Case 1
A 23-year-old woman, professional occupation: a nurse at a city medical unit. First pregnancy, no unhealthy behavioural habits recorded. BMI = 15,8 kg/m2. Foci of infection: chronic maxillary sinusitis. No family history of CVD.
Her mother's pregnancy was without complications, and she was born at term weighing 2.600 g. Female medical history: menarche at the age of 12 years.
Flammer syndrome phenotype demonstrates following strongly pronounced symptoms and signs:
- The patient was always very slim with difficulty to gain the weight, she obviously tends to perfectionism
- Frequently cold extremities, she is freezing even during warm seasons
- Pre-pregnancy hypotension, further strongly pronounced early in pregnancy, symptoms of orthostatic hypotension, further strongly pronounced during pregnancy
- Frequent dizziness and pre-syncopal conditions (lipotemia)
- Difficulties to fall asleep, night sleep duration 6-8 h with shifted sleep patterns towards morning hours accompanied with chronic fatigue upon awakening in the morning.
- She does not feel thirsty, but by mind controls liquid intake against nausea
- Frequent headache, sometimes with aura.
Manifestations of CTD: extended external stigmatisation including thumb and wrist symptoms, amongst others, mitral valve prolapse of moderate hemodynamic significance, a single supraventricular extra-systole according to a single ECG.
Angiological screening resulted in
- peripheral systolic to diastolic blood pressure 106/66 mm Hg and central systolic to diastolic blood pressure 91/68 mm Hg,
- RWVa 9,3 m/s, AIXb -31,1%, AIXaO 3,1%.
Pregnancy course: The pregnancy was complicated by the development of placental insufficiency, the foetal growth restriction of middle severity (grade 2).
Urgent delivery (37 weeks), new-born weight of 2.480 g, height of 48 cm with corresponding BMI = 10,4 kg/m2 (hypotrophy).
Maternal weight gain during pregnancy was 11 kg considered as insufficient.
Case 2
A 25-year-old woman, professional occupation: a designer at the private enterprise, academician with University education diploma
First pregnancy, no unhealthy behavioural habits, BMI = 19,9 kg/m2, foci of infection: none.
No family history of CVD. Her mother's pregnancy was without complications, and she was born at term weighing 3.100 g. Female medical history: menarche at the age of 13 years.
Flammer syndrome phenotype demonstrates following strongly pronounced symptoms and signs:
- Since adolescence there was a tendency to low blood pressure and frequent dizziness, in particular when suddenly standing up.
- Perfectionist frequently suffering from severe psycho-emotional stress
- When agitated she often registers red and white spots on her face and neck
- Slowed and impaired wound healing
- Although she preferred warm clothes before pregnancy, the feeling of freezing got extreme during the pregnancy. Especially in the legs, she also noted a feeling of "creeping" and tingling of the fingertips.
- Frequent headache during the pregnancy.
Manifestations of CTD: significantly elevated external stigmatisation, especially on the craniofacial segment, thumb and wrist symptoms and scoliosis. Abdominal ultrasound revealed an overstretch of the gallbladder.
Angiological screening resulted in
- peripheral systolic to diastolic blood pressure 108/70 mm Hg and central systolic to diastolic blood pressure 99/72 mm Hg,
- RWVa 9,1 m/s, AIXb -25,9%, AIXaO 3,0%.
Pregnancy course: Evident oligohydramnious diagnosed with ultrasound. The pregnancy was complicated by the development of placental insufficiency, chronic fetoplacental insufficiency, disordered uterine-foetal-placental blood flow, the foetal growth restriction grade 1 (minor).
Urgent delivery (38 weeks), the new-born weight of 2.980 g and 51 cm of height with corresponding BMI = 11,46 kg/m2 (hypotrophy).
Maternal weight gain during pregnancy was 10 kg considered as insufficient.
Case 3
A 26-year-old woman, professional occupation: a college teacher, academician with University education diploma
BMI=31,6 kg/m2, foci of infection: none.
Family history: aggravated by arterial hypertension (mother). Believes she was overfed since childhood due to low birth weight.
Her mother's pregnancy was without complications, and she was born at term weighing 2.700g.
Female medical history: menarche at age 15.
Manifestations of CTD: None
No manifestations of the Flammer syndrome phenotype.
Angiological screening resulted in
- peripheral systolic to diastolic blood pressure 122/78 mm Hg and central systolic to diastolic blood pressure 114/80 mm Hg,
- RWVa 10,4 m/s, AIXb -42,2%, AIXaO 4,6%.
The course of pregnancy: no abnormalities
Urgent delivery (38.5 weeks), new-born weight of 3.780g, height of 43cm with corresponding BMI 13,2 kg/m2 (hypertrophy).
Maternal weight gain during pregnancy was 13 kg considered as excessive.
Data interpretation
Presented results fully support working hypothesis of the study
Presented results fully confirm the working hypothesis indicating that depending on the pre-pregnancy BMI of study participants in groups of comparison, there are clear phenotype-specific differences
- in their haemodynamic and vascular status,
- incidence and severity level of CTD,
- spectrum of maternal and foetal complications and
- anthropometric parameters of new-borns
as detailed below.
Maternal haemodynamics
Haemodynamic status of pregnant women with both – low and high BMI differed significantly from this of women in the group with standard BMI range. Moreover, the difference was characterised as being highly specific for each group of comparison. In particular, for group 1 (low BMI), the most significant increase in vascular stiffness was monitored specifically for small peripheral vessels, while aortic stiffness was affected to much lesser extent. Noteworthy, both systolic (PSBP, CSBP values) and diastolic (PDBP, CDBP values) blood pressure in group 1 were decreased compared to group 2 (standard BMI range). In contrast, group 3 (overweight) demonstrated significantly increased aortic stiffness (RWVa and AIXa values) as well as central systolic blood pressure compared to group 2.
Maternal connective tissue dysfunction
CTD was demonstrated as being characteristic for group 1 (low BMI) with their most specific manifestations (thumb and wrist symptoms, chest deformities, valgus deformity of the foot, flat foot, scoliosis, kyphosis, myopia and specific facial signs, mitral valve prolapse and indication of spontaneous pneumothorax, amongst others) scored significantly higher for this group compared to group 2 (standard BMI range). These findings are consistent with observations published earlier demonstrating an increased incidence of CTD with signs of nonspecific variants characteristic for individuals with low BMI [10,12,20].
Connective tissue dysfunction may be associated with the specific morphology of the vessel walls linked to an increased stiffness of small vessels – both characteristic for low BMI individuals clearly demonstrated for extreme cases such as the Marfan, Loeys-Dietz, and Ehlers-Danlos Syndromes, and Nonspecific Connective Tissue Disorders [14,21]. This functional link becomes particularly evident under the extreme vascular stress condition such as pregnancy.
Flammer syndrome individuals – the group of risk with well described phenotype
Noteworthy, data collected in the current study demonstrated CTD as being particularly characteristic for participants with the Flammer syndrome phenotype. Therefore, current study brings together systemic effects characteristic for individuals with FS phenotype – all potentially linked to connective tissue dysfunction and primary vascular dysregulation with increased risks of myopia, normal tension glaucoma, small vessel disease, young ischemic stroke, mitral valve prolapse, impaired wound healing and pathological scarring, metastatic cancer and complications in pregnancy, amongst others [2,3,10,12,22–26]. Contextually, an increased endothelin-1 concentration in blood plasma is characteristic for the Flammer syndrome phenotype that can cause vascular stiffness, particularly in peripheral small vessels and in a long-term way may lead to endothelial dysfunction, low-grade inflammation and related pathologies [4].
Risks characteristic for maternal pre-pregnancy overweight
Of completely different nature is the mechanism of vascular stiffness and endothelial dysfunction in obese individuals reflected in big vessels (aortic) stiffness linked to increased systolic and diastolic blood pressure as clearly demonstrated in our study under the vascular stress condition during pregnancy. This group was generally free of CTD symptoms and signs. These results are well in consensus with data published by other research groups [27,28].
It has been demonstrated adipokines play a major role in increasing arterial stiffness in obesity: adipokine dysregulation may cause endothelial dysfunction, vascular wall inflammation and remodelling, which altogether synergistically contribute to increased arterial stiffness [29–31].
Type and incidence of pregnancy complications are specific for individual phenotypes: far-reaching consequences
Collected data demonstrated group-specific complications in mother and offspring and high relevance of BMI in pre-pregnant mothers recorded. In the literature dedicated to the topic, a particular interest is currently dedicated to pre-eclampsia and gestational arterial hypertension (PE & GAH) [32–34].
Consequently, in patients with pre-eclampsia an increased vascular stiffness was demonstrated from the beginning of the second trimester of pregnancy followed by an increase in the aortic augmentation index and reverse pulse wave velocity reflecting a pronounced arterial stiffness. Accompanied with possible left ventricular dysfunction, this indicates that placental dysfunction may occur secondary to maternal cardiovascular maladaptation characteristic for pregnant women diagnosed with pre-eclampsia [35,36].
To this end, prospective studies [37,38] investigating women diagnosed with pre-eclampsia 6 and 12 months post-partum demonstrated significant differences in their vascular stiffness, blood pressure and molecular blood profiles compared to women without PE. Consequently, PE has been suggested as a new factor to be involved in maternal health risk assessment [37,39–41].
Whereas PE & GAH were characteristic for group 3 (overweight), foetal growth restriction and antenatal mortality was typical for group 1 (low BMI). To this end, specifically FGR attracts a lot of attention of clinical research, due to steadily increasing incidence of this complication and still poorly understood mechanisms and evident deficits in targeted prevention [42–44].
Finally, we found significant deviations in maternal and foetal weight gain in both groups 1 (statistically significant insufficient maternal weight gain linked to frequently monitored foetal hypotrophy) and group 3 (statistically significant excessive maternal weight gain linked to frequently monitored foetal hypertrophy) compared to group 2 (standard BMI range). To this end, it has been demonstrated that infants with both – excessive and reduced BMI are at increased risk of cardiovascular deficits recorded later on in adulthood, moreover, at particular risk are infants with reduced BMI [45,46].
Contextually, investigated here maternal health status reflected in all parameters measured, is decisive for both – potential maternal / foetal complications in pregnancy and long-term postnatal outcomes. This conclusion is well in consensus with other studies [33,34,36,47] considering maternal vascular status in pregnancy as a powerful indicator and predictor of maternal and foetal health later on in life. Further, newborn weight was positively correlated with the parasympathetic PNS index as well as with nitric oxide levels, heart rate variability, and negatively correlated with vascular stiffness.