Osteogenesis imperfect (OI), firstly described in the 17th century,1 is a group of inherited connective-tissue disorders in which synthesis or structure of type I collagen, the major protein constituent of bone and many other connective tissues, is defective and causes osseous fragility. Case reports of pregnancies with type IV OI or type IV OI family are very rare. Here, we reported a case of type IV OI family and their female member's pregnancy and provide a brief discussion on its prenatal diagnosis and management as described in the literature.
A 31-year-old woman with type IV OI during her first pregnancy presented at 26 weeks of gestation. Her height was 89 cm and her weight was 25.5 kg. She had a history of multiple fractures, mainly in the long bones and without any involvement of the pelvis, and the latest one was when she was 14 years old. She was wheelchair bound. She had severe kyphoscoliosis and a small chest volume, but, fortunately, cardiorespiratory function was normal (Figure 1). She did not turn to the physician for genetic counseling before pregnancy. Her mother suffered from severe OI, while her father and brother were normal. Her mother's two pregnancies were terminated by caesarean section (CS) because of pelvic deformity secondary to previous pelvic fracture. At 26 weeks of gestation, a detailed ultrasound examination was performed which confirmed a marked shortening and bowing of femur (femur length 26.5 mm, fibula length 22.1 mm, humerus length 32.7 mm, ulna length 30.1 mm and radius length 24.9 mm) and without significant intrauterine fracture (Figure 2). Other fetal biometric parameters were also small for gestational age (biparietal diameter 62.2 mm, cephalic circumference 214.5 mm and abdominal circumference 165.7 mm). All of the above suggested the fetus with OI. She decided to terminate her pregnancy and abandon rescuing the infant. Considering that she had extremely contracted pelvis and in order to minimize cardiorespiratory compromise in labor, CS at 27 weeks of gestation was performed. The baby weighed 650 g at birth with an Apgar score of 4 at 1 minute after birth, and was confirmed by X-ray to have OI in the neonatal period (Figure 3).
With rare exceptions, OI results from heterozygosity for mutations in one of two genes, that is the COL1A1 gene on chromosome 17 and the COL1A2 gene on chromosome 7 that encode the chains of type I collagen.2 The clinical features of OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature and normal lifespan. Based on the pattern of inheritance, age at presentation, radiologic features and natural history, Sillence et al3 described four types of OI, which provide the clinical framework for diagnosis. With detailed radiographic and bone morphologic studies and molecular genetic analyses, the classification has expanded to seven types.4–6 The total incidence of different types of this disorder has been estimated to be 1 in 10 000 to 30 000 pregnancies, while the incidence of each specific type ranges from 1 in 28 500 to 1 in 62 000 live births.
Vogel et al7 reported a case of second trimester termination of pregnancy with type IV OI via hysterotomy secondary to fetal trisomy 18. The case we report here is a type IV OI family with pregnancy (Figure 4). In this case, the patient's mother, who is a woman with type IV OI, gave birth by CS twice because of pelvic deformity. Because of the patient's economic situation, she did not have any prenatal diagnosis including ultrasonography, biochemical analysis and molecular genetic testing before 26 weeks of gestation. Following diagnosis of fetal OI, the patient gave up rescuing the fetus and the pregnancy was terminated by CS at 27 weeks of gestation.
Historically, maternal abdominal X-ray evaluation of the fetus has led to accurate prenatal diagnosis of skeletal dysplasias. The antenatal diagnosis of OI was made with fetal roentgenograms, which showed extreme radiolucency of the fetal skeleton, known as “invisible fetus”. Other radiological features suggestive of OI include camptomelia (bowing of long bones), shortening of the limbs and narrowing of thorax from repetitive long bone and rib fractures.
Nowadays, prenatal ultrasonography is the first modality of choice for detecting fetal pathologies including OI. OI was diagnosed correctly in 89% of cases by prenatal ultrasonography8. Two-dimensional ultrasonography is a reliable imaging technique, especially for OI type II and III. Sonographic evidence of OI includes increased nuchal translucency in early pregnancy, reduced acoustic shadowing of long bones and marked bowing and shortening of long bones. The diagnosis of OI type I can be made as early as 17 weeks of gestation. Sonographic signs of OI type II can be detected as early as 13 weeks of gestation. For OI type III, limb length generally begins to fall off the growth curve at about 17 to 18 weeks of gestation. OI type III or type IV may show bowing of the long bones with or without shortening and without evidence of fracture or a deficit in bone mineralization, visible by ultrasound in the late second or third trimester. Therefore, in order to monitor suspected OI type III or type IV, serial ultrasound examinations are required.
Magnetic resonance imaging (MRI) serves as a second-line imaging modality to confirm, correct or complete sonographic findings. Because of its high spatial resolution and full imaging of the entire fetus in all planes regardless of fetal positioning, fetal MRI clearly demonstrates the multiple fractures and deformation of long bones and rips. Therefore, fetal MRI can be a complementary imaging tool when prenatal sonography cannot differentiate between OI and other forms of skeletal dysplasia. In addition, fetal MRI can be used to evaluate fetal lung volume which provides important prognostic information about the degree of lung hypoplasia.
To counsel patients on the risk of OI recurring, a detailed family history including at least a three-generation pedigree should be obtained. When fetal OI is suspected, biochemical analysis and molecular genetic testing are of diagnostic value. It is reported that biochemical assay of type I collagen extracted after short-term culture of whole chorionic villi may identify a collagen abnormality.9 However, false positive testing must be noticed because the proportion of type I procollagen produced by chorion villus sampling cells is reduced compared to control cells and resemble cells from individuals with OI. The most widely used diagnostic technique is genetic mutation analysis using chorionic villous cells or amniocytes. Mutant genes include COL1A1, COL1A2, CRTAP, LEPRE1 and PPIB. Mutation identification is an important tool to assess risk and facilitate prenatal diagnosis.10
There are a lot of musculo-skeletal problems associated with pregnancy in women with OI. The most common musculo-skeletal complication is back pain in or after pregnancy, no matter the type of OI or to the mode of delivery. Other problems identified include spinal deformity, non-vertebral fractures, disc problems and ligament problems. The incidence of maternal fractures is not increased in pregnancy, but relatively minor trauma associated with obstetric manipulations can lead to fractures.
The mode of delivery for pregnant women with OI remains controversial and should be decided on individual basis. The cesarean delivery rate is 54%, most of them for nonvertex presentation (usually breech presentation) and secondly because of an antenatal diagnoses of OI. Old maternal fractures which may present crippling skeletal deformities and absolute cephalopelvic disproportion can be an indication for cesarean delivery. Cesarean delivery does not decrease fracture rates at birth in infants with non-lethal forms of OI, nor does it prolong survival for those with lethal forms. Anaesthesia for patients with OI is challenging. General, epidural and spinal anaesthesia for CS have all been described. Epidural and spinal anaesthesia is difficult because of spinal deformities. General anaesthesia carries the risk of difficult intubation and fractures to the mandible, vertebrae and teeth and suxamethonium-induced fasciculations may cause fractures. Hernia following CS, due to collagen deficiency, is a common complication. Therefore, it is suggested for physicians to use permanent sutures to close the rectus sheath when doing CS. Vaginal delivery can be considered relatively safe. Uterine rupture in a gravida 2 with OI is reported complication during pregnancy, histologically finding the reduction in type I collagen and the increase in type III collagen which would predispose the uterus to rupture.11 Therefore, if a woman with OI wished to aim for a vaginal delivery it may be prudent to manage her in the same way as a woman with a scarred uterus would be managed. The risk of postpartum hemorrhage is high, mainly due to impaired platelet aggregation, as well as to uterine atony and laceration.
Chamberlain et al12,13 used adeno-associated virus vectors to successfully target and inactivate mutant COL1A1 and COLA2 genes in mesenchymal stem cells from individuals with OI. These results demonstrate therapeutic potential of mesenchymal stem cells and bring hope for a fetus with OI. In conclusion, it is possible to make a prenatal diagnosis of OI by ultrasound. For the pregnant women with OI, management decision should be made on an individual basis.
1. Sharma A, George L, Erskin K. Osteogenesis imperfecta in pregnancy: two case reports and review of literature. Obstet Gynecol Surv 2001; 56: 563-566.
2. Byers PH, Steiner RD. Osteogenesis imperfecta. Annu Rev Med 1992; 43: 269-282.
3. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979; 16: 101-116.
4. Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000; 15: 1650-1658.
5. Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002; 17: 30-38.
6. Labuda M, Morissette J, Ward LM, Rauch F, Lalic L, Roughley PJ, et al. Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone 2002; 31: 19-25.
7. Vogel TM, Ratner EF, Thomas RC Jr, Chitkara U. Pregnancy complicated by severe osteogenesis imperfecta: a report of two cases. Anesth Analg 2002; 94: 1315-1317.
8. Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, et al. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol 2009; 34: 160-170.
9. Cubert R, Cheng EY, Mack S, Pepin MG, Byers PH. Osteogenesis imperfecta: mode of delivery and neonatal outcome. Obstet Gynecol 2001; 97: 66-69.
10. Pyott SM, Pepin MG, Schwarze U, Yang K, Smith G, Byers PH. Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. Genet Med 2011; 13: 125-130.
11. Christodoulou S, Freemont AJ, McVey R, Vause S. Prospective comparative case study of uterine collagen in a woman with osteogenesis imperfecta type 1 who had previously ruptured her uterus. J Obstet Gynaecol 2007; 27: 738-739.
12. Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, et al. Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science 2004; 303: 1198-1201.
13. Chamberlain JR, Deyle DR, Schwarze U, Wang P, Hirata RK, Li Y, et al. Gene targeting of mutant COL1A2 alleles in mesenchymal stem cells from individuals with osteogenesis imperfecta. Mol Ther 2008; 16: 187-193.