Modified natural cycle in

in vitro fertilization
Jacqueline R. Ho, M.D. and Richard J. Paulson, M.D.
Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles,
California

The first live birth after IVF was achieved in a purely natural cycle. Because early attempts at IVF were associated with low efficiency,
ovarian stimulation was added to achieve a greater margin for error in oocyte retrieval, fertilization, and thus, overall pregnancy suc-
cess. As technology improved, the intuitive appeal of the natural cycle led investigators to once again attempt IVF without antecedent
gonadotropin stimulation. Triggering of ovulation with hCG was added to allow for accurate scheduling of oocyte retrieval and thus
increased oocyte yield. When GnRH antagonists became available, premature ovulations could be prevented, albeit at the cost of adding
some form of ovarian stimulation to continue follicle development until ovulation triggering. This type of cycle came to be known as the
‘‘modified natural cycle.’’ These modified natural IVF cycles are associated with decreased medication costs, they produce acceptable
pregnancy rates, and they may be particularly appropriate for patients at increased risk of ovarian hyperstimulation syndrome, poor
responders, and those wishing to avoid supernumerary embryo production. (Fertil SterilÒ 2017;108:572–6. Ó2017 by American Society
for Reproductive Medicine.)
Key Words: IVF stimulation, IVM, minimal stimulation, modified natural cycle IVF, unstimulated IVF
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/
16110-fertility-and-sterility/posts/19128-24513

ince the first live birth after IVF time laparoscopy. The continued fine- NATURAL CYCLE IVF
S occurred in a purely natural
cycle (1), it is generally not
appreciated that the first attempts at
tuning of cycle monitoring and stimu-
lation protocols led to the current
utilization of controlled ovarian stimu-
Natural cycle IVF refers to oocyte
retrieval from the dominant follicle
formed during a woman's spontaneous
IVF actually involved ovarian stimula- lation (COS), which has since become cycle and subsequent fertilization and
tion. A pregnancy was achieved, albeit standard practice. culture in vitro (6). In the era of laparo-
a tubal gestation (2). The team of The obvious advantage of COS is the scopic oocyte retrieval, the promise of a
Steptoe and Edwards returned to the increased oocyte yield and thus the po- single oocyte, which may or may not
natural cycle for subsequent attempts tential for multiple embryos, facilitating have been successfully recovered, led
and thus achieved the first live birth embryo selection and cryopreservation clinicians to attempt protocols that
in 1978 (1). However, the laparoscopic of supernumerary embryos. Although would increase the yield of oocytes
retrieval of only one egg offered too most patients benefit, COS has draw- obtained by this relatively traumatic
small a margin for error. Therefore, backs, including the risk of ovarian hy- procedure. Subsequently COS became
ovarian stimulation was once again perstimulation syndrome (OHSS) and the norm, and natural cycles were
attempted and was eventually incorpo- higher cost. Endometrial receptivity temporarily abandoned. However, in
rated into clinical practice. Trounson may be decreased, especially in patients the late 1980s the process for oocyte
et al. (3) reported success with the use who experience a rise in serum P levels retrieval transitioned from laparoscopy
of clomiphene citrate to increase oocyte before hCG administration (5). Certain to transvaginal ultrasound guidance
yield, as well as hCG trigger to precisely patients do not respond well to high (7). The minimally invasive nature of
time laparoscopic retrieval. Jones et al. gonadotropin doses and may have this procedure made it a reasonable
(4) then reported successful use of similar pregnancy outcomes from option to attempt oocyte retrieval for
stimulated controlled ovulation with unstimulated or minimal stimulation single follicles, making the natural
the use of hMG and hCG trigger to protocols. cycle a viable alternative.
Received June 15, 2017; accepted August 10, 2017.
J.R.H. has nothing to disclose. R.J.P. has nothing to disclose.
Reprint requests: Richard J. Paulson, M.D., Department of Obstetrics and Gynecology, USC Keck hCG TRIGGER
School of Medicine, 2020 Zonal Avenue, IRD Room 534, Los Angeles, California 90033 (E-mail: To optimize the timing of ovulation,
rpaulson@usc.edu).
clinicians incorporated the use of hCG
Fertility and Sterility® Vol. 108, No. 4, October 2017 0015-0282/$36.00 trigger. Because the cycle was no longer
Copyright ©2017 Published by Elsevier Inc. on behalf of the American Society for Reproductive
Medicine
purely ‘‘natural,’’ a common designa-
http://dx.doi.org/10.1016/j.fertnstert.2017.08.021 tion was ‘‘unstimulated.’’ Whereas egg

572 VOL. 108 NO. 4 / OCTOBER 2017


retrieval became more predictable, patients could still ovulate
before the hCG trigger with the occurrence of a spontaneous
LH surge. In an early series in 1989, Foulot et al. (8) reported
a cancellation rate of approximately 15%, with only 68 of 80
cycles reaching retrieval despite hCG trigger usage. Paulson
et al. (9) reported a cancellation rate of 23% in 101 unstimu-
lated IVF cycles, with 78 cycles reaching oocyte retrieval.
Since then, despite further advances, cancellation rates
reported in case series and cohort studies still range from
15% to 71% (10, 11).
FURTHER MODIFICATIONS
In the early 1990s GnRH antagonists first became available for
clinical trials and were implemented into COS (12, 13). They
were also applied to unstimulated IVF cycles to further
decrease the risk of premature ovulation (14, 15). Because
GnRH antagonists not only stop the LH surge but also
disrupt further FSH stimulation of the growing follicle, some
form of ‘‘add-back’’ was required, in the form of either hMG
or FSH (14, 15). Cycles utilizing GnRH antagonists and
gonadotropin add-back became known as modified natural
IVF (mnIVF) (Fig. 1).
Recent studies have demonstrated the utility of low-dose
hCG in successfully completing follicle maturation in stimu-
lated cycles (16). A Cochrane review comparing the use of
low-dose hCG and FSH in the late follicular phase of COS
cycles concluded that its use does not reduce chances of
clinical pregnancy and likely results in an equivalent number
of retrieved oocytes (17). Paulson et al. (18) reported live
births with the use of low-dose hCG (200 IU daily) in mnIVF
cycles in lieu of gonadotropins for follicular support. The
benefit of using low-dose hCG in place of hMG is a significant
further decrease in cycle cost.
SECONDARY FOLLICLES AND IN VITRO
MATURATION
One limitation of mnIVF is the low oocyte yield in comparison
with COS cycles. However, transvaginal aspiration of second-
ary follicles may lead to retrieval of additional mature oocytes
FIGURE 1
Typical modified natural (mnIVF) cycle. Following baseline evaluation,
serial monitoring begins about 4 days prior to the anticipated day of
natural ovulation.
Ho. Modified natural cycle in IVF. Fertil Steril 2017.
VOL. 108 NO. 4 / OCTOBER 2017
Fertility and Sterility®
(metaphase II [MII]) or immature oocytes that may be cultured
in vitro to become MIIs. In a large retrospective study of
mnIVF cycles by Teramoto et al. (19), more than 25% of
oocytes aspirated from a nondominant follicle had MIIs,
and 85.6% of these were fertilized. The live birth rate was
8.6% per oocyte from nondominant follicles and 19.3% per
oocyte from dominant follicles, showing that secondary folli-
cles can lead to successful pregnancies (19). For immature
oocytes, in vitro maturation (IVM) is well described in the
literature and has led to successful pregnancies (20, 21).
Whereas most experience with IVM comes from polycystic
ovary syndrome patients, IVM can be applied to mnIVF
cycles to substantially increase the oocyte yield and overall
chances of success (18–22). Although initial data showed a
potential association of IVM with chromosomal
abnormalities (23), recent studies report no major
differences in abnormalities and complication rates between
IVF and IVM pregnancies (24). In vitro maturation provides
a safe and feasible technique for producing embryos from
immature oocytes that may be derived from secondary
follicles in modified natural cycle protocols.
PREGNANCY OUTCOMES FOR mnIVF
Pregnancy rates are highly variable among studies
examining mnIVF. An overall lower reported pregnancy
rate per cycle with mnIVF as compared with COS seems to
be primarily due to the higher cancellation rates before ET.
However, in patients who reach the ET stage, implantation
rates have been reported to be similar to or higher than those
of COS cycles (25). It is not clear whether this is due to some
advantage in oocyte quality attributable to the naturally
selected dominant follicle, or whether this is an endometrial
effect. The lack of gonadotropin stimulation in the follicular
phase obviates the premature rise in P that is associated with
stimulated cycles (Table 1). Thus, mnIVF avoids the endome-
trial–embryo dyssynchrony associated with COS, which also
negatively impacts pregnancy outcomes (5, 26, 27).
However, this advantage may be offset by the lack of
embryo selection. Most mnIVF cycles have only one
embryo available for transfer, whereas in COS cycles there
are several, thus allowing for selection of the best embryo.
As seen with stimulated IVF, there is an age-related decline
in fertility, which is reflected in mnIVF outcomes.
Normal Responders
The ideal candidate for mnIVF is an ovulatory woman with
normal ovarian reserve. Retrospective studies of good
TABLE 1
Serum P levels (ng/mL) in patients undergoing unstimulated versus
COS IVF.
IVF Day of hCG Follicle aspiration
Unstimulated 0.5  0.2 0.5  0.1
COS 1.1  0.6a 8.5  2.2a
Note: Adapted from Kolb and Paulson (44).
a
P< .05.
Ho. Modified natural cycle in IVF. Fertil Steril 2017.
573
VIEWS AND REVIEWS

responders have demonstrated good pregnancy rates per cycle

TABLE 3
and per ET (10, 28). A retrospective review of 1,508 fresh
mnIVF cycles by Shaulov et al. (29) reported a clinical Outcomes in poor responders.
pregnancy rate per cycle of 14.6% in normal responders
Age Age Age
aged %35 years and 12.2% in those aged R36 years Variable £35 y 36–39 y ‡40 y Total
(Table 2). The pregnancy rates per ET were 35.1% in women
No. patients 60 69 165 294
aged %35 years and 26.3% in women aged R36 years, No. of cycles 105 120 275 500
reflecting the reality that many patients did not reach the Transfers, n (%) 65 (61.8) 68 (56.9) 152 (55.4) 285 (57.0)
ET stage (29). Ovarian hyperstimulation syndrome has not Pregnacy/cycle (%) 18.1 11.7 5.8 9.8
been reported in mnIVF cycles, making this an excellent Pregnancy/ET 29.2 20.6 10.5 17.1
(implant rate) (%)
option for patients with an elevated risk. Pregnancy/patient 31.7 20.3 9.7 16.7

Adapted from Schimberni et al. (32).

Poor Responders Ho. Modified natural cycle in IVF. Fertil Steril 2017.

Patients who fail to produce multiple follicles in response to

COS are nevertheless good candidates for mnIVF. Two
randomized controlled trials have addressed the use of mnIVF
in poor responders in comparison with COS. Morgia et al. (30)
compared mnIVF with COS (microdose agonist flare protocol)
in poor responders. They found that pregnancy rates per cycle
and ET were not significantly different between treatment
groups across age strata and concluded that mnIVF was a
viable treatment alternative in this cohort, with younger
patients (%35 years) having a better prognosis (30). Kim
et al. (31) compared outcomes between mnIVF and COS in
poor responders. Clinical pregnancy rates per cycle and per
ET were similar between mnIVF and standard groups. Live
birth rates per ET were also not significantly different, at
13.5% for mnIVF vs. 16.7% for conventional protocols. The
authors concluded that mnIVF was as efficacious as IVF using
standard COS protocols, with the benefit of reducing the need
for gonadotropins and stimulation length (31). In 2009
Schimberni et al. (32) reported a series of 500 cycles in poor
responders; pregnancy rates per ET were 29.2% in patients
aged %35 years, 20.6% for women aged 36–39 years, and
10.5% in women aged R40 years. These results for poor
responders are summarized in Table 3.
Patients most likely to benefit from mnIVF are younger,
good-prognosis women who produce high-quality embryos
and may potentially experience delay in transfer due to
OHSS. Modified natural IVF is a second-line option for poor
responders who have suboptimal responses with standard
COS protocols using maximum doses of gonadotropins.
Couples with religious or ethical preferences may also choose
mnIVF to avoid embryo cryopreservation. Anovulatory or
TABLE 2
Outcomes in normal responders.
Variable Age £35 y
No. patients 625
No. cycles 1,119
Transfers/cycle (%) 41.2
No. pregnancies 163
Pregnancy/cycle (%) 14.6
Pregnancy/successful retrieval (%) 19.57
Adapted from Shaulov et al. (29).
Ho. Modified natural cycle in IVF. Fertil Steril 2017.
oligo-ovulatory patients are generally not good candidates
for mnIVF, because they generally do not spontaneously
form a dominant follicle. However, they may be candidates
for gentle stimulations. Women aged >40 years produce
oocytes that result in low embryo implantation rates and
thus likely derive the most benefit from COS and multiple
embryo transfer.
Perinatal Outcomes
Favorable perinatal outcomes have been reported from births
derived from mnIVF cycles. A retrospective cohort study by
Mak et al. (33) compared birth outcomes in 190 fresh mnIVF
vs. 174 stimulated IVF cycles. The average birth weight was
statistically significantly higher in the mnIVF group. Very
preterm births were also much lower in the mnIVF group
(0.52% vs. 6.3%, P< .005). However, these differences were
largely due to earlier delivery after COS, because after con-
trolling for gestational age at delivery, analyses demonstrated
no significance differences in birth outcomes between mnIVF
and standard IVF (33).
DISCUSSION
Protocols for COS were developed to maximize oocyte yield
during the IVF cycle to increase the probability of successful
fertilization and supernumerary embryos from which to
choose for ET. Additionally, some studies have suggested
that live birth rates are correlated with ovarian response
(34). Although multiple embryo transfer can increase the
probability of pregnancy, this may lead to higher rates of
multiple gestation and adverse obstetric outcomes (35, 36).
Controlled ovarian stimulation may not be successful in
poor responders, who may develop a single dominant follicle
or no follicles after down-regulation with a GnRH agonist.
Age ‡36 y There are also concerns that pregnancy rates may be
adversely affected by premature luteinization of the endome-
125
214 trium and the effects on endometrial receptivity associated
46.3 with premature elevation of P in conjunction with high
26 gonadotropin doses in standard COS protocols (37, 38).
12.2
17.69
In addition to potential effects on endometrial receptivity,
there is evidence of diminishing returns after a certain oocyte
yield is achieved. Sunkara et al. (39) reported that 15 oocytes
retrieved were optimal to achieve a live birth, because higher

574 VOL. 108 NO. 4 / OCTOBER 2017


numbers were not associated with higher live birth rates.
Similar findings were confirmed in a retrospective study of
256,381 cycles from the Society for Associated Reproductive
Technology database (40). Further evidence to support this
comes from a recent study by Baker et al. (41), which showed
that increasing gonadotropin dose was negatively correlated
with live birth rates, even when adjusting for age and stimu-
lation protocol.
It has been suggested that high-dose gonadotropins
might adversely affect oocyte quality and subsequently
embryo quality (42). One proposed mechanism of action
suggests that higher doses of gonadotropins may recruit
poorer quality oocytes that may not otherwise have been
selected in a natural cycle (42). However, studies examining
embryo quality and stimulation dose are confounded by the
observation that older patients tend to receive higher doses
of stimulation, and the premature luteinization of the endo-
metrium seen with aggressive stimulation may adversely
affect pregnancy outcomes in fresh IVF cycles. Recent data
do not show differences in aneuploidy if more vs. fewer
embryos are produced, and no difference in rates when
comparing stimulated vs. unstimulated cycles (43).
In conclusion, cycles of mnIVF produce acceptable preg-
nancy rates and implantation rates similar to those seen in
standard stimulated cycles. They are associated with lower
cost and exceedingly low risk of OHSS. It is reasonable to
offer mnIVF as a first-line option for patients who are good
responders and as a second-line option for poor responders
who do not respond well to standard COS protocols.
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