The Marfan and Ehlers - Danlos syndromes and preagnancy
In CHAPTER ONE an introduction is presented to the Marfan and Ehlers-Danlos (EDS) syndromes. Both syndromes are rare, inheritable, and result from complications of these disorders, and the syndromes may affect the course and outcome of pregnancy. The paucity and potential selection and publication bias of data in the pertinent literature preclude adequate preconceptional assessment of risk and counseling, and of optimum medical and obstetric care of pregnant women with Ihesc syndromes. The membership of the Dutch Marfan and Ehlers-Danlos Associations offers an opportunity to collect data and analyze the relationship between these syndromes and pregnancy. The following objectives of the thesis are formulated:
- To review the literature on the Marfan syndrome and EDS, in particular in relation to obstetric aspects and the neonate.
- To assess the course and outcome of pregnancies in women with Marfan and EDS, based on data obtained from the membership of the Dutch patient associations.
- To formulate guidelines for preconceptional assessment of risk and for medical and obstetric care of pregnant women with these syndromes.
In CHAPTER TWO the historical aspects, prevalence, and genetics of both syndromes are discussed. The biology of connective tissue is presented, including the synthesis and breakdown of collagen, and theories of the pathogenesis of both gene (FBN-1) causing deficient cross-linking of collagen fibers; EDS is mainly due morphology of collagen fibers. Diagnosis of the Marfan and Ehlers-Danlos inheritance, and may sometimes be supported by molecular analysis of collagen. In the EDS different types are recognized. Because of the important medical and obstetric consequences it is essential that a correct diagnosis be made before pregnancy.
In CHAPTER THREE the literature regarding the Marfan syndrome and pregnancy is reviewed. The Marfan syndrome is due to an inheritable autosomal dominant disorder of the connective tissue with a 50% risk of the fetus to be affected. Possibilities for antenatal diagnosis are emerging by means of DNA- syndrome in pregnancy is aortic dissection. Pregnancy affects the arterial vasculature and the therapeutic options in case of dissection are presented. A thorough search of the literature revealed three articles describing series of patients with 240 evaluable pregnancies, and 57 case reports covering 99 evaluable pregnancies. The incidence of severe cardiovascular events in the patient series was 3-7% compared with 50% in the case reports. The case reports may be biased because a dramatic event was usually the reason for publication. An aortic diameter compromise are reported as risk factors for cardiovascular events in pregnancy. Other complications related to the Marfan syndrome are rare in pregnancy. Case reports show a high incidence of pretenn delivery, but serial studies do not. The incidence of other obstetric complications seems to be similar to that in a general population of pregnant women.
In CHAPTER FOUR the literature regarding the Ehlers-Danlos syndrome (EDS) and pregnancy is reviewed. The classification in nine different types as used before 1997 was applied. Like Marfan's syndrome the EDS results from an inheritable possible for certain types and families by means of DNA-linkage and mutation analysis. A few patient series were found with 158 evaluable pregnancies, and 44 type IV EDS patients reported in one series of patients was not confirmed in other series. Major complications like uterine rupture and rupture of major blood vessels occurred only in type IV or unknown types of EDS. Complaints of joint laxity and pelvic instability appeared to increase in pregnancy. The preterm delivery rate was increased (25 - 32%), in part iatrogenic, and the cesarean section rate was high (44%), mainly due to elective abdominal delivery because of the condition of the mother. Postpartum hemorrhage was reported in 14% and complications of lacerations of the birth canal in 12% of cases. Neonatal outcome appeared to be mainly determined by the gestational age at delivery.
In CHAPTER FIVE a retrospective study is presented, designed to collect data regarding pregnancy, delivery, the neonate and the postpartum period in women with the Marfan syndrome in an attempt to develop guidelines for preconceplional assessment of risks and counseling, and for providing optimum medical and obstetric care. Patients were recruited from the Dutch Marfan Association. Thirty-eight affected women with 78 evaluable pregnancies beyond 24 weeks gestational age were collected, and data concerning the course and outcome of pregnancy were analyzed. A second group of 44 nonaffected women with 51 evaluable pregnancies beyond 24 week served as controls. Possible bias resulting from this study design are discussed in detail. Aortic dissection was observed in five patients (4,5%); all mothers and infants survived. Two patients were known to have the Marfan syndrome, three women had an aortic root diameter of 40 mm or more before pregnancy. Two neurovascular events were recorded, a complication not previously reported in the literature in relation to pregnancy. The findings in this study support previously reported risk factors for severe cardiovascular events in pregnancy, in found in 8% of the pregnancies of Marfan mothers and not in the control group. The obstetric course and outcome of pregnancy were similar in both groups.
In CHAPTER SIX a similar study is presented concerning pregnancy and the Ehlers-Danlos syndrome (EDS). Patients were recruited from the Dutch Ehlers-Danlos Association. Forty-six affected women with 128 evaluable pregnancies beyond 24 weeks were collected, and data concerning course and outcome of pregnancy analyzed. A second group of 33 nonaffected women with 43 evaluable pregnancies, who gave birth to one or more affected infants, served as controls. The possible role of bias introduced by this study design is discussed. Ruptures of blood vessels or of the uterus were not reported in the patient group, but one woman with EDS type IV had a bowel rupture. Pelvic instability occurred in 25% of pregnancies in women with EDS compared with 7% in controls. Only in women with EDS type IV an elevated abortion rate was found (26%). The preterm delivery rate was 21% in EDS pregnancies, and 40% in controls; spontaneous preterm rupture of the membranes occurred in half the number of pregancies with an affected fetus. Postpanum hemorrhage occurred in 19% and complicated lacerations of the birth canal in 8% of pregnancies in women with EDS. as compared with 7% and 0%, respectively, in controls.
In CHAPTER SEVEN the neonatal outcome is reported of the pregnancies of the groups discussed in Chapters 5 and 6. Hundred and three infants with the Marfan syndrome, and 91 newborns with the EDS were included. Fourteen nonaffected infants of mothers with the Marfan syndrome and 55 nonaffected infants of mothers with the EDS were recorded. The neonatal outcomes of newborns of affected and nonaffected mothers, and the outcomes of affected and nonaffected newborns were compared. In the Marfan group small-for-gestational age was observed slightly more often in affected infants of affected mothers than in those of nonaffecled women. The floppy infant syndrome occurred in 6% of the affected newborns. The incidence of preterm birth in infants with the EDS (31%) was significantly higher than that in nonaffected infants (13%). The preterm birth was usually caused by spontaneous rupture of the fetal membranes, which may be due to the abnormal connective tissue. The floppy infant syndrome was present in 13% of the Ehlers-Danlos newborns. Few congenital or acquired defects were observed in infants with the Marfan or Ehlers-Danlos syndrome. The diagnosis of these syndromes in newborns is often difficult, and longtime follow-up is warranted for infants born to mothers with Marfan or EDS or with a father with one of the syndromes.
In CHAPTER EIGHT conclusions are presented and recommendations and guidelines for preconceptional assessment of risk. counseling, and medical and obstetric care are proposed. In women with the Marfan syndrome assessment of the cardiovascular status and evaluation of other clinical signs and symptoms in relation to the syndrome is essential. Guidelines for management of obstetric and medical but the risk of aortic dissection appears to be small in women with an aortic root of less than 40 mm, and no progression of dilatation. There is no evidence of an elevated incidence of obstetric complications in women with the Marfan syndrome.