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“Every year, about 1 million pregnancies in the U.S. end in a miscarriage… In [up to] half those cases, doctors are at a loss to explain why”1
Women who miscarry often feel like they are alone – stigma, shame, and misconceptions often lead them to stay silent and blame themselves for what happened. These and other trends make miscarriage research difficult, despite the fact that miscarriage is very common – approximately one in four women will experience it in their lifetime1,2.
Just because miscarriage is common doesn’t make it easy – it can be an incredibly difficult process, felt by women in our team’s locale, known for its dense population of young families3–5, and by women around the world6,7.
Women can experience significant pain and, in some cases, serious health complications following miscarriage8–10. Some miscarriages go unnoticed until a medical visit reveals the fetus died weeks previous11. Many feel they have lost a child when they or their spouse miscarries. Many women believe that this loss may be their fault.
In our interviews of women who have experienced miscarriage, we found that many desire additional information about what is going on in their bodies during miscarriage – and this desire is not unique to those we interviewed. Many women, due to the stigma and silence surrounding miscarriage, are unaware of what is normal and known about the phenomenon. For many women, the first question is, “’Why did this happen to me?’”2.
The majority of known miscarriages, such as those resulting from genetic abnormalities in the miscarried fetus, are explainable and are not preventable12. But in a significant number of cases, even scientists don’t have all the answers to why the miscarriage happens - in part because of the stigma that drives women into painful silence and inhibits research1,2.
Women we have surveyed want and need illumination on these issues, and a myriad of others in women’s health. Synthetic biology is poised to make a difference in this space. Our team, Inara – derived from an Arabic word referring to illumination13 - aims to provide the illumination they need.
Acting as a first mover in the space of real-time aptamer-based progesterone monitoring, we intend to provide women and researchers with a ray of light to dispel uncertainty and obscurity surrounding the patterns and mechanisms of miscarriage.
This progesterone monitor will also be very relevant to other areas of women’s health.
Progesterone levels normally increase rapidly during early pregnancy, but can vary significantly over the course of the day14,15, and inadequate14 levels can be associated with negative results in terms of live births.
In other words, successful pregnancies rely on appropriate, continuously controlled levels of progesterone at each stage of early pregnancy – without this, the pregnancy cannot continue correctly and may result in miscarriage. Our team aims to develop a device to measure progesterone, a key female sex hormone, in real time. This would present a novel women’s health capability, as current monitoring practices are urine- or blood-based, with no continuous monitoring options.
This achievement would help address the primary question of many affected women – “why?” - by helping to classify miscarriages through real-time monitoring and providing needed tools to advance scientific research into the more ambiguous causes of miscarriage. In addition, in our personal interviews, we learned that women who have faced recurrent pregnancy loss can face significant uncertainty and anxiety about the health of their next pregnancy. For some women, our monitor could address the anxiety of having no way to know whether their pregnancy is still healthy.
In addition to its role in pregnancy and miscarriage, progesterone levels have other vital roles. Changes in progesterone levels trigger ovulation and regulate contraceptive function, making it a key target for predicting fertility windows and helping women who want to get pregnant (and women who don’t want to to avoid it). Commercial urine-based fertility tests like Mira19 use progesterone tracking over time to improve fertility outcomes, but no continuous monitor exists. Developing this monitor could enable higher accuracy fertility window prediction than anything available on the market currently.
Progesterone is also an important part of the menopause process, and is related to a variety of cancers17,18. Developing this hormone monitor would help illuminate these connections, enable new dimensions of research, and could even provide relevant health information directly to women anticipating menopause or at risk for these particular cancer types.
Aptamers – pieces of DNA that are shaped to fit specific molecules – are our chosen method of detection. Aptamer detection presents several advantages for our continuous monitor concept. In terms of safety, a cell-free, reagent-free technology is essential for use in an in-arm monitor. Aptamers are inherently cell-free, and in many cases can act independent of reagents as well. Another advantage provided by our chosen aptamer is its electrochemical mechanism of action – alternating current (AC) voltammetry allow for its use to take direct measurements using electronics, rather than concentrations being quantified through an intermediary reporter such as fluoresence. Minimizing this complexity makes our system more robust.
In the context of in-vitro fertilization (IVF) and other assisted reproductive therapies (ART), routine blood draws used by some IVF clinicians check progesterone levels in order to make decisions and improve outcomes20–22, both inadequate14 and elevated16 progesterone levels have been associated with fewer successful births, and physicians can prescribe progesterone supplementation to treat low levels that may lead to miscarriage14. There is some disagreement about the proper place of progesterone supplementation, but the essential role of progesterone levels and their proper development throughout the pregnancy process remains unchallenged.
A large retrospective study in 2013 (n = 5414) shows a significant positive effect of progesterone hormone replacement therapy on the number of live births in the context of frozen-thawed embryo transfer (FET)23, while a recent randomized control trial (n=488) likewise shows a significant positive effect of vaginal progesterone tablets on the success of FET scheduled in natural cycles24. However, there is some dissent, controversy, and conflicting results about progesterone supplementation’s effectiveness in preventing miscarriage, especially outside of the IVF / FET context, signaling a research gap requiring more attention24,25. Research needs to be done to fill this understanding gap, regardless of the degree to which inappropriate progesterone levels are a cause of miscarriage or just a signal.
Importantly, serum progesterone levels measured at a variety of time points before and after the FET process all are correlated live birth rate, emphasizing the value of continuous rather than intermittent progesterone monitoring24, especially given the hourly variability of progesterone levels15. This time dependence signals that a continuous monitor would be very helpful in studying the relationship between miscarriage and progesterone levels in entirely new ways.