Yoram Sorokin, M.D.
Mark P. Johnson, M.D.
Nancy Rogowski
David A. Richardson, M.D.
Mark L Evans, M.D.

From the Section of Antenatal Fetal Diagnosis and Therapy, Departments of Obstetrics and Gynecology, and the Section of Molecular Biology, Wayne State University/Hutzel Hospital, Detroit, Michigan, and the Ehlers-Danlos National Foundation, Southgate, Michigan.

This article is reprinted with the permissionof the
Journal of Reproductive Medicine; Volume 39, Number 4, April 1994: pages281 – 284

Women members of the newly formed Ehlers-Danlos National Foundation (EDNF) were surveyed with a very detailed questionnaire with 50 questions concerning family history and inheritance, past medical history, and obstetric and gynecologic problems, They entailed the largest extant database on Ehlers-Danlos syndrome (EDS) patients. The mean age of the 68 women who responded to the survey was 42 years, most had EDS types I, III, IV and unknown. Forty-three women had 138 pregnancies, 13 women never married, The stillbirth rate was 3.15% (3/95); the preterm delivery rate was 23.1% (22/95); and the spontaneous abortion rate was 28.9% (40/138). There was a cesarean delivery rate of 8.4% with 14.7% having perinatal bleeding problems. One woman (EDS type IV) had congestive heart failure. Common gynecologic problems were recurrent anovulation (41.3%), recurrent vaginal infections (53%), abnormal cytologic smears (19%); and sexual dysfunction (61%), irregular menses (28%), endometriosis (15.8%); vaginal dryness (25%); and a need for hysterectomy (19.1%)- In this largest series of pregnancies with EDS, we found relatively high rates of abortion, preterm delivery, pregnancy-related bleeding and stillbirth. Women with EDS also seem to have high frequency of anovulation, vaginal infections, abnormal cytologic smears and dyspareunia.

INTRODUCTION
The Ehlers-Danlos syndrome (EDS) is a heterogeneous collection of at least 10 connective tissue disorders causing abnormal production or secretion of collagens (Table I). Early reports on EDS emphasized joint laxity and skin hyperextensibility in the disorders. The classification of EDS is based on phenotype manifestations, specific biochemical abnormalities and mode of inheritance. The main clinical features are fragility of the skin and of the dermal blood vessels, characteristic "papyraceous" scars, hyperextensible and transparent skin, and hypermobile joints. Most reports in the obstetric and gynecologic literature have been anecdotal and were published before the various types of Ehlers-Danlos syndrome were recognized. There are several case reports that emphasize type IV EDS as distinct in carrying a high risk of major complications and maternal death due to ruptured blood vessels. The maternal mortality rate in type IV EDS has been estimated to be 25%.

It has been suggested for many years that during pregnancy, women with EDS are at increased risk of vascular complications, including varicose veins, aneurysm of blood vessels, cerebrovascular accidents, increased bruising, antepartum and postpartum hemorrhage, separation of the symphysia pubis, hematoma formation, increasing joint laxity, premature rupture of the membranes and prematurity. In nonpregnant women, menometrorrhagia, recurrent pelvic floor relaxation and uterine prolapse have been reported. However, because of the low incidence and multiple types of EDS, there are no recent large series from which one can draw any conclusions regarding obstetric and gynecologic symptoms, signs, morbidity or mortality. Recently, the Ehlers-Danlos National Foundation (EDNF) brought together enough patients with EDS to ask some meaningful questions. Below we report on any obstetrics and gynecologic aspects and complications in the largest extant group of women with EDS.

MATERIALS AND METHODS
A detailed questionnaire was mailed to women members of the EDNF. Fifty questions inquired about family history and inheritance, past medical and surgical problems and complications, obstetric and gynecologic history and issues of sexuality. Sixty-eight questionnaires that were completed and returned formed that database from which this report was generated. There were several cases in which no specific EDS type had been clinically assigned to the patient, and they are referred to below as "unknown".

RESULTS
The women surveyed had a mean age of 42 years. Of the 68 women, at least 30 had some relatives affected by EDS. The diagnosis was made clinically in two-thirds of the women. Very few women used alcohol (2 women, more than six drinks per week) or drugs; only 6 women smoked +\- O.5 packs per day. Eleven women were unemployed, and 30 had a professional career. Of the 68 surveyed, 42 had had 138 pregnancies (3.2 per woman). Thirteen women (19%) were never married.

The outcomes of pregnancies by EDS type are displayed in Table II. The incidence of bleeding problems during pregnancy was 14.7%; there were 40 miscarriages (29%), 3 stillbirths (3.15%) and 13 pregnancies with an antepartu m and/or intrapartum hemorrhage. There was one pregnancy with heart failure (EDS type IV), I with hip pains, I with preeclampsia and I with separation of the symphysis. Difficult or prolonged Iabor was reported for 5 (5.2%) pregnancies and precipitous labor for 2. Forceps delivery, breech delivery and retained placenta occurred in I pregnancy each. The preterm delivery rate was 23.l% (22/95), and there were 15 (15.7%) small for gestational age infants, The cesarean delivery rate was 8.4%.

Recurrent anovulation, frequent and recurrent vaginal infections, abnormal cytologic smear and sexual dysfunction due to dyspareunia were relatively common, with incidences of 41.3%, 53%, 19% and 61% respectively (Table III). Gynecologic problems included irregular menses (16/57), with most women having periods every 15-40 days. Menorrhagia (longer than seven days) was found in eight (13.7%) women. Pubarche and thelarche were in the normal range. Endometriosis was common (10/63, 15.8%), with seven women having severe cases; however, in five women, the diagnosis was made on the basis of the history and physical examination alone. Five of 10 women with endometriosis had EDS type IV. Hysterectomy was the most common gynecologic operation. Three women had a uterine prolapse, and two had cystocele and rectocele repair. Most of the women used contraceptives and had sexual activity with one male partner, however, many expressed having unsatisfactory sexual activity (15/58, 25.8%), dyspareunia (I2/58, 20.7%), sexual dysfunction (7/59, 11.8%), postcoital bleeding (5/59, 8.5%) and vaginal dryness (15/60, 25%).

DISCUSSION
EDS is a heterogeneous collection of connective tissue disorders. The incidence of complications varies with the different types. The precise underlying biochemical nature of the complications in several EDS types is known. However, in most clinical complications, the precise mechanisms are still a matter of speculation. In this series we attempted to look at several clinical obstetric and gynecologic symptoms, signs and complications in a large group of women with EDS.

This was the first attempt to create an EDS obstetric and gynecologic database, The need for such a database was obvious at the first meeting of the EDNF. This type of database has the limitation of selection bias and dependence on retrospective patient reporting.

In this series, we found suggested associations between miscarriages, antepartum hemorrhages, stillbirth and EDS. Previous series had similar findings as well as increased frequencies of backache, varicose veins and straie gravidarum, In 1966, Barabas reported on 39 pregnancies with 14 premature deliveries (defined as < 5.5 lb.), of which 13 started with premature rupture of the membranes. All the deliveries occurred between 32 and 35 weeks of pregnancy. The other reports were published earlier, had smaller numbers, did not contain information on EDS typing or defined prematurity as a neonatal weight < 2.5 kg. Beighton reported a 350%, (9/32) premature delivery rate in EDS type I (gravis). In the present series, we found a high preterm delivery rate, 23.1% (22/95); however, most women having preterm deliveries did not have premature rupture of the membranes. When the 95 deliveries are classified according to EDS type, there are still too few pregnancies in each type for meaningful conclusions.

Lethal complications of EDS (especially EDS type IV) have been reported extensively. The present series was biased toward women with survival and very low rate of serious complications (dissecting aneurysms, arterial rupture, vascular complications). We did not find high rates of postpartum hemorrhages or surgical interventions, as found in some earlier series. None of the patients in the present series had serious bleeding problems during pregnancy.

The literature on gynecologic problems in women with EDS is much scantier than that on obstetrics problems. Most of the clinical gynecologic problems could be easily explained by the skin and supportive tissue fragility in women with EDS. In our series very few women had surgery for symptoms of pelvic relaxation; however, recurrent vaginal infections, sexual dysfunction, vaginal dryness and dyspareunia were very common complaints. A more extensive gynecologic and urogynecologic evaluation in women with EDS is planned.

Obstetricians and gynecologists should be aware of the clinical symptoms and signs that reveal the possible presence of EDS and should understand that today many of the disorders can be confirmed by biochemical examination. Diagnosis should entail the patients' obstetric and gynecologic risks as well as the risk of transmitting the disease to their children.

Editor's Note: References available upon request.