Abstract
Pregnancy poses significant physiological demands, and women of extreme short stature may be particularly at risk of complications. Described here are two pregnancies in a woman who was 130 cm tall with a body mass index of 12 kg/m2 and the maternal and neonatal outcomes. The challenges encountered in the care of our patient included cardiorespiratory compromise, management of medication dosing, management of delivery and bleeding risk.
Keywords
Introduction
Short stature is defined as height that is 2 or more standard deviations below the mean height for age and sex within a population (less than the 2.5th percentile). The aetiology is varied and includes normal variants of growth (e.g. familial short stature), endocrine causes (e.g. growth hormone deficiency, congenital adrenal hyperplasia), genetic causes (e.g. collagenopathies such as Bethlem myopathy and Ullrich Congenital Muscular Dystrophy, skeletal dysplasias such as osteogenesis imperfecta, achondroplasias, mitochondrial storage disorders and other genetic syndromes such as Noonan and Turner syndrome), and short stature secondary to other diseases (e.g. malnutrition, coeliac disease, congenital heart disease). The median height of adult women in the UK is 163 cm (Lai et al.'s 1 study of over 200,000 women from the UK biobank indicated a range 132–199 cm), so women with height of 130 cm or under are uncommon. Whilst infertility is more common amongst patients with certain conditions associated with short stature (e.g. anorexia nervosa, 2 coeliac disease, 3 congenital adrenal hyperplasia, 4 perhaps with a common shared theme of congenital or acquired hypothalamic-pituitary dysfunction dysfunction 5 ), this is not universal and pregnancy can and does occur.
Pregnancy is a physiologically demanding state. It is therefore reasonable to expect that women with extreme short stature might experience a higher rate of complications in their pregnancy. Pregnancy risks in some conditions associated with short stature (e.g. achondroplastic dwarfism) have been described, and include increased rate of caesarean delivery and preterm birth (both iatrogenic and spontaneous), alongside maternal cardiac and respiratory complications. 6 These complications are likely to be more common in all women of extreme short stature (independent of underlying condition). This is illustrated in the patient described here and discussed in relation to management principles.
Case
A 22-year-old woman booked in her first ongoing pregnancy at 7 weeks and 3 days of gestation at her local hospital. She previously had 4 early miscarriages. The pregnancy was planned but she had not received preconceptual counselling. At booking her weight was 21 kg, her height was 130 cm and her body mass index (BMI) was 12 kg/m2. Severe congenital scoliosis, torticollis and chest deformity had required surgical intervention aged 6 and 12. From the age of 13 years she had used a wheelchair and overnight non-invasive positive airway pressure ventilation (18 cm H2O of inspiratory positive airway pressure, IPAP, and 4 cm H2O of expiratory positive airway pressure, EPAP) due to hypoventilation as a result of her severe kyphoscoliosis. She had soft skin, variably loose and tight joints, contractures of her elbows and long fingers. She was described as having ‘pelvic obliquity’ and was unable to fully abduct her legs. She was prescribed aspirin 75 mg daily from 12 weeks’ gestation to reduce the risk of pre-eclampsia. At 15 weeks’ gestation the woman was referred to the tertiary maternal medicine unit. She had never had been able to complete pulmonary function tests as she was unable to produce the required respiratory effort, and her last echocardiogram had been 9 years prior. Her VTE score was 2 (reduced mobility and smoking) and therefore antenatal pharmacological thromboprophylaxis was not prescribed. Arterial blood gases at 16 weeks revealed pH 7.42, pO2 11.7 kPa, pCO2 5.08 kPa and base excess 0.3. The woman was referred to a geneticist because of the suspicion of an underlying, unifying diagnosis. She had clinical features of a collagenopathy and rapid whole exome sequencing was offered. This identified heterozygosity for a COL6A3 mutation; it was felt that her clinical picture fitted with being on the border of severe Bethlem myopathy and mild Ullrich Congenital Muscular Dystrophy (UCMD). Options for genetic screening of the fetus during pregnancy were discussed and declined, and the option of pre-implantation genetic diagnosis in future pregnancies was mentioned. An echocardiogram was performed and was normal. Ultrasound at 24 weeks revealed a normal cervical length and normal uterine artery Doppler studies. All drugs likely to be required in an acute setting were reviewed by the maternal medicine team and a specialist maternity pharmacist and the appropriate doses calculated and documented in her electronic patient record and handheld notes.
At 28 weeks’ gestation, the woman developed proteinuric hypertension (blood pressure 142/93 mmHg, urinary PCR 329.4 mg/mmol, SFlt-1/PLGF ratio 89.7) and was admitted to hospital. She was commenced on methyldopa 125 mg twice daily. An ultrasound scan demonstrated intrauterine growth restriction with an estimated fetal weight of 1125 g (less than 5th centile) but normal Doppler studies. Corticosteroids were administered (2 doses of 12 mg betamethasone given 24 h apart) for fetal lung maturation, and she was given intravenous iron (ferrous carboxymaltose 500 mg) as her haemoglobin was 92 g/L. This then improved to 109 g/L. Her pre-eclampsia remained stable as an inpatient but her respiratory function deteriorated (with PaCO2 on repeated blood gas analysis increasing from 5.08 to 6.5 kPa). Her IPAP was therefore increased from 18 to 20 cm H2O but there was no improvement in her hypercapnia. A decision was made for caesarean delivery at 31 weeks and 1 day of gestation given her worsening type 2 respiratory failure. A multidisciplinary meeting was held, and featured discussion about management of blood loss and the threshold at which a major obstetric haemorrhage would be declared (given her small size and reduced blood volume). Additional anaesthetic concerns included the risk of respiratory compromise after a general anaesthetic (the woman declined neuraxial anaesthesia), difficult vascular access and difficulty with intubation. Appropriate paediatric equipment (for intubation, venous/arterial access, urinary catheter) was sourced and available prior to delivery. It was also noted that the woman's contractures made pressure sores a significant risk.
The caesarean delivery was performed under general anaesthetic and a male infant was born, weighing 1160 g (1st centile). An Alexis retractor was used as a Doyen retractor was too large. A levonorgestrel-intrauterine system (IUS) was sited for contraception. Estimated blood loss was 300 ml, the majority of which was returned by intraoperative cell salvage such that there was no drop in the maternal haemoglobin levels. Six 1 unit boluses of intravenous oxytocin were required intra-operatively and rectal misoprostol 400 mcg was administered for ongoing uterine tone management post-operatively. Elective postnatal admission to intensive care whilst intubated had been planned given her lack of respiratory reserve and potential for respiratory deterioration.
The infant spent 4 days in the neonatal intensive care unit, and then 75 further days in a local special care baby unit. Breastfeeding was initiated with the woman hand-expressing milk. He was discharged to the care of community paediatrics and was subsequently found to have the same genetic mutation as his mother on postnatal testing. The woman was discharged on enalapril 2.5 mg daily.
Unfortunately the IUS was expelled in the postpartum period and the woman became pregnant again, with her last menstrual period 6 months after her first delivery. No reassessment of her respiratory function had occurred between her pregnancies.
The second pregnancy was uncomplicated until the woman presented in pre-term labour at 30 weeks and 5 days of gestation. On assessment by a senior obstetrician it was felt that her pelvis was too small to allow vaginal delivery, even at the early gestation which, in combination with her inability to adequately abduct her legs, meant that a caesarean delivery would be safer. She therefore underwent an uncomplicated emergency caesarean section under general anaesthesia delivering a male infant weighing 1265 g (2nd centile). This occurred overnight without the availability of intraoperative cell salvage; the estimated blood loss was 350 ml and the woman's haemoglobin dropped from 117g/L pre-operatively to 94g/L post-operatively. The infant spent 69 days in neonatal intensive care, requiring two laparotomies for necrotising enterocolitis. He was discharged to his local special care baby unit and was subsequently found to have the same mutation as his brother and mother. Tubal ligation had been discussed in the antenatal period but was not performed due to the emergency nature of the delivery. Following counselling by a specialist in complex contraception another IUS was inserted under ultrasound guidance at 6 weeks postnatally, and remained in situ at the time of post-natal debrief 6 months later.
Discussion
Pregnancy in women with extreme short stature is uncommon; women are often assumed to have an inadequate hypothalamic-pituitary axis and therefore infertility is more likely. Pregnancy is physiologically demanding in all women, but particularly in women of extreme short stature. Risks may vary according to height and weight of pregnant women, even when BMI is maintained. 7
Bethlem myopathy and UCMD are collagen VI-related muscular dystrophies caused by a mutation in the COL6A3 gene; Bethlem myopathy is associated with heterozygosity and a milder phenotype while UCMD is associated with homozygosity and is generally more severe. There is considerable overlap in the features of the disease and as such they are considered to be part of a continuum. Patients experience progressive muscle weakness (including the respiratory muscles, leading to progressive respiratory insufficiency) as well as joint stiffness and contractures. Both Bethlem myopathy and UCMD are usually inherited as autosomal dominant conditions, meaning that the child of an affected mother has a 50% chance of developing the disease. Developments in reproductive techniques and genetic testing mean that affected couples have the option of pre-implantation diagnosis, or testing during pregnancy following amniocentesis. Our patient did not receive her genetic diagnosis until she was midway through her first pregnancy, and the second pregnancy was unplanned. She declined the offer of invasive testing during pregnancy.
Cardiac risks
Whilst cardiac consequences of the more common causes of short stature, for example Turner and Noonan's syndrome are well described, minimal evidence was found in the literature regarding cardiac risks in pregnancy in women of short stature of other causes. Pregnancy in two women with the same genetic condition have been described, and cardiac dysfunction was noted. Flock et al. 2014 described a case in which symptomatic progressive cardiac dysfunction (left ventricular dilatation with reduced ejection fraction) led to delivery being required at 36 weeks of gestation. 8 In this case, repeat echocardiogram showed a return to baseline cardiac function after delivery, alongside functional status. Nunes et al. 9 described a case in which pulmonary hypertension was identified during pregnancy (although it is unclear if this was a new diagnosis, and whether it resolved after pregnancy), but the woman had a planned vaginal delivery at term. 9 Neither patient's height nor BMI was commented upon.
Respiratory risks of pregnancy
Comparing this case with previously published cases of pregnancy in women with Bethlem Myopathy/UCMD is challenging, as this patient's stature and pre-existing degree of respiratory compromise is unusual.10–12 Respiratory monitoring (and regular clinical review) was crucial in the case described here given her degree of respiratory failure that preceded pregnancy. Ekblad and Kanto describe a similar case of a short woman (booking height 145 cm, weight 28 kg and BMI 13 kg/m2) who also developed respiratory failure requiring delivery at 32 weeks’ gestation. 13 No other evidence regarding respiratory risk in pregnancy in women of short stature was identified in the literature, but it seems inevitable that in these women the risk of respiratory compromise in later pregnancy is increased given the size of the gravid uterus in relation to the size of the mother. The choice of monitoring should be individualised, as to whether oxygen saturation measurement is sufficient, or whether regular arterial blood gases are required if there is a high suspicion of respiratory failure. Overnight oximetry may also be useful in some women. In the future, transcutaneous end-tidal CO2 monitoring may also be readily available and of clinical utility.
Medications
An important but potentially overlooked aspect of her management was ensuring all medication doses were reviewed with her body weight in mind, as the normal obstetric doses assume ‘normal’ adult-sized patients. As has been reported in cases of non-pregnant individuals of low body weight, toxicity from routine medications can occur. 14
An extensive review of medications likely to be required during pregnancy was undertaken by a specialist maternity pharmacist in conjunction with the maternal medicine team, given her low body weight (equivalent to a child 7–8 years of age) and BMI, but adult physiology (renal and hepatic clearance). A literature review was undertaken to search for evidence regarding pharmacokinetics and dosing of the specific drugs in question for underweight pregnant women. As no specific evidence was returned, a decision was made that the dose for a weight-based medication would not exceed the maximum dose for a paediatric patient of the same weight, and that side effect profiles, renal and liver function would be closely monitored for any drug administered to minimise risk of toxicity.
The expert advice with proposed pragmatic doses and drug-specific advice on toxicity risks were provided to clinicians, covering all medications commonly required in pregnancy or the postnatal period including uterotonics, common antibiotics used in pregnancy and the puerperium, analgesics and anti-emetics (see Table 1 for examples).
Examples of drug dosing in pregnancy in patients with low BMI.
BNF: British National Formulary; SPC: summary of product characteristic.
Additionally, senior anaesthetic input is required given the potential complications of use of neuromuscular blocking agents in individuals with muscular dystrophies.
Mode of delivery
In this case, cephalopelvic disproportion was considered likely. It was noted that the patient could not abduct her legs, and short stature is a known risk factor for malpresentation and labour dystocia. 15 It was therefore planned that she should have a semi-elective caesarean section if she developed evidence of respiratory decompensation, or signs of preterm labour.
While the case report by Flock et al. described a similar approach in a patient with the same condition (semi-elective caesarean section in the context of evolving maternal cardiorespiratory compromise), 5 Nunes’ case report described a plan for vaginal delivery at term, in which a planned ventouse extraction to support the second stage was successful in achieving safe delivery, 6 but in both these cases the height of the woman was not described. Boujenah et al. describe the mode of birth of 178 women of short stature in a retrospective cohort study where 70% achieved a vaginal birth. 16 However they do not provide information on the specific diagnoses of their subjects so it is difficult to know if the findings of this study can be applied to our woman who was known to have a contracted pelvis and was unable to fully abduct her legs. The mean height of the women in their study was 148 cm, significantly taller than our patient.
Bleeding risk
The circulating volume of an adult female is approximately 65 ml/kg, based on radio-isotope studies performed in the 1960s. 17 It is well known that circulating volume increases in pregnancy, and more recent work shows this is about 80 ml/kg. 18 The circulating volume of this patient at delivery (weight approximately 25 kg) was therefore about 2000 ml, far less than that of the average adult pregnant woman, on whom guidance about haemorrhage and thresholds for concern are based. The threshold for massive obstetric haemorrhage being declared was decided to be 400 ml.
Contraception
There is a paucity of literature regarding contraception in women of short stature. Allanson and Hall discuss the difficulties of appropriate contraception in women with chondrodystrophies, noting difficulties with oral contraceptives due to problems with achieving the correct dose for body weight. 19 Few women in their cohort of 150 used an intrauterine device and the main concerns reported were those pertaining to heavy and painful bleeding: no women used a levonorgestrel IUS although such a device was available on the market at that time. The rate of expulsion of an intra-uterine device inserted at caesarean section is around 5% which is no higher than the expulsion rate when inserted outside of pregnancy. A smaller IUS has been developed, however our patient was given the usual sized one. While it could be speculated that the size of the IUS contributed to its expulsion, the fact that the second remained in situ 6 months later goes against this. Women with short stature, regardless of aetiology, should be referred for preconception counselling in a timely manner to discuss the risks of pregnancy in their individual case. A discussion should also be had around the inheritance of the particular condition and whether genetic testing is available either prior to, or during pregnancy.
Conclusion
This case demonstrates the importance of careful pregnancy planning and the involvement of the multidisciplinary team, making certain that all aspects of care are considered at an early stage. Of particular importance are thresholds for blood loss and ensuring the correct medication doses are used.
Whilst cases like this are uncommon, it is important not to assume subfertility and to counsel women about pregnancy and effective contraception, in any healthcare setting in which they are reviewed. The importance of preconception counselling should be emphasised to enable the women to be fully aware of the risks a future pregnancy entails and the options for genetic testing.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
Oxford University Hospitals NHS Foundation Trust does not require ethical approval for reporting individual cases or case series.
Informed consent
Written informed consent was obtained from the patient for their anonymised information to be published in this article.
Contributorship
JOS reviewed the literature and wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.
