Giants in Obstetrics and Gynecology Series: a profile of Ivo Brosens, MD, PhD, FRCOG (ae)

Ivo has been an inspiration to me as a physician and scientist. His contributions have had a great and lasting effect on the practice of obstetrics and gynecology. The understanding of preeclampsia has evolved as a result of his pioneering studies of the spiral arteries and placental bed. Although Ivo has greatly influenced our discipline and has been called “the doyen of Belgian gynecology,” I know him to be an intensely private and modest person. For his groundbreaking work, Dr Ivo Brosens is recognized as a “Giant in Obstetrics and Gynecology.”

In 1977, Ivo invited Dr Robert Winston, a gynecologist and obstetrician from London, to visit Leuven, as Ivo was about to launch a major program in microsurgical approaches to gynecologic surgery. The challenges at the time were two-fold: the reversal of tubal sterilization and the treatment of infertility due to tubal disease. For the next 10 years, Ivo organized an international, hands-on microsurgery course for gynecologists. Dr Gloria Vasquez, a Chilean physician living in Belgium, took the course, became an expert in scanning electron microscopy, and together with Ivo, produced a series of detailed studies of the anatomy and pathology of the Fallopian tube mucosa in ectopic pregnancy and hydrosalpinx. 26 , 27 Over the years, it became clear that microsurgery was not effective in restoring fertility in one-third of women with tubal infertility, and that tubal surgery was associated with an increased risk of ectopic pregnancy. In vitro fertilization (IVF) had emerged as an alternative to microsurgery in the late 1970s, especially after the first success of this treatment in England by Dr Patrick Steptoe and Dr Robert Edwards in 1978. 28 Dr Pieter De Somer, the first lay Rector of KU Leuven, approved an IVF program at the University, and the first Belgian IVF baby was born in 1983. Although news of the pregnancy had been leaked to the media, the details surrounding the birth were kept quiet. Given the sensitivity about the use of assisted reproductive technology at a Catholic university, the pioneering team led by Ivo discontinued its efforts. In the fullness of time, IVF methods became available to infertile couples in Leuven, and Ivo and his colleagues established a private practice center. The concept of the luteinized unruptured follicle also comes from Ivo. Stein and Leventhal first suggested in 1935 that failure of the follicle to rupture could occur; 29 however, it was not until 1978 that evidence coalesced to support its existence. Dr Philippe Koninckx et al 30 reported the results of a prospective study in women with infertility, regular menstrual cycles, and apparently normal ovarian function. There were two groups of patients: one with infertility attributed to either tubal occlusion or male factor, the other with unexplained infertility. During laparoscopy performed in the early luteal phase, a stigma was present in only 10 of 24 patients with unexplained infertility, and in 15 of 16 patients of the other group. Based on the dating of the endometrial biopsy, basal body temperature records, and progesterone and LH determination, the authors concluded that some patients with unexplained infertility had anovulation with in situ luteinization as a potential cause for infertility. Subsequent studies demonstrating low concentrations of estradiol and progesterone in peritoneal fluid after ovulation and ultrasound observations supported the existence of a condition that remains interesting to the present time. 31 – 35

In 1953, Drs John McClure Browne and Norman Veall at Hammersmith Hospital in London reported a series of studies designed to determine whether there was a reduction in maternal placental blood flow in patients with preeclampsia. 1 Placental ischemia was considered key in the etiology of preeclampsia. Browne and Veall 1 injected radioactive sodium into the choriodecidual space of women with a normal pregnancy and those affected by preeclampsia and chronic hypertension after 38 weeks of gestation to calculate maternal placental blood flow. The investigators reported that the estimated maternal placental blood flow was 600 mL per minute at term, and there was a reduction by one-third in patients with preeclampsia and chronic hypertension. This report was of considerable interest to Dr Marcel Renaer, Professor of Obstetrics and Gynecology at the Katholieke Universiteit of Leuven (KU Leuven), who was interested in the pathophysiology of preeclampsia, and this interest led to the start of the lifework of Ivo on the placental bed. As the story goes, during a first-year medical school lecture, Dr Renaer asked whether anyone wanted to join a research project on preeclampsia, and Ivo undertook this challenge. “It was not standard practice for a first-year medical student to embark on a research project, but after studying philosophy for several years, I was eager to do some science,” Ivo told me. The studies of the placental bed required careful examination of histological sections of the uterus: to learn this, Ivo spent a summer holiday in 1958 visiting the laboratory of Dr William Hamilton, a famous placentologist, at London’s Charing Cross Hospital Medical School. The precise task was to learn techniques for cutting and preparing large histological sections from uterine specimens with the placenta in situ. “Dr Hamilton believed that analysis of caesarean hysterectomy specimens was the only practical way to study morphological changes in the spiral arteries,” Ivo said. In 1963, Dr Renaer and Ivo published their first observations on the spiral arteries of the decidua basalis in hypertensive complications of pregnancy. 2 That same year, obstetrician Dr Geoffrey Dixon and pathologist Dr William Robertson, both at the University College of the West Indies in Jamaica, introduced a technique for placental bed biopsy. 3 “To investigate preeclampsia, they used this technique to collect tissue from the interface between the placenta and the myometrium (the ‘placental bed’) during caesarean deliveries,” Ivo remarked. Ivo had graduated Maxima Cum Laude in medicine, an honor that was exceptionally rare at the KU Leuven, and he decided to pursue a PhD in London. When Drs Dixon and Robertson returned to England from Jamaica in 1964, Ivo began a collaboration to study the placental bed, which would become a lifelong passion. During Christmas 1964, Ivo’s sister visited him in London, travelling by car and ferry across the English Channel. His sister and brother-in-law brought several buckets containing caesarean hysterectomy specimens preserved in formaldehyde, much to the consternation of Her Majesty’s customs officers. After explaining that these precious specimens were intended for research at Hammersmith Hospital, the peculiar cargo was allowed into the country. The team at Hammersmith created full-size serial uterine sections to trace the spiral arteries from the inner myometrium to their opening in the intervillous space. This method enabled tracing of spiral decidual vessels back to their origins in the myometrium, thereby identifying these vessels as remodeled uteroplacental or spiral arteries, and revealed the vascular pathology associated with preeclampsia for the first time. The initial results were described in Ivo’s PhD thesis entitled “The Placental Bed,” 4 awarded by the University of London in 1965,3 and the study’s findings were published in the Obstetrics and Gynecology Annual in 1972. 5 Ivo returned to KU Leuven and was appointed Associate Professor in 1966. The next year, Ivo, Dr Dixon, and Dr Robertson published their observations on the anatomy of the placental bed in normal pregnancies in the Journal of Pathology and Bacteriology ( Figure 1 ). 6 They believed that the presence of cytotrophoblastic cells in the walls of the vessels was responsible for the structural changes and proposed the term “physiologic change of the spiral arteries” (page 578), which subsequently became “physiologic changes of the spiral arteries.” Ivo, Dr Dixon, and Dr Robertson argued that these changes did not affect the basal arteries because these arteries are not subject to cytotrophoblast invasion. 6

Ivo was born in 1931 in Morkhoven, Belgium, where his father was a general practitioner with a pharmacy that served a 12-village region. Ivo was the fourth of nine children delivered at home. As three siblings died shortly after birth from infection and heart disease, Ivo grew up with one brother and four sisters, all of whom pursued careers in science and medicine. He was educated in a Jesuit school and then studied philosophy and philology before deciding to pursue a career in medicine instead. He entered medical school at the age of 24, which was a relatively late start at the time.

Aware of the problems with open fetal surgery, Ivo, along with Drs Puttemans and Jan Deprest at KU Leuven, developed animal models for endoscopic fetal surgery using amnioinfusion and specially designed balloon-tipped cannulas ( Figure 10 ). 41 The technical skills, talent, and imagination of the team led to many of the pioneering contributions of the fetal surgical group at KU Leuven led by Dr Deprest. The video-endoscopic capability offered new vistas for fetal surgery and propelled KU Leuven to become a leading center for endoscopic fetal surgery.

Ivo’s contributions have been recognized worldwide by the Royal Society of Medicine Section on Obstetrics and Gynecology of England, the Royal College of Obstetricians and Gynaecologists, the World Endometriosis Society (for which he is a founding member), and the American Society of Reproductive Medicine. Ivo’s pioneering work on endometriosis and novel surgical techniques, such as transvaginal hydrolaparoscopy, continues to advance through the work of former students and colleagues in Belgium, including Drs Gordts, Puttemans, Rombauts, Campo, Koninckx, and his son Jan Joris Brosens, who is now Professor of Reproductive Medicine at the University of Warwick, United Kingdom. Ivo also supervised the doctoral theses of several well-known investigators, including Dr de Wolf (1974), Dr Pijnenborg (1975), Dr Koninckx (1980), Dr Willy Boeckx (1982), Dr Regis Denjean (1982), Dr Vasquez (1984), Dr Yolande Land (1985), and Dr Brigitte Karbowski (1988).

Ivo met his wife, Lutgard “Ludi” Verhulst, through their parents, who had enjoyed a close friendship. Ludi was born in Leuven, and her father was a Professor of Chemistry at KU. Ivo and Ludi came to know each other when he attended KU for medical school, and they married in 1961 ( Figure 13 ). Their first child, Peter, was born the following year in Leuven, where their two daughters, Ann and Lieve, would also be born years later. Their second son, Jan, was born at Hammersmith Hospital during Ivo’s tenure in England ( Figure 14 ). Ludi was involved in projects supporting refugee care, particularly refugee families with children from Latin America. Ludi passed away at home in 2018.

Neonatal vaginal bleeding occurs in approximately 5% of cases and is considered benign. Ivo has been fascinated with this phenomenon, which is thought to be due to withdrawal of steroid hormones that are abundant during pregnancy. However, he was puzzled by the fact that only a small fraction of all neonates has bleeding, when all of them undergo estrogen and progesterone withdrawal after birth. This has been attributed to an “ontogenic progesterone resistance” present in most neonates. 42 , 43 Ivo and Pino advanced a novel theory that endometrial stem cells disseminate in the pelvis at the time of neonatal uterine bleeding through retrograde menstruation, 44 – 49 an extension of Sampson’s theory about the origin of endometriosis published in 1927, 50 which explains the occurrence of premenarcheal endometriosis. Ivo and Pino have not only proposed a theory but also outlined a systematic approach to investigate this concept, which could have important implications, given that endometriosis in premenarcheal girls is particularly severe. The concept is that during thelarche, the increasing estrogen concentrations stimulate endometrial stem cells and progenitor cells to proliferate, and may lead to ectopic endometrial lesions of endometriosis ( Figure 11 ). 45 , 47

Although Ivo retired from KU Leuven in 1996 by University regulation, his contributions to the study of human reproduction have continued at a fast pace. “Traditionally, retirement has meant a decrease in scientific activity and publications,” Ivo said. In his case, he has an active intellectual life, collaborates with colleagues worldwide, and reflects a strong presence in major scientific journals and congresses. In 2019, Ivo published two papers summarizing research on the anatomy of the placental bed and on the functional and immunologic research in this field ( Figure 12 ). 14 , 51 In 2020, he reported findings about lipid deposition in placental bed vessels with acute atherosis, 52 which were a part of his initial PhD thesis in 1965. Among his most recent collaborators are Dr Benagiano from the University of Rome, Italy; Dr Caroline Gargett at Monash University, Australia; Dr Sun-Wei Guo at Fudan University, People’s Republic of China; Drs Marit Lier and Velja Mijativic at VU University Centre, the Netherlands; Dr Marwan Habiba at the University Hospitals of Leicester, United Kingdom; Dr Felice Petraglia at the University of Firenze, Italy; and me (Perinatology Research Branch, Eunice Kenedy Shriver National Institute of Child Health and Human Development, National Institutes of Health], US Department of Health and Human Services). Since his “retirement,” Ivo’s intellectual contributions have covered the pathogenesis of the “great obstetrical syndromes,” 53 the role of the myometrial junctional zone in pregnancy, 54 decidualization of the human endometrium, 55 and ovarian endometriosis. 24 , 25 , 56 He has also reported on the risk of spontaneous hemoperitoneum in pregnant women with endometriosis, 57 , 58 uterine immaturity, 59 and the role of menstrual preconditioning of the uterus for successful pregnancy. 60

The research unit was strengthened in 1974 following the appointment of Dr Robert Pijnenborg, a scientist who devoted a large part of his professional career to the study of cellular and molecular events at the placental bed. The main focus of the group was the study of trophoblast and decidual cell interaction and how this related to the vascular changes in the spiral arteries of normal and complicated pregnancies. In 1986, Ivo, collaborating with Drs T.Y. Khong, de Wolf, and Robertson, reported that the placental bed of patients who delivered small-for-gestational-age infants had the same lesions he had observed in preeclampsia. 13 This observation broadened the role of failure of physiologic transformation of the spiral arteries as a mechanism of disease to other obstetrical syndromes. 13 An interesting account of the chronology of placental bed research was described in a paper by Ivo, Dr Patrick Puttemans, and Dr Giuseppe Benagiano in 2019 (page 444). 14 The placental bed has been the subject of more than 1,000 publications as of 2018.

Ivo’s talent and surgical skills were instrumental in developing endoscopic techniques to improve the management of infertility and gynecologic disorders. In 1992, Ivo founded the Center for Surgical Technologies at KU Leuven. The Center is now one of the most prestigious training and research institutes for endoscopic surgery worldwide. Gordts et al 36 – 38 established transvaginal hydrolaparoscopy as an outpatient procedure for the diagnostic workup of infertility ( Figure 9 ). This technique was developed as an alternative to transabdominal diagnostic laparoscopy, consisting of the placement of an endoscope through the posterior fornix using normal saline and under local anesthesia. This procedure allowed visualization of tubo-ovarian structures in their natural positions without manipulation. The technique was used to detect subtle endometriotic lesions, neoangiogenesis, and flimsy adhesions. In 1998, the authors reported the first endoscopic visualization of fimbrial ovum retrieval in women. 39 A patient with a history of infertility was scheduled for hydrolaparoscopy on day 13 of the cycle—the luteinizing hormone (LH) assay was positive when the ultrasound showed a 20-mm follicle. During endoscopy, the ovulation stigma was identified, as was a distended fimbria embracing the ovary. The video showed the close relationship between the fimbrial mucosal and ovarian surface with slow release of the cumulus. This paper was selected as an “Outstanding Contribution” by the prestigious journal Human Reproduction . 39 Thirty years after its inception, physicians from the Netherlands have recommended the use of transvaginal hydrolaparoscopy as a diagnostic procedure for couples experiencing conception delay. 40

Even as Ivo is internationally known for his contributions to obstetrics, he became a subspecialist and Chief of Reproductive Endocrinology and Infertility at KU Leuven. His longstanding fascination with the enigmas posed by the ectopic endometrium led to his groundbreaking work on the pathophysiology, diagnosis, and medical and surgical treatment of the condition. In 1997, Ivo argued that endometriosis was an ovarian steroid hormone-dependent process that is physiological, as long as no bleeding occurs in the ectopic implants ( Figure 7 ). 23 However, an ectopic endometrium becomes pathologic and often symptomatic, especially when chronic recurrent bleeding leads to the formation of endometriomas. Ivo proposed that non-invasive methods, such as ultrasonography and magnetic resonance imaging, would be more suitable than laparoscopy to monitor disease progression and response to treatment, and that medical treatment without hypoestrogenism could suppress or eliminate menstrual-like bleeding in ectopic implants. 23 Many innovations followed, including work with Ivo’s long-time friend and colleague, Dr Benagiano (known as “Pino” to his friends). For example, they proposed that intracystic administration of synthetic progestins or selective progestin modulators could be effective in patients with an endometrioma. 24 , 25 In 2018, the German Scientific Endometriosis Foundation selected Ivo to receive the Rokitansky Award for his contributions to the study of endometriosis ( Figure 8 ).

Intent on building collaborations during the 1970s and 1980s, Ivo lent his valued expertise to universities worldwide. He has been a Visiting Professor at many institutions, including the University of Bristol in England; Columbia University, New York, and the University of New Mexico, Albuquerque, in the United States; King Edward Memorial Hospital for Women in Perth, Australia; the University of Hong Kong; and Universiteit van die Vrystaat in Bloemfontein, South Africa. I first met Ivo when he was a Visiting Professor at Yale University in the 1980s.

In 1972, Ivo established a research unit at KU Leuven to investigate the anatomy and pathology of the placental bed. This international hub of placental research had its humble beginnings in a refurbished locker-room equipped with transmission and scanning electron microscopes. That year, he examined placental bed biopsies of cesarean hysterectomy specimens from 400 normotensive women and 58 women with preeclampsia, and he found that restriction of physiologic transformation of the spiral arteries in the decidua and myometrial segments was a feature of the placental bed of women with preeclampsia. Ivo and his collaborators proposed that these findings were due to a developmental defect and accounted for reduced blood supply to the placenta. The electron microscopies were essential to describe the ultrastructure of the spiral arteries in the human placental bed in normal pregnancy, as reported in a paper published in AJOG in 1973. 7 Dr Frank De Wolf, Dr Christiane de Wolf-Peeters, and Ivo described how the muscular tissue of the arterial media was replaced by fibrillar and granular material in which giant cells were found, and which were morphologically identical to trophoblastic cells. They proposed that the structural modifications to the arterial wall were a direct consequence of invasion of the wall by the trophoblast cells, and that the changes were more pronounced in the decidua than in the myometrial portion of the spiral arteries. The observations were the basis for a diagram that describes changes in the spiral arteries in women with a normal pregnancy and those with preeclampsia ( Figure 2 ). 8 This diagram appears in textbooks and review articles worldwide. Figure 3 is a modification made by one of Ivo’s collaborators, Dr Roger McMaster-Fay, 9 and illustrates how maldevelopment of the spiral arteries can lead to subsequent narrowing and occlusion in the presence of acute atherosis, a lesion described by Dr Arthur Hertig, 10 Professor of Pathology at Harvard Medical School. The name of the lesion was chosen because of its resemblance to the images observed in atheromas. In 1975, Dr de Wolf, Dr Robertson, and Ivo published the first electron microscopy study of atherosis. In a paper entitled “The ultrastructure of acute atherosis in hypertensive pregnancy,” 11 the team at KU Leuven reported that the lesions were characterized by endothelial damage and medial wall necrosis, and showed macrophages engulfing lipid-rich material (foam cells). This report provided clear evidence of endothelial injury in preeclampsia, thus strengthening the case for the similarity between vascular lesions of atherosclerosis and atherosis. A key concept advanced by Ivo and his collaborators was that atherosis was restricted to vessels that did not have physiologic transformation of the spiral arteries (non-transformed myometrial segments, decidual segments of the basal arteries), and in the spiral arteries in the decidua vera parietalis of the margins of the placenta. 12