NEWS ABOUT OBSTETRICS & PERINATOLOGY
The long-term consequences of severe maternal morbidity in a pregnancy
A recent paper and accompanying Editorial in JAMA (1, 2) addressed the potential impact on future attitudes toward pregnancy in women who experienced significant morbidity during a pregnancy. Though to a degree it should be considered what we call a “self-fulfilling prophecy study”—because its outcome is largely predictable—some such studies do have value (many, or most, do not and are a waste of time, money, and effort), and this is one of them.
As expected, the study revealed that women who experienced significant morbidity in a pregnancy were subsequently less likely to have another birth, especially after severe uterine rupture, cardiac complications, cerebrovascular accidents, and severe mental health conditions in a first birth. Sibling analysis—though we are not certain to what degree—was not suggestive of any familial confounding. However, the study did not isolate the effect of medical advice. And medical advice is, of course, very influential and traditionally always very conservative, sometimes overly so.
A good example is maternal cardiac disease, which—with very few exceptions—can be safely managed within qualified medical settings (3). However, whether a patient has access to such a setting may, and should be, decisive in reaching a decision about a future pregnancy. We, therefore, fully agree with the authors’ conclusion that adequate reproductive counseling and the availability of enhanced antenatal care are crucial for the decision-making process of women who experienced prior severe morbidity in a pregnancy—as they, of course, also are for every woman with a significant medical problem planning a first pregnancy.
References
1. Tsamantioti et al., JAMA 2025;333(2):133-142
2. Husby A, Boyd HA. JAMA 2025;333(2):122-123
3. Elkayam et al., J Am College Card 2016;68(4):396-410
Unintended pregnancies after renal transplant
As the British National Health Service Blood and Transplant website noted, women can try having a child after a kidney transplant. A woman’s fertility, indeed, will likely improve. Transplant recipients are, however, advised to wait at least a year before trying, to give time for tolerance pathways for the kidney to fully establish themselves. Moreover, treating physicians need to be informed because immunosuppressive medication patients take may need to be changed (1).
But unintended pregnancies happen quite frequently in this population, leading recently to publication of an interesting paper describing the effects of such unintended pregnancies on pregnancy outcomes and graft survival (2).
Among 1,723 pregnancies of kidney transplant recipients, 1,081 (62.7%) were intended and 642 (37.3%) were unintended pregnancies. Risk factors for unintended pregnancy included younger age, Black race, nulliparity, chronic hypertension, and transplant from a deceased donor. Unintended pregnancy was independently associated with allograft loss at 2 years from the end of pregnancy (8.1% vs 3.5%, AOR 2.27, 95% CI, 1.32–3.94, P=.003) but not allograft survival (adjusted hazard ratio 1.22, 95% CI, 1.00–1.49, P=.05). There were no differences in severe maternal morbidity (3.3% vs 3.6%) or neonatal composite morbidity (12.9% vs 14.3%) by pregnancy intention.
References
1. NHS Blood and Transplant Website. https://www.nhsbt.nhs.uk/organ-transplantation/kidney/living-with-a-kidney-transplant/familyplanning/#:~:text=Your%20transplant%20team%20will%20usually,contraception%20during%20this%20first%20year. Accessed March10, 2025
2. O&G Open 2024;1(4)::p.040
Gestational diabetes
It is now well accepted that pregnancy is a diabetogenic state. This means that women who already are prediabetic or diabetic may, respectively, become diabetic or may need more treatment once pregnant than in the non-pregnant state. Gestational diabetes is, however, distinct from these two circumstances in that it is defined by the development of diabetes during pregnancy which after delivery, however, resolves.
First reported in 1824 in Berlin, Germany, an excellent recent review of gestational diabetes in the JCEM deserves attention (1). Focusing mostly on the clinical management of this condition, the paper reviews lifestyle-based therapy as well as pharmacotherapy, obstetric management, and discusses the lifelong potential health consequences a diagnosis of gestational diabetes then represents. Clearly a recommended read!
Reference
1. McIntyre et al., J Clin Endocrinol Metab 2025;110:e19-e31
Non-chromosomal congenital anomalies increase at very young as well as advanced maternal ages.
It has been known for quite some time that both very young and advanced age reduce fertility treatment success, for example, in IVF. It has also been reported that chromosomal abnormalities demonstrate a similar pattern in pregnancies, with very young and older women showing more aneuploidy than women in intermediate age groups. Now, however, comes a paper from Hungarian investigators that also demonstrates the same pattern for non-chromosomal congenital abnormalities (1).
Selecting for a systematic review 72 studies in the literature, maternal age >35 years was associated with an increased risk of congenital abnormalities, with the risk rising further and notably after age 40. Specifically, cleft lip/palate and cardiovascular defects were associated with age over 40. Conversely, gastroschisis was associated with very young maternal age, under 20 years.
Reference
1. Pethö et al., Am J Obstet Gynecol 2024;231(5):P490-P500
A first placenta-centric treatment of preeclampsia or, maybe, even much more?
A very interesting hypothesis has in recent years been gaining ground among investigators, which tries to explain not only how the normal maternal immune system tolerates an embryo immediately from implantation at a microscopic size, but also until delivery, by which time the average fetus has a roughly 3.5 kg average weight (and often even more). In other words, the maternal immune system must adjust to the exponential growth of the invading, and usually well-tolerated parasite, called a fetus.
And this is exactly where the placenta enters the discussion, because the placenta is, of course, growing in parallel with the growth of the fetus. It does so outside of the fetus and, ultimately, is not only disposable but was apparently destined by nature to be disposed of once it has done its job.
The placenta—widely believed in its principal function to provide oxygen and nutrition to the fetus—has now, however, been hypothesized to have a possibly even more fundamental function in preventing the euploid fetus from being rejected. And since this organ grows in parallel with the fetus, it maintains the effectiveness of this function in normal pregnancies until the onset of labor and the subsequent delivery. At that point, the placenta is no longer needed and, therefore, is disposed of by nature.
How the placenta protects the fetus from rejection is still largely unresolved, but the above-noted hypothesis suggests that protection of the fetus from rejection may be the principal reason why the placenta until term remains contaminated by aneuploid cells, while the fetus, for very obvious reasons, of course, cannot be seeded by aneuploid cells. Proponents of this hypothesis—which has been prevalent at the CHR for decades—have indeed proposed that, similar to cancer, where especially aneuploidy of metastatic disease has been demonstrated to “confuse” immune checkpoints enough to allow cancers to spread, the placental-fetal unit does something similar in principle, with placental aneuploidy helping to confuse the mother’s immune checkpoints which, outside of pregnancy, would violently attack any allogeneic invasion into the body.
Considering that preeclampsia is increasingly recognized as an immunologically mediated condition of the placenta (likely the cause of waning immune tolerance to the fetus), a recent paper in Nature magazine was of great interest to us (1).
As the authors noted, pre-eclampsia, now indeed widely considered a placental disorder, affects 3-5% of pregnancies and is a leading cause of maternal and fetal morbidity. Currently, no treatment exists to either prevent or treat the condition, except for the delivery of the fetus plus placenta, which in a large majority of cases almost instantly “cures” preeclampsia (there exist rare exceptions where preeclampsia can occur postpartum or last into the postpartum period).
It has been reported that lipid nanoparticles ferry therapeutic mRNA to the placenta (2). The investigators in the discussed study, therefore, concluded that, with no drug available to slow disease progression in preeclampsia, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta could be a therapeutic option for preeclampsia. In their paper, they, therefore, used high-throughput screening to evaluate a library of 98 LNP formulations in vivo before identifying a placenta-tropic LNP (LNP 55) that mediated more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the FDA-approved Onpattro LNP (DLin-MC3-DMA).
From this observation, they suggested the existence of an endogenous targeting mechanism based on β2-glycoprotein I adsorption that enables LNP delivery to the placenta. They then confirmed their hypothesis by demonstrating in mouse models of inflammation- as well as hypoxia-induced pre-eclampsia that a single administration of LNP 55 encapsulating vascular endothelial growth factor (VEGF) mRNA resolved maternal hypertension (a typical symptom of preeclampsia) until the end of gestation.
Using their VEGF mRNA LNP 55 therapeutic, they additionally demonstrated improvements in fetal health and partially restored the placental vasculature, the local and systemic immune landscape, and serum levels of soluble Fms-like tyrosine kinase-1, a clinical biomarker of pre-eclampsia.
For the authors, the most important conclusion of their study was, of course, the potential of this mRNA LNP platform for treating placental disorders such as pre-eclampsia. In our opinion, their accomplishment was, however, even bigger because they for the first time conclusively confirmed that preeclampsia must indeed be considered an immunologic placental disorder.
From that, as already noted above, one can then further conclude that the placenta must indeed be actively involved in the production and maintenance of immunological tolerance during pregnancy. And, if this is really the case, the placenta may teach us how to induce perfect tolerance against allogeneic organ transplants and—maybe also—how to enhance tolerance pathways in general, which may also offer new treatment avenues for autoimmune diseases.
But that may not even yet be the end of the story. Because—as also increasingly appears likely—cancers have over evolution “stolen” pregnancy’s ability to induce tolerance and applied this ability to the cancer’s survival in an immunologically hostile host immune system. By understanding in detail how the placenta succeeds in maintaining tolerance for a logarithmically growing fetus, we should also be able to learn how to interrupt the development of such tolerance, which, in turn, could teach us how to better treat metastatic disease.
References
1. Swingle, et al., Nature. 2025;637(8945):4120421
2. Eccleston A, Nat Rev Drug Discov 2025;24(2):90
So, what’s the story with maternal Vitamin D levels in pregnancy?
It is practically impossible to open just a few medical journals every week without finding an article on the negative effects of low Vitamin D levels in one or another medical condition. Yale University’s F. Perry Wilson, MD, MSCE, whose weekly Medscape Impact Factor we frequently cite in these pages for its smart analyses of published data, in one of his most recent postings actually made fun of all the various claims about allegedly positive Vitamin D effects, challenging readers to show him even one example where such an effect was truly confirmed.
But—of course, to his own surprise—he finally found a paper that did exactly that and, therefore, became the subject of his weekly Commentary (1), in which he, in his usually very detailed and analytical way, reexamined the data in the paper, confirming that Vitamin D was indeed beneficial in a large study of patients with Multiple Sclerosis (MS), as the figure below demonstrates (2).
Which brings us back to reproductive medicine, because a paper in The American Journal of Clinical Nutrition recently also reported Vitamin D effects dependent on maternal status during pregnancy, on fetal growth patterns and adverse pregnancy outcomes (3). In a study that claimed to determine whether first- and second-trimester maternal Vitamin D levels affected fetal growth patterns and obstetrical outcomes, the authors concluded that first-trimester levels were indeed linearly associated with fetal growth, and low levels of Vitamin D (< 40 nmol/L) were associated with a higher risk of preterm birth. In contrast, second-trimester Vitamin D levels did not demonstrate any of these associations.
We are not certain that this study would withstand Wilson’s analysis as well as the MS study did; but, considering how inexpensive Vitamin D supplementation is, and considering that most women nowadays take a prenatal vitamin that contains Vitamin D, it may make sense to consider some additional supplementation during the first trimester, though caution regarding the data is indicated, and here is why: Some time ago, the so-called VITAL trial, a 5.3-year-long, randomized, 2x2 factorial, double-blind, placebo-controlled trial, suggested that Vitamin D supplementation significantly reduced the general incidence of autoimmune disease. A follow-up study two years after trial termination then demonstrated, however, that the protective effects of 2,000 IU of daily Vitamin D had fully dissipated (4,5).
What made this finding even worse for Vitamin D was the fact that 1,000 mg per day of n-3 fatty acids, which in a parallel investigation in the VITAL trial had also proven to be effective, maintained its effectiveness in this two-year follow-up. This is clearly an additional example that even published, prospectively randomized clinical trials are not always reliable and, certainly, not always the final word.
References
1. Wison FP. Medscape Impact factor. March 10, 2025. https://www.medscape.com/viewarticle/rare-win-vitamin-d-this-time-ms-2025a10005ul
2. Thouvenot et al., JAMA 2025; doi:10.1001/jama.2025.1604 Online ahead of prin.
3. Beck et al., Am J Clin Nutr 2025;121(2):376-384
4. Costenbader et al., Arthrit Rheumat 2024. https://doi.org/10.1002/art.42811
5. Osterwell N. Medscape Medical News. February 7, 2025. https://www.medscape.cm/viewarticle/preventing-autoimmune-diseaseses-new-findings-vitamin-d-omega-2024a10002nc
Is Clomiphene Citrate really increasing stillbirths and neonatal death?
This is what Australian investigators suggested in a recent paper in the JCEM that, obviously, passed peer review (1). And that is troublesome at multiple levels because the authors very clearly intended to suggest—and stated so outright in the paper—that the risk of perinatal death may be increased in pregnancies conceived with Clomiphene Citrate. And they did so, even though one would expect the authors to know that studies decades ago demonstrated that these increased risks are mostly associated with medical characteristics of infertile patients rather than the treatment method used to achieve pregnancy.
To simply minimize this point by adding to the above-noted conclusion that, “while established confounding factors related to infertility were taken into account, there may be some residual contribution of underlying infertility,” is simply not good enough. Everybody in the field knows that, and one, for example, must wonder why the control group was not simply another group of infertile women receiving gonadotropins instead of Clomid.
This kind of paper makes infertility practice around the world only more difficult because it unnecessarily frightens patients. Reviewers and editors, therefore, should at least have insisted on a much clearer emphasis on the principal weakness of the study: the absence of an adequate control group. We, therefore, can only reemphasize a point routinely made in these pages: Every study starts with careful selection of study and control populations. Nothing is more important!
Reference
1. Moore et al., J Clin Endocrinol Matab 2024;dgae741
Congenital adrenal hyperplasia in pregnancy
In a retrospective multicenter study at tertiary centers in Austria, Germany, Italy, Sweden, and the U.S., 72 adult women with congenital adrenal hyperplasia (CAH) were included. Among them, 34 had nonclassical CAH, 21 had the simple virilizing form, and 17 had salt-wasting CAH. These women experienced 133 pregnancies, resulting in 112 live births and 25 abortions (1).
Though these numbers appeared to lie within a somewhat low but still normal range, patients interestingly demonstrated a clearly prolonged time to conception. In the salt-wasting form, the median time to conception was 11 months; in the simple virilizing form, it was 24 months; and in the nonclassical form, it was only 8 months. Moreover, even this timing was achieved with the use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Indeed, over half of all participants qualified for a diagnosis of infertility, since it took them over 12 months to conceive. The average number of live births, however, was 1.4-1.6, comparable to the general population and similar among CAH subtypes.
The spontaneous abortion rate of 18% was also within the normal population range, but Cesarean sections were more frequent (60.9%).
Reference
1. Auer et al., J Endocr. Soc. 2024;9(1):bvae211
Cardiovascular complications in patients during pregnancy
It does not happen often that we discuss papers in the cardiology literature here; but here are two exceptions: In an article in JACC Advances, colleagues in cardiology reported on cardiovascular complications in pregnancy in women with psoriasis (1).
Psoriasis is, of course, an autoimmune disease, and even though in many, if not most, cases, it is not considered a major medical problem, it is associated with all the typical complications of autoimmune diseases in association with pregnancy, including increased risks for miscarriages, premature labor and delivery, and, as this study again confirmed, preeclampsia/eclampsia. What came as somewhat of a surprise was the finding of more cardiac arrhythmias in these patients, a finding that, to the best of our knowledge, has not been reported before.
More important, however, is to reemphasize that obstetrical risks in patients with autoimmune diseases, as we often repeat in these pages, are not linked to one or the other laboratory test, as is often argued in the reproductive immunology literature. And many risks are also not particularly linked to one or another autoimmune disease (though there are, of course, disease-specific risks as well) but to the hyperactive immune system characteristic of all autoimmunity.
In a second paper, interestingly, Ob/Gyn colleagues from the U.S. reported in a cardiology journal on cardiovascular complications in the year after delivery of a twin pregnancy (2). This is a question that, to the best of our knowledge, has never been investigated before.
And the results were indeed very interesting: Using the Nationwide Readmission Database of U.S. hospitals between 2010 and 2020, cardiovascular readmissions in the first year after twin and singleton pregnancies were 1105.4/100,000 and 734.1/100,000, respectively. Compared to singleton pregnancies without hypertensive diseases of pregnancy (including preeclampsia), the adjusted hazard ratio for a cardiovascular readmission was the highest for twins with hypertensive disease, followed by singletons with hypertensive disease, and twins without hypertensive disease.
These are fascinating findings, though we would interpret them somewhat differently from the authors, who emphasized that—compared to singletons without hypertension—even in the absence of hypertension, twin pregnancies demonstrated increased admission rates in the first postpartum year, suggesting that twin pregnancies put an increased strain on the maternal cardiovascular system. But in our opinion, the authors did not stress enough the additional risk that a hypertensive pregnancy denotes, of course, more so in twin pregnancies.
The study, therefore, really suggests that all twin pregnancies should be carefully followed during the first postpartum year—but especially hypertensive twin pregnancies and, maybe also hypertensive singleton pregnancies.
Finally, readers of The Reproductive Times will likely be familiar with the CHR’s disagreement with the widely held belief in infertility as well as obstetric/perinatal practice that twin pregnancies in young and healthy women carry significantly increased maternal and/or fetal risks. As the CHR’s investigators have published in several papers over the years, this incorrect conclusion, held by so many colleagues, has been mostly based on the comparison of outcomes in one twin pregnancy to one singleton pregnancy—an inappropriate statistical comparison because it compares apples with oranges (i.e., one vs. two newborns). A correct comparison must compare outcomes of one twin pregnancy to two consecutive singleton pregnancies, and even such a comparison falls short because an infertile woman can never be guaranteed the chance of a second pregnancy.
At the same time, we, however, now must acknowledge that the findings reported in this paper may indeed represent a valid argument against twin pregnancies in infertility practice.
References
1. Agrawal et al., JACC Advance 2025; 4(2):101562
2. Lin et al., Europ Heart J. 2025;:ehaf003
And finally, a word on maternal mortality rates in the U.S.
The National Center for Health Statistics at the CDC in February published maternal mortality rates in the U.S. for 2022. Maternal mortality rates decreased significantly from prior years (see below the 1st figure).
This applied to practically all races (see below the 2nd figure) but the observed decrease for Asian non-Hispanic women was not statistically significant. In 2022, the maternal mortality rate for Black women (45.9 deaths/100,000 live births) remained, however, significantly higher than the rate for White (19.0), Hispanic (16.9), and Asian (13.2) women.
1. Statistically significant decrease from previous year (p < 0.05).
2. Hispanic people may be of any race.
NOTE: Race groups are single race.
SOURCE: National Center for Health Statistics, National Vital Statistics System, mortality data files.
Rates also decreased significantly for all age group from 2021 to 2022: (The 3rd figure below). Rates in 2022 were 14.4 deaths per 100,000 live births for women younger than 25, 21.1 for those ages 25–39, and 87.1 for those age 40 and older. The rate for women of age 40 and older was six times higher than the rate for women younger than age 25. Differences in the rates between age groups were statistically significant.
Though these rates in this one year greatly improved, one bird still does not make spring. U.S. maternal mortality rates are still among the highest among developed countries and clearly require further improvements.