Turning a Turner to a twin mother

Abstract

Women with Turner syndrome (TS) are subfertile due to premature ovarian insufficiency. Most women require hormone replacement therapy for attaining menarche and assisted reproductive technology (ART) using donor oocytes, autologous oocytes or in-vitro fertilisation for conception. Irrespective of the karyotype, monosomy X (45, X) or mosaic pattern, women with TS hold a very high risk for pregnancy due to high mortality rate secondary to aortic dissection and severe pre-eclampsia. Such high-risk pregnancies mandate extensive prepregnancy counselling, the need for multidisciplinary teams, close surveillance and follow-up to attain a successful outcome. In this article, we report one such case of pregnancy in a woman with TS carrying a twin gestation following ART with donor oocyte.

Background

Turner syndrome (TS) occurs 1 in 2500 live born females.¹ Among them, approximately 50% are missing an entire X chromosome (most common karyotype) and have a karyotype of 45, X, about 25% have a partial deletion of one X chromosome, while about 20% have varying degrees of mosaicism.² Even though 3% of all pregnancies begin with XO embryos, 99% of these pregnancies terminate spontaneously during the first trimester. The common explanation for this termination is hypothesised as haploinsufficiency of pseudoautosomal genes on the X chromosome.¹ Diagnosis of TS can be made prenatally by evaluating the cell-free DNA in maternal blood. Although amniocentesis or chorionic villus sampling has higher sensitivity rate, these babies require a further confirmatory test after birth. Women with TS have streak ovaries with accelerated follicular atresia, leading to hypergonadotropic hypogonadism. Although most of these women attain puberty with hormone replacement therapy (HRT), reproduction is always a challenge. They require advanced screening, counselling and follow-up for a successful outcome. Therefore, it is vital to understand the preconceptional counselling and management required during gestation.

Case presentation

A 26-year-old primigravida, at the age of 21, was evaluated for primary amenorrhea. She weighed 44.5 kg with a height of 143 cm. Physical examination revealed a short stature with mild webbing of neck and low set ears. Ultrasound of the pelvis revealed linear hypoechoic structures similar to that of the uterus measuring 2.9×0.7 cm in the pelvic floor, posterior to the bladder with both ovaries not visualised, suggestive of hypoplastic uterus with ovarian agenesis. Chromosomal analysis (GTG banding with 500 band resolution) revealed 45, X pattern in all the metaphases analysed, confirming the diagnosis of TS. To induce puberty, estradiol was started for 6 months and then replaced with combined sequential HRT to protect the endometrium and effectuate progesterone withdrawal bleeds. Her Thyroid Stimulating Hormone (TSH) levels were monitored for her primary hypothyroidism, and with a multidisciplinary approach, her levothyroxine doses were altered.

Married at the age of 25 (non-consanguineous), with adequate screening for endocrine disorders, structural heart defects (coarctation of aorta, bicuspid aortic valve), prepregnancy counselling and workup was done (Follicle Stimulating Hormone (FSH) of 101 IU/mL, estradiol (E2) <10 pg/mL and anti-Mullerian hormone (AMH) <0.01 ng/dL). In view of reduced ovarian reserve, with the help of assisted reproductive technology (ART) (donor oocyte) she was able to achieve a pregnancy on her first cycle of treatment by a fertility specialist. She was later referred to our centre with dichorionic diamniotic twin gestation at 19 weeks for further antenatal care.

Investigations

Preconception

• Ultrasound of the abdomen pelvis was done and revealed a uterus measuring 5.5×3 cm with an endometrial thickness of 8 mm and normal kidneys.

• 2 Dimensional (2D) echocardiography was done and showed a normal study with aortic size index (ASI) of 1.6 cm/m² and no other structural abnormalities.

• She was started on preconceptional folic acid and aspirin (as prophylaxis for pre-eclampsia).

First trimester

• Scan done at 8 weeks showed dichorionic diamniotic intrauterine twin gestation corresponding to dates.

• 2D echo repeated in the first trimester was consistent with the previous finding.

• First trimester screening was negative.

• Nuchal translucency scan done at 13 weeks was normal. She had prophylactic cervical cerclage done by the referring consultant.

Second trimester

• Target scan done at 20 weeks ruled out anomalies.

• Fetal echocardiography reports of both the twins were normal.

• Diagnosed to have gestational diabetes and was started on oral metformin 500 mg two times per day.

Third trimester

• Fetal growth with Doppler was assessed by serial ultrasound at 29 and 33 weeks, showing adequate growth and normal fetal Doppler studies.

• For fetal lung maturation, she was administered with injection betamethasone.

• 2D echocardiography was done and revealed no evidence of dilatation of aortic root and the ASI maintained as the gestation advanced.

• Blood pressure was within normal limits in all the trimesters.

Treatment

Discussion for the mode of delivery was initiated at 29 weeks where the possibility of vaginal delivery was explained if the presenting part of the first twin would be cephalic at the time of delivery. Given that both the fetuses continually presented breech, the decision was made to deliver by elective lower segment caesarean section at 37 weeks.

Outcome and follow-up

A baby boy weighing 2350 g and a baby girl weighing 2945 g were delivered by breech extraction. Both infants had an Apgar score of 8/10 and 9/10 at 1 and 5 min, respectively. Intraoperatively, atonic postpartum haemorrhage was managed with uterotonics and Hayman uterine compression sutures. Bilateral tubes appeared normal, while bilateral ovaries appeared atrophic. During the immediate postpartum period, the patient developed pre-eclampsia and was started with oral labetalol and oral nifidipine, which further deteriorated to grade IV hypertensive retinopathy with exudative retinal detachment on evaluation and was resolved in due course with remarkable blood pressure control. In view of suspected imminent eclampsia, magnesium sulfate was covered. Antihypertensives were eventually tapered and stopped by the third postnatal week. Fasting and postprandial blood sugar levels were within normal limits postoperatively. As both babies and mother were well without any further complications and with well-established breast feeds, they were discharged on postoperative day 5 and was advised to follow-up with MDT to rule out development of aortic dissection in the postpartum period but the patient was lost to follow-up.

Discussion

TS is a common chromosomal abnormality with clinical manifestations affecting multiple organ systems including cardiovascular, endocrine, hepatic, neurocognitive, renal, gastrointestinal, ophthalmologic, otorhinolaryngological and metabolic. Here, we are discussing a Turner management specific to fertility and pregnancy.

TS can be diagnosed prenatally by genetic screening and ultrasound during pregnancy. Most of the women have gonadal dysgenesis which predisposes them for primary amenorrhea, premature ovarian failure and subfertility later in life. Our patient presented with primary amenorrhea and on evaluation was diagnosed with a homogeneous X monosomy (45, X) with karyotyping. Spontaneous pubertal development and menarche are rare in TS. Only 14% have reported with spontaneous menarche in those with monosomy X and third with mosaicism.³ Oestrogen replacement with low-dose estradiol by systemic or transdermal route is recommended to start at 11–12 years of age and to increase to an adult dosing in 2–3 years. Progesterone is added once breakthrough bleeding occurs or after 2–3 years of oestrogen treatment.⁴

Spontaneous pregnancy occurs only in 2%–7% of women with TS, hence most women require ART using donor oocytes, autologous oocytes or in-vitro fertilisation (IVF) for conception.⁵ With FSH of 101 IU/mL, E2 <10 pg/mL and AMH <0.01 ng/dL, she was worked up for IVF using donor oocytes and proceeded with two embryo transfer at a fertility clinic. Although only a single embryo transfer is recommended as per the various guidelines,^{4 6–8} due to grade 2 quality embryos, she was transferred with two. The National Institute for Health and Care Excellence recommends 75–150 mg aspirin daily from 12 weeks of gestation until delivery for women at risk of pre-eclampsia.⁹ There is an increased predisposition for diabetes in women with TS due to the impaired phase 1 insulin secretion caused by the pancreatic beta cell dysfunction along with the increased levels of oestrogen and progesterone in pregnancy.¹⁰ This mandates for diligent screening for diabetes. Our patient was diagnosed with gestational diabetes and the same was managed with oral hypoglycaemic agents. The most morbid risk for the mother with TS is aortic dissection, aortic dilatation or aortic rupture leading to death.¹¹ It is therefore recommended to evaluate the patient with transthoracic echocardiography at the end of the first trimester, second trimester and every month in the third trimester and if there is an increase in aortic diameter >10%, to confirm with a cardiac MRI to avoid unanticipated risk of mortality associated with aortic root complications.⁷ The risk of hypertensive disorders is 35%–67% in singleton and a 100% in multiple gestation.^{4 11 12} The risk of aortic dissection during multiple gestation is estimated to be approximately five times higher than that associated with a singleton pregnancy.¹² It is therefore recommended to monitor the cardiovascular system with periodic 2D echocardiography and keep blood pressure levels under strict control. During the antenatal period, our patient required no intervention for her blood pressures and her ASI was within normal limit. Vaginal delivery can be allowed if not contraindicated though, operative intervention is high due to short stature, small pelvimetry, prematurity and aortic dysfunction.^{4 6–8} As women with TS have a significantly higher rate of C-section than those without TS, the risks of C-section delivery including haemorrhage, uterine atony, damage to the bladder or bowel, and complications from anaesthesia should be discussed thoroughly during prepregnancy counselling. In our case, caesarean section was indicated as both the twins persistently presented breech. Careful contraceptive counselling is essential to avoid unintended pregnancy given these serious complications for women with mosaic variant of TS.

Several professional organisations have laid down guidelines emphasising the care required to achieve a good quality of life and regarding pregnancy in women with TS. The guidelines set in the Cincinnati International Meeting are very similar to the others and is recommended to be taken into consideration irrespective of the karyotype pattern (monosomy X or mosaic) (table 1).

Table 1.

Recommended guidelines

Organisation	Preconception counselling	Contraindication to pregnancy	ART	Antenatal management	Mode of delivery	Postnatal follow-up
Cincinnati International Turner Syndrome Meeting (2016)4	Fertility treatment to be considered at a younger age Adoption or gestational carrier as an option for motherhood Intensive cardiac evaluation prior to conception TTE and CT/MRI within 2 years before planned pregnancy or ART	ASI>2.5 cm/m2 Ascending ASI 2–2.5 cm/m2 with associated risk factors such as Bicuspid aortic valve (BAV) Elongation of transverse aorta Coarctation of aorta (COA) Hypertension	Young mosaic TS women with persistent ovarian function should consider oocyte cryopreservation after controlled ovarian hyperstimulation Single embryo transfer	MDT including maternal–fetal medicine, cardiologists TTE at least once during pregnancy, preferably around 20 weeks If ascending ASI>2 cm/m2 with any risk factors, TTE at 4-week to 8-week intervals Blood pressure control <135/85 mm Hg In case of acute ascending aortic dissection Before viability: Perform aortic surgery first After the period of viability: Emergency CS followed by aortic surgery, under near normothermia, pulsatile perfusion, high pump flow and avoiding vasoconstrictors	ASI<2 cm/m2: Vaginal delivery is reasonable Ascending ASI of 2.0–2.5 cm/m2: Vaginal delivery with epidural anaesthesia and expedited second stage is preferred or a CS may be considered Ascending ASI of 2.5 cm/m2 or history of aortic dissection CS is mandated	If ascending ASI>2 cm/m2 with any risk factors, TTE to be done once within 6 months post partum
American Society for Reproductive Medicine6	Increased risk for maternal morbidity and mortality. Increased risk for premature maternal mortality in months and years after delivery because of pregnancy-related aortic dilation or not yet identified changes of the vessel wall. Encourage for gestational surrogacy or adoption.	Cardiac MRI revealing any abnormality and/or ASI>2 cm/m2 TS itself is considered as a relative contraindication	Single embryo transfer	Periodic 2D-Echo and consultation with cardiologist treatment of hypertension	ASI<2 cm/m2 Vaginal delivery may be attempted under epidural anaesthesia With baseline or progressive aortic root dilatation: Elective CS under epidural anaesthesia	Formal re-evaluation post partum
French Joint Practice Committee (2010)7	Multidisciplinary check-up involving: Cardiology Nephrology Hepatology Endocrinology	H/O aortic surgery or dissection Aortic dilatation >25 mm/m2 COA Uncontrolled hypertension Portal hypertension	Single embryo transfer	CVS monitoring: 2D-Echo at the end of the first trimester, second trimester and every month in the third trimester. If there is increase in aortic diameter >10% confirmation by: Cardiac MRI. In case of acute aortic dissection: <25 weeks: Aortic root surgery with extra corporeal circulation with foetus in utero with cardiotocography >25 weeks: Emergency CS followed by immediate aortic root surgery Treatment of hypertension with beta-blockers Evaluation for gestation diabetes by O’Sullivan test at 24 weeks Renal function tests every month in case of any renal malformations	ASI <2.5 mm/m2 Vaginal delivery or assisted vaginal delivery is allowed >2.5 mm/m2 CS with steroid coverage (for fetal lung maturation)	2D-Echo to be repeated between 5 and 8 days post delivery If pregnancy was without oocyte donation, check for chromosomal abnormalities If pregnancy was with oocyte donation, nothing specific
							Turner Syndrome Consensus Group— Bethesda Maryland (NIH 2006)8	Cardiovascular evaluation with: 2D-Echo Cardiac MRI ECG	Relative contraindications include: Surgically repaired CVS defect BAV Aortic dilatation H/O of COA Women with above conditions are counselled against attempted pregnancy.	1 to 2 years of HRT prior to conception to increase the size and improve the blood flow of the uterus Optimal thickness of endometrium 7 mm Single embryo transfer	All pregnancies to be followed up with MDT including cardiologists and endocrinologists. Thyroid status and glucose tolerance should be monitored.	Vaginal delivery allowed under ‘optimal condition’	Follow-up with cardiologist

ART, assisted reproductive technology; ASI, aortic size index; CS, caesarean section; CVS, Cardiovascular System; 2D-Echo, 2D echocardiography; HRT, hormone replacement therapy; MDT, multidisciplinary team; TTE, transthoracic echocardiography.

Based on this case with several recently published papers,^12–15 we can state that it is possible for a woman with TS to achieve a favourable maternal and fetal outcome with extensive prenatal screening, prepregnancy counselling and multidisciplinary teams, and regular follow-up.

Learning points.

• Most women require assisted reproductive technology using donor oocyte or in-vitro fertilisation for conception, where only a single embryo must be transferred.

• Alternative methods of motherhood like gestational carrier or adoption must be counselled.

• Pregnancy is contraindicated in Turner syndrome (TS) women with uncontrolled hypertension and structural cardiac disease (bicuspid aortic valve, coarctation of aorta, aortic dilatation).

• Pregnant women with TS pose an increased risk of developing maternal morbidities like severe pre-eclampsia, aortic dissection and fetal morbidities such as preterm birth, fetal growth restriction.

• Unless contraindicated vaginal delivery is possible, but operative intervention is high due to short stature, small pelvimetry, prematurity and aortic dysfunction.

• Periodic 2D echocardiography at the end of every trimester and consultation with cardiologist is mandated as there is an increase in haemodilution leading to increased cardiac output in pregnancy and postpartum period.

• A lifelong follow-up is necessary as the patient is at risk for developing aortic dissection.

Ethics statements

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