There is a relative lack of research on how certain diseases affect the course of pregnancy, since many ethics committees do not approve of conducting experimental trials on pregnant women.
Most clinical trials look for participants with roughly the same characteristics: adult male, healthy, nonsmoker, and committed to completing the trial for its full duration. Once suitable participants are found, the researchers will test the experimental drug at the lowest dose possible and observe the patient. Once the safety profile of the drug is established, researchers usually recruit other patients to administer higher and eventually therapeutic doses of the drug.
Only at the final stage of a clinical trial are women usually involved—first, women who are not pregnant, and finally, pregnant women. This is because pregnancy is a highly unpredictable environment for a clinical trial. In the worst-case scenario, the fetus is affected, resulting in either a termination of pregnancy or congenital defects.
Hence, medical researchers rightfully treat any clinical trials involving pregnant women with the utmost caution, with stringent protocols they must adhere to. The same is true for conducting active studies on pregnant women with particular diseases, even without the use of experimental drugs.
In a study published in Bioethics, Ballantyne and colleagues highlighted the difficulty in recruiting pregnant women for clinical trials. According to their research, some pregnant women do indeed understand the importance and value of research during pregnancy. However, certain hurdles remain. For example, there are concerns regarding:
- The ultimate decision-maker for participation (the extent to which their partners are involved in the decision-making process)
- Time commitments
- The weight of the risk
- The perceived safety of the study.
Also, there are concerns that drug kinetics behave differently during pregnancy, thus rendering any results less applicable to the general population. In Pharmaceutical Research, Koren and Pariente highlighted a few key changes in maternal physiology that can impact clinical studies: intestinal absorption, pulmonary absorption, drug distribution, and drug elimination.
An Alagille Syndrome Case Study
Given the potential pitfalls of conducting clinical trials on pregnant women, some researchers opt to report on case studies involving pregnant women as a means to increase our body of knowledge regarding the disease course and the efficacy of treatment in pregnant women. In Obstetric Medicine, Morton and Kumar provided 2 case reports of pregnant women with Alagille syndrome (ALGS).
We will recount 1 of the 2. The case involved a 33-year-old woman who was pregnant for the first time. She presented for antenatal care at 14 weeks gestation.
In infancy, the patient had been was diagnosed with ALGS with a JAG1 mutation. She had undergone pulmonary valvotomy and arterioplasty, and subsequently the stunting of her left pulmonary artery.
Read more about Alagille syndrome etiology
Upon presentation as an adult, it was noted that she had characteristic facies for ALGS: a broad forehead, deep-set eyes, a small-pointed chin, and a relatively short stature. An echocardiogram demonstrated moderate pulmonary regurgitation and mild pulmonary stenosis. Liver and renal function tests were within the normal range.
At 22 weeks gestation, the patient complained of mild pruritus. Liver function tests revealed elevated serum bile acids, but the patient refused treatment. From 32 weeks gestation onward, there was a decrease in fetal growth velocity as seen on ultrasound.
At 38 weeks gestation, the patient had a Cesarean section and successfully delivered a healthy 2520 g male infant (about 5.5 lbs). The weight of the placenta was 293 g (.6 lbs), which is under the 3rd percentile for gestational age. In addition, there were multiple foci of intervillous hemorrhage. The fetal/placental weight ratio was 8.6. Fortunately, the infant had no clinical features suggestive of ALGS, which was confirmed via genetic testing.
Lessons From the Literature
To be clear, in the case of this patient, no clinical trial was carried out. However, the fact of the matter is that we understand precious little about how ALGS affects the course of pregnancy, especially in severe cases. For example, in the other case study, the pregnant woman had an abnormal liver profile and experienced persistent hypertension, generalized pruritus, and superimposed preeclampsia. Her physicians managed those symptoms the best they could and the patient was able to safely deliver a male infant.
Read more about Alagille syndrome treatment
“Including the two cases detailed in this manuscript, there have been a total of only 11 successful pregnancies in women with ALGS described in the literature,“ Morton and Kumar wrote. “Of these, fetal growth restriction was present in seven pregnancies (64%), pre-eclampsia in two pregnancies (18%), and one case of postpartum maternal pulmonary edema. Neonatal death following cardiac surgery occurred in one case.”
In other words, we know from the medical literature that women with ALGS are more likely to experience complications while pregnant. The question circles back to what we can do about it.
In order to get to any real depth of understanding of how ALGS drives pregnancy pathology, clinical studies need to be conducted. Experimental drugs to treat those pathologies may need to be tested as well. However, given the special status of pregnant women mentioned earlier, it would be an uphill battle, at best, for researchers to carry out such work.
Morton A, Kumar S. Alagille syndrome and pregnancy. Obstet Med. 2021;14(1):39-41. doi:10.1177/1753495X19849738
Koren G, Pariente G. Pregnancy-associated changes in pharmacokinetics and their clinical implications. Pharm Res. 2018;35(3):61. doi:10.1007/s11095-018-2352-2
Ballantyne A, Pullon S, Macdonald L, Barthow C, Wickens K, Crane J. The experiences of pregnant women in an interventional clinical trial: Research In Pregnancy Ethics (RIPE) study. Bioethics. 2017;31(6):476-483. doi:10.1111/bioe.12361