not specifically examined the relationship between the serum progesterone level and
possible differences in serum progesterone for patients with both weight and BMI. A power analysis determined that 281
obesity. There is a need to better understand how to best cases would be sufficient to detect differences in LBR previ-
care for our patients with obesity as the majority of American ously reported by serum progesterone level (45% in serum
infertility patients meet the criteria for overweight or obesity progesterone level of <15 ng/mL; 64% for serum progester-
(22). Anecdotally, our program has noticed that women with one level of >15 ng/mL) (21) using 2-tailed chi-square test
higher weight and BMI tend to require an increase in proges- with 80% power and a ¼ 0.05 and assuming a distribution
terone dosage. As it is important to know whether we are of 1:3. Logistic regression was performed to examine the rela-
adequately supplementing progesterone for our patients, the tionship between progesterone level and live birth while con-
aim of our study was to determine if weight or BMI affects trolling for age, parity, smoking history, anovulation
the serum progesterone level at the time of the pregnancy diagnosis, and weight. Chi-square test with a post hoc z-test
test in cryopreserved IVF/intracytoplasmic sperm injection using Bonferroni correction was used to determine the differ-
embryo transfer cycles and if those serum progesterone levels ences between weight classifications at various progesterone
affect live birth in a clinic at which the dose of progesterone is levels. We repeated all analyses with the sample stratified by
increased if the serum progesterone level is <15 ng/mL on the BMI instead of weight because a majority of the prior litera-
day of the pregnancy test. ture has focused on the BMI.

MATERIALS AND METHODS RESULTS

The University of Iowa institutional review board approved A total of 633 patients met the inclusion criteria and were
this retrospective cohort study (IRB 201303841). Patients un- included in the analysis. The BMI of the patients ranged
dergoing their initial vitrified cryopreserved blastocyst em- from 17.6 to 50.1 kg/m2, with a median of 26.1 (interquartile
bryo transfer cycle between January 2015 and December range 22.7–31.6) kg/m2. Patient weights ranged from 100 to
2018 were included in both the serum progesterone level 323 lbs, with a median weight of 157 (interquartile range
and live birth analyses. The upper BMI limit for IVF treatment 138–190) lbs. Spearman’s rank correlation revealed a nega-
at the clinic during that time was 50 kg/m2. To prepare for tive correlation between BMI and serum progesterone level
cryopreserved blastocyst transfer, patients were started on at the time of the pregnancy test (rho ¼ 0.521, P< .001),
oral estradiol (estradiol 2 mg three times daily) starting on cy- with BMI accounting for 27% of the variance in the progester-
cle day 1 or 2. Intramuscular progesterone in oil (50 mg) was one level. Weight was found to be a better predictor of proges-
initiated 5 days before embryo transfer, starting at noon, with terone level, with weight accounting for 29% of the variance
the same dose given at 8 PM the same day and continued daily in the progesterone level at the time of the pregnancy test

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(rho ¼ 0.536, P< .001). As weight was more predictive of the Information for pregnancy outcomes by progesterone
progesterone level, we focused on weight for the remaining level at the time of the pregnancy test for subgroups of
results. women weighing R90.7 kg and BMI R30 kg/m2 is presented
Demographic characteristics by weight category are in Table 4. Among women weighing R90.7 kg, there was no
shown in Table 1 and demographic characteristics by BMI significant correlation between the progesterone level at the
are shown in Table 2. There were no significant differences time of the pregnancy test and the pregnancy outcome. The
in mean age, race, gravidity, or number of previous IVF cycles LBR was 47% for women with serum progesterone level of
across the categories. Both history of smoking and diagnosis <15 ng/mL at the time of the pregnancy test compared with
were found to differ by weight and BMI category, with the 49% for women with serum progesterone level of 15–19.9
high weight and BMI groups being more likely to have a his- ng/mL and 44% for women with serum progesterone level
tory of smoking and a diagnosis of anovulation. of R20 ng/mL (Table 4). In women weighing R90.7 kg, there
The progesterone levels at the time of the pregnancy test were no ectopic pregnancies. Abnormal pregnancies did not
can be seen listed by weight and BMI category in Table 3. In differ among serum progesterone levels in women weighing
general, higher weight categories were associated with lower R90.7 kg. No significant differences were found for these
progesterone levels. Serum progesterone levels of <15 ng/mL outcomes within the subsample of patients with BMI R30
were found in 3% of women weighing <68 kg compared with kg/m2.
29% of women weighing R90.7 kg (P< .001). Only 27% of
the women weighing R90.7 kg had progesterone levels of
R20 ng/mL. DISCUSSION
We did not find a difference in the odds ratio for live birth The primary objective of our study was to determine whether
between women with a progesterone level of <15 ng/mL and the serum progesterone level was influenced by increasing
those with a progesterone level of 15–19.9 ng/mL (adjusted BMI or weight in cryopreserved embryo transfer cycles,
odds ration [AOR], 95% confidence interval [CI]: 0.86, 0.47– when patients rely on progesterone supplementation. We
1.60) or R20 ng/mL (AOR, 95% CI: 1.06, 0.58–1.92) when discovered that both increasing BMI and increasing weight
controlling for age, smoking history, parity, a diagnosis of an- negatively affected the serum progesterone levels on the
ovulation, and weight group. Similarly, we found no signifi- day of the pregnancy test and that increasing weight was
cance difference in LBR between women with a progesterone more influential than BMI. This was in agreement with the
level of <15 ng/mL and those with a progesterone level findings from a prior study at our institution (14). We hypoth-
of 15–19.9 ng/mL (AOR, 95% CI: 0.89, 0.48–1.64) or esized that this could be because of an increased volume of
R20 ng/mL (AOR, 95% CI: 1.05, 0.58–1.90) when BMI group distribution for progesterone or perhaps the inability of
was included in the model instead of weight. standard-length needles to reach the muscular layer of the

TABLE 1

Participant characteristics by weight.

Weight <68 kg Weight 68-90.3 kg Weight ‡90.7 kg
Characteristic (n [ 248) (n [ 266) (n [ 119) P value
Age (y) 33.70  4.58 34.03  4.74 33.88  4.52 .720
White 219 (89%) 243 (92%) 105 (90%) .649
History of smoking 36 (15%) 50 (19%) 31 (26%) .030
Current smoker 2 (1%) 10 (4%) 3 (3%) .099
Gravidity 1 (0–2) 1 (1–2) 1 (0–2) .066
Parity 1 (0–1) 1 (0–1) 0 (0–1) .151
Previous cycles 1 (1–1) 1 (1–2) 1 (1–1) .311
Diagnosisa
Advanced maternal age 16 (7%) 20 (8%) 3 (3%) .155
Anovulation 40 (16%) 58 (22%) 38 (32%) .003
Diminished ovarian 24 (10%) 22 (8%) 18 (15%) .128
reserve
Endometriosis 27 (11%) 27 (11%) 11 (9%) .872
Male factor 80 (33%) 97 (37%) 48 (40%) .320
Tubal factor 39 (16%) 43 (16%) 21 (18%) .916
Uterine factor 8 (3%) 12 (5%) 17 (14%) < .001
Unexplained 63 (26%) 50 (19%) 15 (13%) .011
Other 33 (14%) 35 (13%) 17 (14%) .969
No. of embryos transferred 1 (1–1) 1 (1–1) 1 (1–1) .274
Use of preimplantation 26 (11%) 40 (15%) 14 (12%) .285
genetic testing
Note: Data are presented as mean  standard deviation with P values for analysis of variance, number (%) with P values for chi-square test, or median (interquartile range) with P values for
Kruskal-Wallis test.
a
Two hundred participants in the dataset had multiple diagnoses, so sum across diagnoses categories will not total 100%; 42 cases did not have any diagnosis specified.
Whynott. BMI effect on serum progesterone in IVF. Fertil Steril Rep 2021.

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suggested that lower serum progesterone levels can decrease

TABLE 2
the LBR in both frozen and fresh embryo transfer cycles
Participant characteristics by BMI.
(21, 23–25). Although prior studies have typically measured
the progesterone level on the day of transfer, this is not
BMI <30 kg/m2 BMI ‡30 kg/m2
Characteristic (n [ 438) (n [ 194) P value consistent in practice, with some clinics measuring the level
on the day of the pregnancy test. The route of progesterone
Age (y) 33.94  4.56 33.76  4.81 .656
Caucasian 396 (91%) 170 (89%) .518
supplementation is also not standardized across IVF
History of smoking 67 (15%)a 50 (26%) .003 programs. Our goal was to determine if the lower
Current smoker 8 (2%)b 7 (4%) .254c progesterone levels on the day of the pregnancy test were
Gravidity 1 (0–2) 1 (1–2) .764 associated with a higher rate of an abnormal pregnancy
Parity 1 (0–1) 1 (0–1) .044
Previous cycles 1 (1–1) 1 (1–1) .527 (miscarriage or biochemical or ectopic pregnancy) or
Diagnosisd decreased LBRs. This determination was made in the
Advanced 31 (7%) 8 (4%) .220 context of a clinical policy of increasing the dose of
maternal age
Anovulation 81 (19%) 55 (29%) .006
intramuscular progesterone in anyone with a serum
Diminished ovarian 39 (9%) 25 (13%) .157 progesterone level of <15 ng/mL. We did not find evidence
reserve of a difference in live birth between serum progesterone
Endometriosis 47 (11%) 18 (9%) .698 levels on the day of the pregnancy test when intramuscular
Male factor 151 (35%) 73 (38%) .464
Tubal factor 68 (16%) 35 (18%) .479 progesterone supplementation was increased for those with
Uterine factor 20 (5%) 17 (9%) .056 serum progesterone levels of <15 ng/mL. Our findings
Unexplained 99 (23%) 29 (15%) .039 suggest that intramuscular progesterone in oil (50 mg) is
Other 59 (14%) 26 (14%) 1.000 sufficient to allow for implantation regardless of serum
No. of embryos 1 (1–1) 1 (1–1) .557
Transferred progesterone levels and patient weight or BMI; however,
Use of 54 (12%) 26 (13%) .807 because we did not have a comparison group that did not
preimplantation receive additional supplementation if the serum
genetic testing
progesterone level was <15 ng/mL, we do not know if
Note: Data are presented as mean  standard deviation with P values for Student’s t test,
number (%) with P values for chi-square test, or median (interquartile range) with P values increasing the supplementation changed the live birth
for Mann-Whitney U test. BMI ¼ body mass index. outcome. In the prior study by Brady et al. (21),
a
Missing data for 1 case.
b
Missing data for 16 cases. intramuscular progesterone was used as well, although the
c
P value for Fisher’s exact test as the expected counts for chi-square test were not met.
d
Two hundred participants in the dataset had multiple diagnoses; so sum across diagnoses starting dose of progesterone ranged from 50 to100 mg
categories will not total 100%. Moreover, 42 cases did not have any diagnosis specified. without an explanation of the dose choice or of how many
Whynott. BMI effect on serum progesterone in IVF. Fertil Steril Rep 2021. patients received each starting dose. Differences in our
outcomes may be because of our larger patient sample, a
standardized starting dose of progesterone, our analysis of
cryopreserved embryo cycles instead of fresh embryo
tissue to provide an actual intramuscular injection in women transfer cycles, or our testing of the serum progesterone
weighing R90.7 kg or with a BMI >30 kg/m2. level on the day of the pregnancy test instead of the day of
Our secondary objective was to determine if the LBR the embryo transfer.
would be affected by differences in serum progesterone level Given the increasing prevalence of overweight and
in women weighing R90.7 kg in a program that automati- obesity in the United States, it is important to evaluate how
cally increases the progesterone supplementation (to 75 mg) increasing weight or BMI affects treatment outcomes and to
if the serum progesterone level is noted to be <15 ng/mL determine adjustments that can be made to accommodate
on the day of the pregnancy test. Previous studies have and improve the success rates of IVF in this population.

TABLE 3

Progesterone level outcomes by weight and BMI.

Progesterone level at Grouped by Weight Grouped by BMI
the time of the
pregnancy test Weight <68 kg Weight 68-90.3 kg Weight ‡90.7 kg BMI <30 kg/m2 BMI ‡30 kg/m2
(ng/mL) (n [ 248) (n [ 266) (n [ 119) (n [ 308) (n [ 124)
<15 8 (3%)a 20 (8%)a 34 (29%)b,c 15 (3%)d 47 (24%)e
15–19.9 19 (8%)a,c 72 (27%)a,b 53 (45%)b,c 70 (16%)d 74 (38%)e
R20 221 (89%)a,c 174 (65%)a,b 32 (27%)b,c 353 (81%)d 73 (38%)e
Note: Data are presented as number (%). P values are for chi-square test of independence. BMI ¼ body mass index.
a
Proportion differs significantly from the weight R90.7 kg group at .05 level.
b
Proportion differs significantly from the weight <68 kg group at .05 level.
c
Proportion differs significantly from the weight 68-90.3 kg group at .05 level.
d
Proportion differs significantly from the BMI R30 kg/m2 group at .05 level.
e
Proportion differs significantly from the BMI <30 kg/m2 group at .05 level.
Whynott. BMI effect on serum progesterone in IVF. Fertil Steril Rep 2021.

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TABLE 4

Pregnancy outcomes by progesterone level at the time of the pregnancy test for the subsample of patients weighing 90.7 kg and with BMI ‡30 kg/
m2.
Pregnancy Type Progesterone <15 ng/mL Progesterone 15-19 ng/mL Progesterone 20+ ng/mL P
Subsample weighing R90.7 kg
n 34 53 32
No pregnancy 9 (27%) 11 (21%) 7 (22%) .879
Abnormal pregnancya 9 (27%) 14 (26%) 11 (34%)
Clinical pregnancy 16 (47%) 28 (53%) 14 (44%)
Live birth 16 (47%) 26 (49%) 14 (44%) .893
Subsample with BMI R30 kg/m2
n 47 74 73
No pregnancy 12 (25%) 19 (26%) 21 (29%) .972
Abnormal pregnancya 11 (23%) 17 (23%) 14 (19%)
Clinical pregnancy 24 (51%) 38 (51%) 38 (52%)
Live birth 24 (51%) 36 (49%) 37 (51%) .956
Note: Data are presented as number (%). P values are for chi-square test of independence. BMI ¼ body mass index.
a
Abnormal pregnancy was defined as biochemical or ectopic pregnancy or miscarriage.
Whynott. BMI effect on serum progesterone in IVF. Fertil Steril Rep 2021.

A recent meta-analysis revealed that female obesity nega- <15 ng/mL, a value associated with lower LBRs in prior
tively impacts the IVF success rate (26). Several theories studies. However, we did not find evidence for a 19% reduc-
have been postulated for this finding, including decreased tion in LBR among patients with low progesterone levels after
oocyte quality, inadequate folliculogenesis, poorer embryo cryopreserved embryo transfer cycle in a clinic where proges-
development, and an impaired endometrial environment terone dosing was started at 50 mg intramuscularly daily and
(26). We hypothesized from our findings that the endometrial increased if levels were <15 ng/mL on the day of the
environment, in part, can be optimized with adequate proges- pregnancy test.
terone dosing, and that women with obesity may have higher
progesterone supplementation requirements. Our study sug-
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