Auto-PAP Therapy For Improved Fetal Growth
Phase: NA
Conditions: Obstructive Sleep Apnea, Pregnancy
Sponsor: University of Michigan

Title: Auto-PAP Therapy For Improved Fetal Growth 
 
Statement of issues to be addressed/target population: The target population is pregnant women with sleep-
disordered breathing (SDB). SDB affects up to 35% of 3rd trimester pregnant women in the general population1, 
2 and up to 85% of those with hypertensive pregnancies3, 4. It is associated with fetal growth restriction (FGR),5-
7 a serious condition that affects approximately 10% of fetuses and is a significant disease burden not only for 
mothers but also for the long-term health of the child. The purpose of this proposal is to prospectively 
demonstrate that fetal growth trajectories are altered by maternal SDB such that estimated fetal weight measures 
will slow across the last trimester in women with SDB, a pattern that will not be observed in women treated with 
APAP therapy. Moreover, we will provide evidence that SDB induces placental hypoxia and vasculopathic 
inflammation, mechanisms by which SDB could cause poor fetal outcomes. Findings will demonstrate that APAP 
therapy, a non-invasive and non-pharmacological intervention, will have clinical utility as a novel therapy to 
address fetal growth problems.  
 
Description: goals, measurable objectives, action plans, and capacity to carry out the study:   
Goal: The primary goal is to provide evidence that in women with SDB fetal growth trajectory is impaired, defined 
as fetal weight falling across standard centile curves, but that fetal growth is not impaired in women treated with 
APAP therapy. In addition, we will show that placental tissue of women with SDB has evidence of hypoxia and 
inflammation, which will not be found in women treated with APAP therapy. These data will demonstrate that 
APAP therapy can minimize serious morbidity in pregnant women.  
 
Background: Fetal growth restriction is associated with increased perinatal morbidity and mortality including 
preterm birth, admission to the NICU, stillbirth, and long-term morbidities such as neurodevelopmental 
impairment and cardiovascular dysfunction.8-11 In the majority of cases, FGR is the result of placental 
insufficiency, usually caused by dysfunction of feto-placental perfusion with subsequent hypoxia and acidosis in 
the fetal circulation. It presents a major challenge in perinatal healthcare. The birth of a growth-restricted infant 
brings considerable emotional and economic costs to families and has implications for public-sector services, 
such as health insurance, educational, and other social support systems.12, 13 There currently are no effective 
clinical interventions that improve intrauterine growth.  
Maternal sleep disruption, specifically SDB, has emerged as a predictor of poor maternal outcomes. 
Symptoms of SDB affect up to 15% of women at conception,2, 14 up to 35% of women in the 3rd trimester,1 2 and 
up to 85% of women with hypertensive disorders of pregnancy.4, 15 Objectively-diagnosed SDB has been found 
in 8% of all pregnant women by mid-gestation,16 15% of obese pregnant women,14 and approximately half of 
hypertensive pregnancy women.4, 15 There is now a wealth of literature that demonstrates independent 
associations between maternal SDB and gestational hypertension, preeclampsia, and gestational diabetes.2, 17-
20 Maternal SDB has also been associated with FGR,6, 19 including a large study by our group.7 In some exciting 
and novel preliminary data we have demonstrated that APAP use in pregnancy is associated with improved 
infant birth weight: infants born to women who used APAP during pregnancy (n=18), compared to infants born 
to women with SDB who did not use APAP (n=17), have larger birth weight (3036±833g vs. 2485±1050g, p=0.08) 
even after accounting for duration of PAP use. In addition, we have preliminary data to show that APAP in 
pregnancy is associated with longer gestation; women who used APAP (n=18) continued their pregnancies for 
a mean of 2.5±3.4 weeks longer than those who did not use PAP (n=17; 37.7±2.8 weeks vs. 35.1±4.1 weeks, 
p=0.03). This is a clinically significant duration that will have long-term impact on infant health. Moreover, in a 
retrospective study we have data to show that fetuses of women with SDB have a fall in growth across the 
centiles, a pattern that was not present in women using APAP therapy.21 In a small pilot study it has recently 
been reported that SDB in women with preeclampsia is associated with reduced fetal movement, which was 
partially reversed with APAP therapy.22 Taken together, these preliminary findings suggest that APAP treatment 
of pregnant women with SDB is a window of opportunity to provide an urgently-needed clinical intervention that 
will improve fetal growth trajectory and thus have a positive impact on not only short-term pregnancy outcomes 
but also on longer-term morbidity.  
Placental dysfunction is central to many complications of pregnancy, including preeclampsia, FGR, and 
stillbirth.23 Disruption of the normal tightly-regulated developmental cascade that occurs during gestation can 
lead to abnormal placentation, which may manifest by functional and structural alterations such as changes in 
blood flow and changes in placental shape, texture, and patterns of injury.24 One of the major insults that impacts 
placental function is hypoxia, a major regulator of angiogenesis and thus placental vascular development. 
Chronic hypoxic stress or cycles of intermittent hypoxia during gestation result in an inadequate supply of oxygen 

to the fetus. Animal models have shown that 
rodents exposed to intermittent hypoxia deliver 
growth-restricted pups,25-27 and that these pups 
have long-term metabolic consequences similar to 
those seen in humans born with FGR.25, 28 Emerging data suggest that placentas from women with SDB have 
markers of hypoxia and angiogenesis.29, 30 Our preliminary data shows that the feto-placental weight ratio, a 
common metric of the balance between fetal and placental growth, decreases with increasing severity of SDB 
(see Figure). Furthermore, we have found that women with SDB have markers of hypoxia such as chorangiosis 
and increased nucleated red blood cells at a 2-fold higher frequency than women without SDB. Despite the 
critical role of the placenta, studies investigating uteroplacental function and structure in maternal SDB are 
lacking. We will provide pathologic evidence that SDB induces placental hypoxia and vasculopathic 
inflammation, patterns of injury that are not observed in women treated with APAP, providing highly novel 
mechanistic insight into mechanisms by which SDB could cause poor fetal outcomes. 
 
Measurable objectives: 1) To conduct serial fetal growth measures via ultrasound every 4 weeks from 28 
weeks’ gestation to 36 weeks’ gestation to demonstrate that growth falls across centiles (defined as ≥30% fall in 
centile in women with SDB but not in those using APAP; 2) To obtain placental tissue and perform histologic 
examination using a rigorous, methodical pathologic review adapted from Salafia & Popek31 to demonstrate that 
placentas of women with SDB show significantly more hypoxic injury and inflammation that placentas of women 
using APAP therapy.   
 
Action Plan: Recruitment: Pregnant women will be recruited from both clinical sleep referrals and obstetric 
clinics as in our previous studies.2, 4, 5, 32 Those who report snoring at least 3 nights/week will be invited to undergo 
a home sleep study. This approach will ensure that the majority of eligible women will be identified early in 
pregnancy, which will allow ample sample size to recruit from and sufficient time to initiate treatment in those 
enrolled and randomized to APAP. Inclusion criteria: <24 weeks gestation, singleton pregnancy, and objective 
evidence of SDB, defined as an AHI≥533 or a respiratory disturbance index (RDI)≥5. Exclusion criteria: unable to 
give informed consent, smoking, alcohol or drug use, current PAP treatment, and multiple gestation pregnancies. 
Women with severe SDB (AHI≥30) or severe daytime sleepiness (ESS>15) will not be randomized and instead 
triaged to clinical care. However, while these women will receive clinical treatment for SDB we will still follow 
them in an observational manner through the rest of the protocol (see below). No data exist to support or refute 
the hypothesis that among women with SDB, those with low AHI’s may suffer less impact. Published data from 
small series indicate that very mild SDB during pregnancy could have profound impact on pregnancy 
outcomes.22, 34-36 Furthermore, the vast majority of pregnant women with SDB have mild-to-moderate disease. 
Women with AHI≥5 or RDI≥5 will be randomized to no-APAP therapy or APAP therapy using the biased coin 
minimization technique,37 a CONSORT-approved method for assignment of treatment groups in RCTs.38 
The first subject is truly random; for subsequent subjects the treatment allocation that minimizes the imbalance 
of selected factors between groups is identified and subjects are assigned to the treatment or non-treatment 
group, with higher probability being given to assignment to the group that results in the least imbalance between 
groups. This maintains randomness in the assignment with the advantage of making small groups closely similar 
for subject characteristics at all stages of the trial. Minimization is the only acceptable alternative to true 
randomization and may be superior.39 We will use minimization to assign to the two study groups based on the 
following variables: blood pressure groups (hypertensive vs. not hypertensive), diabetes (diabetic vs. non-
diabetic), BMI (normal vs. overweight/obese), education (high school or less vs. post-high school), and SDB 
severity (AHI 5-14.9 (RDI 5-14.9) vs. AHI 15-29.9 (RDI 15 and above)). Women with an AHI≥30 or a daytime 
sleepiness score ≥16 on the Epworth Sleepiness Scale40 will not be randomized and will be referred for clinical 
APAP care. However, these women will still undergo the 3rd trimester assessments (see below). 
 
Polysomnography and APAP: Ambulatory polysomnography will be used to determine SDB status at baseline. 
We have previously validated home-based polysomnography in pregnant women.32 Following the nocturnal 
study, data will be down-loaded and analyzed using criteria of the American Academy of Sleep Medicine.33 
Women with SDB will be randomized to APAP therapy; use of auto-titrating machines allows delivery of the 
lowest effective pressure without need for multiple in-laboratory re-titrations as pregnancy progresses. Women 
will use APAP for the remainder of their pregnancies and will be closely followed by the study team. This will 
include remote monitoring of adherence, a major strength of our prior work. Ambulatory polysomnography will 
be repeated at 32-weeks with the addition of nocturnal fetal monitoring. Any woman in the non-APAP group who 

no longer has SDB in the 3rd trimester will not be included in the final analysis. In our experience it is uncommon, 
although not impossible, for a women with SDB early in pregnancy to no longer have SDB in the 3rd trimester. 
Typically the severity of SDB worsens as pregnancy progresses.  Nonetheless, to ensure that all non-APAP 
women still have SDB in the 3rd trimester it is important to repeat the sleep study in the 3rd trimester.  
 
Fetal Assessment: Fetal growth: Women will undergo traditional Doppler ultrasounds three times during the 3rd 
trimester (28, 32, and 36 weeks) for estimated fetal weight which will be adjusted for key, non-pathological 
maternal variables known to affect fetal growth, using the US dataset of the GROW software.41 Such 
customization is superior to population-based fetal weight standards as it generates an in utero growth standard 
that is customized for each fetus, to adjust for relevant maternal characteristics that may impact fetal growth. 
Thus the growth is optimized to obtain the growth potential of the fetus in the absence of pathology such as 
smoking, preeclampsia, or diabetes. Birth weight and gestational age will be abstracted from medical records. 
Birth weight will be converted into an adjusted birth centile using the GROW software.41 The purpose is to 
calculate the ‘term optimal weight’ as an ideal standard, against which the actual weight can be assessed. We 
have successfully used this software in a previous large cohort study.5 During a second home sleep study in the 
3rd trimester women will undergo in-home continuous portable fetal monitoring using the Monica DK, a small 
Holter-type device (Nottingham, UK), which has been validated against cardiotocography.42-44 Patterns of fetal 
movement will be assessed at the same three time-points in the third trimester as the ultrasounds.  
 
Placental Pathology: At the time of delivery, 3 full-thickness placental disc samples will be obtained and 
processed in routine fashion. Gross placental pathology will be performed including placental weight, and feto-
placental weight ratio. Histologic examination will be conducted using a rigorous, methodical pathologic review 
adapted from Salafia & Popek31 and developed with the intention of identifying underlying pathophysiologic 
processes. These factors include acute and chronic inflammation, uteroplacental vascular pathology and villous 
lesions, and intraplacental vascular pathology. This examination was piloted45 and refined in our preliminary 
analysis of placental tissue. Samples of placental tissue will also be banked for future research. 
 
Potential Problems and Alternative Strategies: Although our preliminary data solidly support the hypotheses 
there is the possibility that no differences will be found for fetal growth trajectory. In the unlikely even that this 
occurs, we will examine fetal heart rate variables and subjective measures of fetal movement for any subtle signs 
of fetal compromise that may not translate to large enough insults to significantly affect fetal growth measures 
but which may aid in the understanding of fetal wellbeing. Another potential problem is that insufficient women 
with SDB will be identified. However, given the large pool of women (approximately 4500/year) we do not foresee 
problems with recruitment. Although infrequent, it is possible that women with SDB in early pregnancy may not 
meet the threshold later in pregnancy. To minimize this (as well as drop out for other reasons), we will over-
enroll women to allow our final sample size to be sufficient for analysis (at least 27 women per group). Women 
could decline to undergo home monitoring; this is not likely to occur, since >50% of high and low-risk women 
approached for home monitoring have enrolled in our protocols. An additional potential problem is the use and 
adherence to APAP. However, we have previously demonstrated our ability to maintain adherence in 80% of 
pregnant women in a longitudinal study of APAP therapy in hypertensive pregnancies, of which about half did 
not even meet present criteria for SDB (K23HL095739); of those with SDB, we were able to maintain adherence 
in >90%. Our success was due to the ability to build a strong rapport along with frequent contact. The current 
study will only randomize women with SDB and thus, we believe that we are in a strong position to retain sufficient 
women on APAP. A further possibility exists in that no differences in gross placental pathology will be found. 
However, histological differences may still be present. If markers of hypoxia are not found, we will use the banked 
placental tissue to investigate the presence of angiogenic factors and receptors e.g., vascular endothelial growth 
factor, placental growth factor, and soluble fms-like tyrosine kinase 1. We will also investigate neutrophil 
extracellular traps as we have previously described45 or epigenetic changes.   
 
Sample Size and Power Calculation: To estimate the sample size required to detect a clinically important 
difference between groups we calculated the difference in birth weight between newborns of women with SDB 
who used APAP vs. those who did not use APAP, using a linear regression model which accounted for length of 
APAP use. From preliminary data of n=18 APAP users and n=17 non-PAP users, the APAP users delivered 
infants who were 551grams (over 1 pound) larger than non-APAP users. Assuming a mean birth weight of 2485g 
for the SDB group and 3036g for the APAP group with a standard deviation of 625g, a sample size of n=27 per 
group has 90% power to detect a difference with α=0.05. Even with a sample size of n=21 per group, we would 

still have >80% power to detect this difference. We are therefore confident that our milestones will be obtained 
if we enroll n=30 women per group. There is ample power to detect a clinically significant endpoint.   
 
Statement of how patients will be recruited and retained:  
Recruitment: Pregnant women will be recruited from obstetric clinics as described above. Our wealth of 
experience in conducting sleep-related protocols with pregnant women has allowed efficient, targeted screening 
in order to identify those at highest risk of SDB, and reserving objective confirmatory testing to those likely to 
provide the highest yield of SDB diagnoses. Our preliminary data demonstrate that report of habitual snoring 
(snoring ≥3 nights per week) is an excellent marker for the presence of objectively confirmed SDB. In a group of 
n=67 pregnant women (mean gestational age 28.2±7.8 weeks) who underwent polysomnography, mean AHI 
was significantly higher in habitually snoring pregnant women compared to non-snoring pregnant women (17.3 
vs. 3.3; p<0.01). We found that habitual snoring has good sensitivity (0.80), specificity (0.77), positive (0.70) and 
negative (0.90) predictive value for identifying women with confirmed SDB. Our approach thus minimizes the 
need for widespread objective testing. Furthermore, we have successfully treated pregnant women with APAP. 
Of n=51 pregnant women with SDB who were offered PAP (K23 HL095739) we enrolled n=45 women (88% of 
invited).  
 
Retention: We are one of a handful of centers that has conducted longitudinal sleep protocols in pregnant women 
and the PI was the first investigator to receive funding to study the impact of APAP therapy in pregnancy. We 
have been able to retain >90% of women with SDB on APAP therapy of >4 hours/night until delivery and therefore 
have demonstrated ability to promote excellent adherence to APAP therapy in pregnancy. An experienced team 
with APAP adherence in pregnant women is critical for the success of this proposal. Our team has been working 
together for several years to maximize retention and adherence of pregnant women in APAP-therapy protocols. 
The close relationships forged with study subjects together with APAP education, initial daily contact, and use of 
web-based software for real-time monitoring of APAP adherence have been major strengths to our success. 
Real time monitoring allows for same-day identification of problems and thus subsequent targeted intervention; 
the ability to intervene and address concerns early is key for maximum adherence.  
 
Impact Statement: The societal burden, medically, emotionally, and financially, of poor pregnancy outcomes is 
immense. Despite multiple strategies to reduce the incidence of FGR, prematurity, and stillbirth, figures 
demonstrate that little improvement has been made in recent years.33 There are currently no effective 
interventions that improve fetal growth yet our exciting preliminary data suggest that APAP therapy could indeed 
be such a novel target for early intervention in women with SDB. The latter is a significant population that is 
currently under-diagnosed. In our opinion, the proposed research is innovative because it will target maternal 
sleep as modifiable risk factor for fetal growth, using an RCT design, which has never been used in this 
population. This will generate a substantial new rationale for the clinical use of a non-invasive, non-
pharmacological intervention that is safe in pregnancy. The benefits of APAP therapy to two vulnerable 
individuals will be clearly demonstrated, paving the way for a novel application of a standard therapy that may 
ultimately have significant public health impact with beneficial ramifications on healthcare spending. 
 
Timetable: The time required for training staff and launch of the protocol is minimal (<1 month) due to our 
extensive experience in conducting APAP trials in pregnant women, together with our existing collaborations 
with Maternal-Fetal Medicine and Pathology. This then allows maximal time to run the protocol and enroll n=4 
women per month to ensure that all women are randomized by month 17. This will allow for intervention, 3rd 
trimester ultrasounds, and collection of all placental tissue by month 23, prior to analysis for grant submissions 
(month 24). 
 
EVALUATION: Plans for evaluation, how success will be measured and how progress/results will be 
documented: Successful milestones will be considered as follows: a) ≥95% of women have good quality home 
sleep tests with ≥4 hours sleep time; b) serial fetal growth measures are obtained on ≥95% of participants; c) for 
women randomized to APAP, ≥85% of women will use APAP ≥4 hours per night, ≥4 nights/week, and d) placental 
tissue is obtained on ≥95% of women. The PI and coordinator will meet twice per week to discuss progress and 
troubleshoot difficulties. The whole team will meet monthly. The main outcome will be longitudinal fetal growth 
trajectory and the secondary outcome will be placental histology. Analytic approach: A multi-level model will 
be the primary analysis method used to assess fetal growth measures over time and between groups. The model 
will account for the repeated collection of these measures over time Nonlinear time trends will also be 

investigated as it is hypothesized that the slope for fetal growth over time will not be as steep in the third trimester, 
especially for women with SDB. The model will take the general form: yij = β1 + β2x2ij + β3ij + ...+ βp xpij +ϕ0 j +ε 
ij where yij is the fetal growth measure at visit i for participant j and ϕ0 j is the participant specific random intercept. 
β1 through βp are the fixed effect parameters estimated by the model and ε ij is the time varying residual. The β 
coefficients associated with group membership are of primary interest. In addition to the random intercept per 
participant, random slopes will also be investigated for inclusion into the final model. For analysis of placental 
histology a Chi-square goodness of fit test will first be used to test for mean differences in the binary placental 
histology measurements between groups and a multivariable logistic regression will be used to assess group 
differences while controlling for potentially confounding polysomnographic variables (e.g., oxygen saturation 
nadir or AHI). We expect that the presence of SDB will slow fetal growth across the third trimester (>30% fall in 
centiles), a phenomenon not present with use of APAP therapy. Furthermore, we expect to demonstrate 
decreased feto-placental weight ratio, increased chorangiosis (hypoxia), and increased vasculopathic 
inflammation in SDB placentas, phenomena not observed with use of APAP therapy. These data will show that 
maternal SDB exerts an effect on the fetus that is at least partially reversible with APAP therapy.   
 
Expected results and dissemination: The societal burden, medically, emotionally, and financially, of poor 
pregnancy outcomes is immense. Despite multiple strategies to reduce the incidence of FGR, prematurity, and 
stillbirth, little improvement has been made in recent years.33 Identification of novel targets for early intervention 
that will yield significant real-world benefit is crucial. The proposed research is innovative because it will target 
maternal sleep as a modifiable risk factor for fetal growth. This will be the first study to prospectively assess the 
impact of APAP therapy on fetal growth. We will demonstrate that fetal growth trajectory falls across centiles in 
women with SDB during pregnancy and that APAP therapy prevents poor growth. We will also provide 
mechanistic data via placental pathology to support that APAP therapy minimizes hypoxic injury to the placenta. 
Our innovative approach requires a fusion of multidisciplinary investigators from Sleep Medicine, Maternal-Fetal 
Medicine, and Pathology; this represents a substantive departure from current methods of fetal surveillance. Our 
preliminary data strongly support a timely need for the proposed study, findings from which will be disseminated 
at national and international conferences and in international high-impact journals. Our findings will promote a 
considerable new rationale for the clinical use of APAP therapy as a novel tool in obstetric practice.  
 
Covid19 amendment March 2020: 
Due to Covid19 research operations involving face-to-face interaction were suspended. Research ultrasound 
visits were cancelled for all women except those on active APAP therapy. We are able to continue with some of 
the follow ups remotely such as questionnaire adminstration. However, subsequently we were no longer able to 
have access to offices and were thus unable to mail out home sleep test devices. In order to avoid missing a 
critical measure central to the project, we are requesting that disposable devices are mailed to participants – 
directly from the manufacturer - who would otherwise miss their third trimester home sleep test. We currently 
have approximately 4 women who are due to have their third trimester home sleep test in the upcoming month. 
 
These devices are the newer models of the devices that we currently use for this project (see below). The 
WatchPAT device is a home sleep test that we typically give to women and they self-administer it at home. It is 
a wrist-worn device with a finger probe and snore/position sensor. The new version of the WatchPAT 
(“WatchPAT One”) is the disposable version. The algorithm is the same as the current WatchPAT and the probes 
are the same. The difference is that the data are not stored directly on the device (which typically requires 
physical collection and downloading via USB to a laptop). The WatchPAT One utilizes a smartphone and a 
secure cloud. Thus, no physical contact with a person is required. Indeed, Itamar Medical Inc. provides a shipping 
service and participants simply put the device in the trash the following morning. The sleep data will be captured 
in the cloud (coded IDs on a server only for the study team). This is the methodology that will be adopted in new 
studies going forward, but we currently have no other option (other than lose a vital data point) than to utilize it 
sooner due to Covid19.  
 
Current device: 
  
Newest version (WatchPAT One): 
 
 
 
 
 

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Amendments: 
 
Add team member (OBGYN) approved 4/2/18 
 
Add research assistant (BL) approved 4/12/18 
 
Clarify the inclusion criteria to include women with a respiratory disturbance index of at least 15 events 
per hour even in the absence of an AHI of at least 5. This is an alternative definition of sleep disordered 
breathing. 

Approved 7/3/18 
 
Change the threshold for SDB identification to RDI of 5 in line with other studies in pregnancy. Also to 
clarify that gestational age threshold is <=20 weeks for inclusion (not just <20 weeks). Approved  
9/20/18 
 
Expanding the gestational age to include up to 24 weeks (was previously 20 weeks). We have been 
having difficulties with recruitment and in consultation with maternal-fetal medicine the most efficient 
upper limit for gestational age was agreed to be 24 weeks. Approved 1/16/19 
 
We are adding study staff LH and SR to the study and removing MN and KN. Approved 6/26/19 
 
Addition of AM, OB research coordinator.  Approved 7/19/19 
 
We are adding JM as a study coordinator approved 7/24/19 
 
Retain women triaged to clinical care w/ severe sleep apnea. Approved 8/26/19 
 
Add SH (sleep physician) to the study team approved 10/7/19 
 
Removing LH (coordinator) approved 2/19/20 
 
Time-sensitive: mail-out home sleep devices during Covid19 shutdown; follow up questionnaires by 
phone; cancelation of ultrasounds for non-intervention women. Approved 4/10/20 
 
Some of the data and samples (placental tissue) from this study will be shared with the University of 
Manchester in the UK for study HUM00133250.  
 
Study team members that are no longer working on this project have been removed. Approved 4/20/20