Osteogenesis imperfecta (OI) is a primary bone fragility disorder with an estimated prevalence of 1/15,000 births and is a hereditary syndrome characterized by one or more of the following: fractures, blue sclerae, impaired hearing, defective dentition, and hyperlaxibility throughout life.[1,2] We report a pregnant woman with type II OI and review her prenatal counseling, diagnosis, and pregnancy management to assist obstetricians in understanding the disease and managing it in emergency situations.
CASE
A 30-year-old female was evaluated for her 3rd trimester, who was diagnosed with OI at 5 years old after she had a right tibial fracture. She underwent several thoracic to lumbar spine surgeries for scoliosis correction and permanent internal fixation in 2009. Before she was pregnant, she was diagnosed with type II OI because her genetic testing suggested a novel heterozygous mutation in the cyclic adenosine monophosphate (AMP) responsive element binding protein 3-like 1 (CREB3L1) gene: c.753+1 G>A. Her husband did not undergo relevant genetic examinations. During pregnancy, early and mid-term screening for Down’s syndrome and non-invasive prenatal testing (NIPT) did not show any abnormalities. In addition, 4-dimensional ultrasound and fetal echocardiography showed no obvious abnormalities in her 2nd trimester. She had a prenatal diagnostic ultrasound at the 30th gestational week, which showed that fetal long bones were shorter for gestational age. In consideration of her permanent internal fixation of the spine and other complications during delivery, the care team performed a cesarean delivery under general anesthesia at 37 weeks and 4 days. A 2.950 kg male neonate was delivered with an Apgar score of 8 at 1 min and 9 at 5 min. The patient was discharged on the 2nd post-operative day with her baby. The mother and the infant were in good health during follow-up visits.
DISCUSSION
There is wide variability in the presence and severity of the clinical features among patients with OI.[2,3] Clinically, OI is classified into five types: type I, dominantly inherited OI with blue sclerae; type II, lethal perinatal OI with radiographically crumpled femora and beaded ribs; type III, progressively deforming OI with normal sclerae; type IV, dominantly inherited OI with normal sclerae; and type V, progressive OI with calcification abnormalities.[4,5] The main cause of OI is mutations in the COL1A1 and COL1A2 type I genes.[6,7] Other pathogenic variants related to OI have been discovered in more than 20 different genes.[5] In this case, the patient’s genetic testing suggested a novel heterozygous mutation in the CREB3L1 gene. This variant causes a prenatal/perinatal lethal OI in homozygotes, similar to that seen in type II OI as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members.[5,6]
The management of OI during pregnancy includes confirming diagnosis, assessing disease severity and maternal risk, and managing delivery. Prenatal counseling is necessary for all affected expectant parents.[5] When consulting for the fetal risk of OI, a detailed family history should be obtained, including at least a three-generation pedigree.[7,8] Genetic testing confirms diagnosis and allows for invasive prenatal diagnosis of future pregnancies to search for identical variants in fetal DNA.[5,7]
Prenatal ultrasonography is the most common non-invasive choice for detecting fetal pathologies, including OI. Sonographic evidence of OI includes reduced acoustic shadowing of long bones and marked bowing and shortening of long bones.[8] Sonographic signs can be detected as early as 13 weeks and become prominent in the late 2nd or 3rd trimester.[8] Therefore, it is necessary to perform serial ultrasound tests to monitor suspected OI. Magnetic resonance imaging (MRI) is an imaging modality to confirm ultrasound examination results. MRI can take full images of the entire fetus in all planes regardless of fetal positioning and serve as a complementary imaging tool to demonstrate the multiple fractures and deformations of long bones and ribs for differential diagnosis.[8]
NIPT is an effective method of detecting OI early in the 1st trimester (7-10 weeks). However, placental mosaicism and twins may lead to misdiagnosis, and positive results sometimes require further invasive prenatal testing and postnatal genetic diagnosis.[5] Invasive prenatal screening increases the risk of abortion.[7] Chorionic villus sampling is performed at 10-12 weeks, and amniocentesis is usually performed at 15-20 weeks. Cordocentesis is performed at 22-24 weeks of gestation when other prenatal tests are not available, accompanied by the highest risk of miscarriage among all other invasive methods.[5]
Musculoskeletal problems such as back pain, spinal deformity, non-vertebral fractures, and disk and ligament problems are common during pregnancy.[7,8] Pregnant women with OI are at an increased risk of ante-partum hemorrhage, diabetes, placental abruption and fetal growth retardation, and their neonates face a higher risk of neonatal intensive care unit admission and overall mortality up to 28 days of birth.[3,7] The delivery mode remains controversial. Some people are in favor of cesarean delivery because this method is faster and better controlled. However, anesthesia for OI patients is challenging. Scoliosis and spinal deformities can cause difficulty in spinal anesthesia, and short necks may cause difficulty in intubation. Any trauma, even minor trauma, such as squeezing the uterus and cannula, may cause fractures to the mandible, vertebrae and teeth.[7,8] Uterine and vascular problems in OI patients could cause uterine atony, inadequate vasoconstriction, and impaired platelet activity, which place the patient at much higher risk of postpartum hemorrhage.[7] Therefore, OI patients should undergo cesarean delivery according to obstetric indications. While vaginal delivery is considered relatively safe for OI women with mild symptoms, there is evidence indicating higher risk of uterine rupture.[3] In fact, the risk of thrombosis, pain, uterine inertia, and postpartum bleeding during cesarean delivery in OI women is comparable to that of the general population, and it is recommended to manage them in the same way as women with a scarred uterus.[7,8]
The most commonly used medication for treating OI is bisphosphonates (BPs), which may have adverse effects on the fetus due to their relatively long degradation period. Therefore, there are still contradictions in reproductive women.[2,7] In addition, there is controversy over BPs during pregnancy and lactation, as the dosage of BPs transmitted through the placenta or into breast milk is unclear. Koumakis et al[1] suggest that breastfeeding should be avoided in postpartum patients with OI.
In conclusion, for pregnant women with OI, medical decisions should be made based on individual situations.
Funding: None.
Ethical approval: Not needed.
Conflicts of interest: The authors declare that they have no competing interests.
Contributors: All authors contributed substantially to the writing and revision of this manuscript and approved its contents.
Reference
Osteogenesis imperfecta: characterization of fractures during pregnancy and post-partum
DOI:10.1186/s13023-021-02148-x
PMID:35090500
[Cited within: 2]
Pregnancy and breastfeeding are associated with bone density loss. Fracture occurrence during pregnancy and post-partum, and its determinants, remain poorly known in Osteogenesis Imperfecta (OI). The aim of this study was to characterize fractures that occurred during pregnancy and post-partum in OI patients.We conducted a retrospective multicentric study including a total of 50 previously pregnant OI women from 10 Bone Centers in France. Among these patients, 12 (24%) patients experienced fractures during pregnancy or in the 6 months following delivery, and 38 (76%) did not experience any fracture. The most frequent localizations were: proximal femur (25%), spine (25%), distal femur (12.5%), and pelvis (12.5%). Fractures during pregnancy occurred during the third trimester and post-partum fractures occurred with a mean delay of 2 months following delivery. No fractures occurred during childbirth. We next compared the 12 patients with pregnancy or post-partum fractures with the 38 patients without fractures. Mean age at pregnancy was 32.7 ± 3.1 years-old in the fractured group, vs 29.3 ± 5.0 years-old in the non-fractured group (p = 0.002). Breastfeeding was reported in 85.7% of patients in the fractured group, vs 47.1% in the non-fractured group (p = 0.03). All patients with post-partum fractures were breastfeeding. Bone mineral density was significantly lower in patients with pregnancy-related fractures compared with other patients: spine Z-score - 2.9 ± 1.6DS vs - 1.5 ± 1.7DS (p = 0.03), and total hip Z-score - 2.0 ± 0.7DS vs - 0.5 ± 1.4DS (p = 0.04). At least one osteoporosis-inducing risk factor or disease other than OI was identified in 81.8% vs 58.6% of fractured vs non-fractured patients (not significant). Fracture during pregnancy or post-partum was not associated with the severity of OI. Bisphosphonates before pregnancy were reported in 16.7% and 21.1% of patients with pregnancy-related fractures and non-fractured patients, respectively (not significant).OI management during pregnancy and post-partum should aim for optimal control of modifiable osteoporosis risk factors, particularly in patients with low BMD. Breastfeeding should be avoided.© 2022. The Author(s).
Osteogenesis imperfecta: current and prospective therapies
DOI:10.3390/biom11101493
URL
[Cited within: 3]
Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.
Pregnancy outcomes in women with osteogenesis imperfecta: a retrospective cohort study
DOI:10.1038/jp.2016.111
PMID:27442154
[Cited within: 3]
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by defects in type I collagen that can pose serious complications during pregnancy. The aim was to evaluate maternal and fetal outcomes in pregnant women with OI.This was a retrospective cohort study, using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. We examined the records of pregnant women with OI during the period 2003 to 2011. We evaluated antenatal complications and method of delivery among 295 women with OI, using unconditional logistic regression.Of the total 7 287 994 births in our cohort, we encountered 295 deliveries among women with OI. The prevalence was 4 per 1 00 000 deliveries per year over the study period. Births to women with OI were more likely to be complicated by antepartum hemorrhage (odds ratio (OR) 2.01, 95% confidence interval (CI) 1.04 to 3.91), placenta abruption (OR 2.50, 95% CI 1.24 to 5.03), intrauterine growth restriction and small-for-gestational-age infants (OR 2.42, 95% CI 1.42 to 4.14), congenital malformation (OR 7.33, 95% CI 4.20 to 12.78) and preterm birth (OR 2.24, 95% CI 1.63 to 3.06). Seventy-five percent of women with OI delivered by cesarean section, and they had an increased rate of tubal sterilization at delivery (OR 1.67, 95% CI 1.18 to 2.36). No differences in rates of stress fracture and maternal death were found.These findings suggest that there are increased risks to both mother and fetus in pregnancies complicated by OI.
Genetic heterogeneity in osteogenesis imperfecta
DOI:10.1136/jmg.16.2.101
PMID:458828
[Cited within: 1]
An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.
Reproductive options for families at risk of osteogenesis imperfecta: a review
DOI:10.1186/s13023-020-01404-w
PMID:32460820
[Cited within: 7]
Osteogenesis Imperfecta (OI) is a rare genetic disorder involving bone fragility. OI patients typically suffer from numerous fractures, skeletal deformities, shortness of stature and hearing loss. The disorder is characterised by genetic and clinical heterogeneity. Pathogenic variants in more than 20 different genes can lead to OI, and phenotypes can range from mild to lethal forms. As a genetic disorder which undoubtedly affects quality of life, OI significantly alters the reproductive confidence of families at risk. The current review describes a selection of the latest reproductive approaches which may be suitable for prospective parents faced with a risk of OI. The aim of the review is to alleviate suffering in relation to family planning around OI, by enabling prospective parents to make informed and independent decisions.The current review provides a comprehensive overview of possible reproductive options for people with OI and for unaffected carriers of OI pathogenic genetic variants. The review considers reproductive options across all phases of family planning, including pre-pregnancy, fertilisation, pregnancy, and post-pregnancy. Special attention is given to the more modern techniques of assisted reproduction, such as preconception carrier screening, preimplantation genetic testing for monogenic diseases and non-invasive prenatal testing. The review outlines the methodologies of the different reproductive approaches available to OI families and highlights their advantages and disadvantages. These are presented as a decision tree, which takes into account the autosomal dominant and autosomal recessive nature of the OI variants, and the OI-related risks of people without OI. The complex process of decision-making around OI reproductive options is also discussed from an ethical perspective.The rapid development of molecular techniques has led to the availability of a wide variety of reproductive options for prospective parents faced with a risk of OI. However, such options may raise ethical concerns in terms of methodologies, choice management and good clinical practice in reproductive care, which are yet to be fully addressed.
Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively
Management of osteogenesis imperfecta type I in pregnancy: a review of literature applied to clinical practice
DOI:10.1007/s00404-016-4012-2
PMID:26781260
[Cited within: 10]
Osteogenesis imperfecta (OI) is a rare heritable heterogenous disorder characterized by bone fragility and susceptibility to fractures with a wide spectrum of clinical expression due to defects in collagen type I biosynthesis. The purpose of the review is to highlight the practical norms in pregnancies with osteogenesis imperfecta.We carried out a literature review in MEDLINE on OI during pregnancy, focusing on diagnosis, therapy and delivery. We reviewed 28 articles (case reports, original articles and reviews).Pregnant women affected by type I OI should be closely monitored to assess fetal well-being and detect pregnancy-related complications associated with an increased risk for osteoporosis, restrictive pulmonary disease, cephalopelvic disproportion and other problems related to connective tissue disorders. Mode of delivery remains controversial and should be determined on an individual basis.In conclusion, women affected by type I OI represent a subset of patients whose pregnancies should be considered high risk and warrant a multidisciplinary approach in a referral center.
A type IV osteogenesis imperfecta family and pregnancy: a case report and literature review
